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WO2008121107A1 - Formes posologiques orales de minocycline pour le traitement de l'acné - Google Patents

Formes posologiques orales de minocycline pour le traitement de l'acné Download PDF

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Publication number
WO2008121107A1
WO2008121107A1 PCT/US2007/008086 US2007008086W WO2008121107A1 WO 2008121107 A1 WO2008121107 A1 WO 2008121107A1 US 2007008086 W US2007008086 W US 2007008086W WO 2008121107 A1 WO2008121107 A1 WO 2008121107A1
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WO
WIPO (PCT)
Prior art keywords
disorders
dosage form
minocycline
oral dosage
release
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PCT/US2007/008086
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English (en)
Inventor
Mitchell Wortzman
R. Todd Plott
Kuljit Bhatia
Bhiku Patel
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Medicis Pharmaceutical Corporation
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Application filed by Medicis Pharmaceutical Corporation filed Critical Medicis Pharmaceutical Corporation
Priority to PCT/US2007/008086 priority Critical patent/WO2008121107A1/fr
Publication of WO2008121107A1 publication Critical patent/WO2008121107A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates to oral tetracycline-class antibiotic dosage forms, and in some embodiments, to control led-release oral dosage forms of minocycline and methods of using them to treat acne.
  • Oral tetracycline-class antibiotics are frequently used in the treatment of acne. Tetracycline-class antibiotics are known to have some side effects. These side effects include vestibular symptoms such as vertigo, dizziness or blurred vision. These effects are sometimes disabling. See, Gould & Brookler, Arch. Otolarang. Vol. 96, p. 291 (1972); Williams et al., Lancet, Sep. 28, 1974, p. 144-45; Fanning & Gump, Arch. Intern. Med., Vol. 136, pp. 761-62 (1976). Headache and general malaise, along with gastrointestinal symptoms such as the diarrhea, nausea, gas, or cramps may also occur. Dry nose and dry mouth are also occasionally encountered.
  • minocycline hydrochloride One of the oral tetracycline-class antibiotics used in the treatment of acne is minocycline hydrochloride.
  • Oral dosage forms of minocycline hydrochloride are available commercially under various trade names.
  • the Approved Drug Products with Therapeutic Equivalence Evaluations (“Orange Book") lists a number of oral dosage forms of minocycline hydrochloride that are AB-rated to the MINOCIN® brand of minocycline hydrochloride.
  • U.S. Patent No. 5,908,838, which is hereby incorporated by reference, discloses slowly dissolving dosage forms of oral tetracycline- class antibiotics, including minocycline hydrochloride, that reduce the incidence or severity of vestibular side effects resulting from the treatment of acne.
  • An embodiment provides controlled-release minocycline oral dosage forms that are pharmacokinetically distinct from the MINOCIN® brand of immediate-release minocycline hydrochloride.
  • embodiments Upon administration, e.g., at minocycline free base equivalent dosages in the range of about 0.75 mg/kg to about 1.5 mg/kg, embodiments provide substantially similar or better acne treatment efficacy and/or reduced incidence of at least one adverse effect, as compared to administration of the MINOCIN® immediate-release dosage form.
  • administration on a once-daily basis is effective.
  • administration without food is effective.
  • An embodiment provides an oral dosage form, comprising: minocycline or a pharmaceutically acceptable salt thereof; and an amount of a controlled- release carrier composition that is effective to render said oral dosage form pharmacokinetically distinct from MINOCIN® immediate-release minocycline hydrochloride.
  • Another embodiment provides a method of treating acne, comprising administering such an oral dosage form to a subject in need thereof.
  • Another embodiment provides a method of distributing minocycline, comprising: distributing such an oral dosage form; and concomitantly distributing information that the oral dosage form may cause an adverse effect.
  • Another embodiment provides a method of making such an oral dosage form, comprising intermixing the minocycline or pharmaceutically acceptable salt thereof and the controlled-release carrier composition to form an admixture.
  • Another embodiment provides a method of administering an oral dosage form comprising: (i) administering to a patient an oral dosage form, which oral dosage form comprises: an oral tetracycline-class antibiotic; a fast dissolving carrier; and a slow dissolving carrier; and (ii) providing information to the patient, wherein the information comprises that the administering of the oral dosage form may cause one or more adverse effects selected from pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • Another embodiment provides a method of distributing an oral dosage form, comprising: distributing an oral dosage form comprising an oral tetracycline-class antibiotic, a fast dissolving carrier and a slow dissolving carrier; and concomitantly distributing information that the oral dosage form may cause one or more adverse effects selected from pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • Another embodiment provides a method of administering an oral dosage form comprising: (i) administering to a patient an oral dosage form, which oral dosage form comprises: an oral tetracycline-class antibiotic; a fast dissolving carrier; and a slow dissolving carrier; wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of 0.3 to 0.5 of fast dissolving carrier to slow dissolving carrier; and (ii) providing information to the patient, which information comprises that the administering of the oral dosage form may cause one or more adverse effects.
  • Another embodiment provides a method of distributing an oral dosage form, comprising: distributing an oral dosage form comprising an oral tetracycline-class antibiotic, a fast dissolving carrier and a slow dissolving carrier, wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of 0.3 to 0.5 of fast dissolving carrier to slow dissolving carrier; and concomitantly distributing information that the oral dosage form may cause one or more adverse effects.
  • Another embodiment provides a minocycline oral dosage form, comprising minocycline or a pharmaceutically acceptable salt thereof and an amount of a controlled-release carrier composition that is effective to provide an in vitro release rate of the minocycline or pharmaceutically acceptable salt thereof of about 90% in about 4 hours to about 6 hours.
  • Another embodiment provides a method of treating acne, comprising administering such a minocycline oral dosage form to a subject in need thereof.
  • Another method provides a method of distributing minocycline, comprising: distributing such a minocycline oral dosage form; and concomitantly distributing information that the minocycline may cause an adverse effect.
  • Another embodiment provides a method of making such a minocycline oral dosage form, comprising intermixing the minocycline salt and the controlled-release carrier composition to form an admixture.
  • kits comprising any of the minocycline oral dosage forms described herein; and information that the oral dosage form may cause one or more adverse effects.
  • kits comprising (i) an oral dosage form comprising: an oral tetracycline-class antibiotic; a fast dissolving carrier; and a slow dissolving carrier; wherein the fast dissolving carrier and slow dissolving carrier are at a weight ratio of 0.3 to 0.5 of fast dissolving carrier to slow dissolving carrier; and (ii) information that the oral dosage form may cause one or more adverse effects.
  • Figure 1 is a plot showing minocycline plasma concentrations as a function of time across different dosages and formulations.
  • Figure 2 is a plot showing the logarithm of minocycline plasma concentrations as a function of time across different dosages and formulations.
  • Figure 3 is a plot showing minocycline plasma concentrations as a function of time for patients under fed and fasted conditions.
  • Figure 4 is a plot showing the logarithm of minocycline plasma concentrations as a function of time for patients under fed and fasted conditions.
  • Figure 5 is a plot showing minocycline plasma concentrations as a function of time across fed and fasted conditions and formulations.
  • Figure 6 shows minocycline plasma concentrations as a function of time across fed and fasted conditions and formulations.
  • Figure 7 shows the logarithm of minocycline plasma concentrations as a function of time across fed and fasted conditions and formulations.
  • Figure 8 shows the logarithm of minocycline plasma concentrations as a function of time across fed and fasted conditions and formulations.
  • Figure 9 shows minocycline plasma concentrations as a function of time across formulations.
  • Figure 10 shows minocycline plasma concentrations as a function of time across formulations.
  • Figure 11 shows minocycline plasma concentrations as a function of time across formulations.
  • Figure 12 shows minocycline plasma concentrations as a function of time across formulations.
  • Figure 13 shows percentage decrease from baseline in inflammatory lesion counts in several extended-release minocycline hydrochloride dose groups and a placebo group.
  • Figure 14 shows mean inflammatory lesion counts by study day.
  • Various embodiments provide oral dosage forms in which the active ingredient is a tetracycline-class antibiotic such as minocycline.
  • active ingredient refers to a component or mixture of components of a formulation that has a significant medicinal effect on the patient to which it is administered.
  • the significant medicinal effect is a reduction in one or more symptoms associated with acne, e.g., acne vulgaris.
  • bioequivalent as used herein has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non-limiting example, a drug or dosage form that, upon administration to a suitable patient population, provides principle pharmacokinetic parameters (AUC and C max ) that are in the range of 80% to 125% of those provided by a reference standard.
  • AUC and C max principle pharmacokinetic parameters
  • pharmacokinetically distinct refers to a drug or dosage form that, upon administration to a patient population, provides a pharmacokinetic profile that is outside the range of 80% to 125% of the reference standard.
  • pharmacokinetics of a drug can vary from patient to patient, such clinical trials generally involve multiple patients and appropriate statistical analyses of the resulting data (typically ANOVA at 90% confidence).
  • Pharmacokinetic distinctness is determined on a dose-adjusted basis, as understood by those skilled in the art.
  • the reference standard is an immediate-release minocycline dosage form.
  • the immediate-release minocycline dosage form appropriate for use as the reference standard in the determination of pharmacokinetic distinctness is the legend immediate-release minocycline dosage form, widely available commercially as the MINOCIN® brand of minocycline hydrochloride.
  • the U.S. government regulates the manner in which prescription drugs can be labeled and thus reference herein to MINOCIN® immediate- release minocycline hydrochloride has a well-known, fixed and definite meaning to those skilled in the art.
  • pharmacokinetic profile has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non- limiting example, a characteristic of the curve that results from plotting blood serum concentration of a drug over time, following administration of the drug to a subject.
  • a pharmacokinetic profile thus includes a pharmacokinetic parameter or set of parameters that can be used to characterize the pharmacokinetics of a particular drug or dosage form when administered to a suitable patient population.
  • Various pharmacokinetic parameters are known to those skilled in the art, including area under the blood plasma concentration vs. time curve (AUC), maximum blood plasma concentration after administration (C ma ⁇ ), time to maximum blood plasma concentration (T max ), blood plasma concentration decay half-life (Un), etc.
  • Pharmacokinetic parameters may be measured in various ways known to those skilled in the art, e.g., single dosage or steady-state, as described in the examples below.
  • the AUC parameter may be extrapolated to infinite time, e.g., AUCi n f indicates the estimated area under the blood plasma concentration vs. time curve for all time following administration. Examples of pharmacokinetic profiles suitable for determining pharmacokinetic distinctness include those that comprise one or more of an AUC parameter, a C max parameter and a T max parameter.
  • pharmacokinetic parameters include in vivo plasma minocycline concentration profiles such as single-dosage C max , steady-state C max , single- dosage AUC(o-72), steady state AUC(o-72), single-dosage T max , and steady state T max , as well as pharmacokinetic parameters reported in the examples provided herein. Differences between pharmacokinetic profiles are determined using statistical methods that are known and accepted by those skilled in the art, e.g., as illustrated in the examples provided herein.
  • dosage form has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non-limiting example, a formulation of a drug or drugs in a form administrable to human.
  • the illustrative embodiments of the invention have been described primarily as being directed to oral dosage forms such as tablets, cores, capsules, caplets and loose powder, but other suitable oral dosage forms such as solutions and suspensions are also contemplated.
  • release rate has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non-limiting example, a characteristic related to the amount of an active ingredient released per unit time as defined by in vitro or in vivo testing.
  • An in vitro release rate is determined by a "standard dissolution test.," conducted according to United States Pharmacopeia 24th edition (2000) (USP 24), pp. 1941-1943, using Apparatus 2 described therein at a spindle rotation speed of 100 rpm and a dissolution medium of water, at 37°C, or other test conditions substantially equivalent thereto.
  • a release rate can define a formulation.
  • reference herein to a formulation or dosage form as a "4-hour" formulation or dosage form indicates that the point at which about 90% of the active ingredient has been released occurs within a range of about 4 hours to about 6 hours after commencement of the release test.
  • Reference herein to a controlled-release or extended release formulation or dosage form includes such 4-hour formulations.
  • immediate release has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non-limiting example, release of a drug from a dosage form in a relatively brief period of time after administration.
  • immediate-release dosage forms are those that have a release rate that is up to and including 125% of the release rate for MINOCIN® immediate-release minocycline hydrochloride.
  • modified release has its o ⁇ dinary meaning as understood by those skilled in the art and thus includes, by way of non-limiting example, release characteristics of time, course and/or location of the drug from the dosage form in a manner that is chosen to provide therapeutic or convenience features that are significantly different from those provided by the immediate-release form.
  • controlled release has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non-limiting example, release of a drug from a dosage form in a pre-determined manner or according to a pre-determined condition.
  • delayed release has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non-limiting example, release of drug at a time later than immediately after administration.
  • extended release or “sustained release”, as used herein, has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non-limiting example, the controlled release of a drug from a dosage form over an extended period of time.
  • controlled release carrier has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non-limiting example, an ingredient or ingredients that are included in a pharmaceutical formulation in amounts that are effective to extend the release rate of the active ingredient from the formulation as compared to an immediate-release formulation.
  • controlled release carriers include hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpryrollidone.
  • a controlled release carrier composition may contain one or more controlled release carriers, along with other suitable ingredients.
  • Minocycline may be in the form of a free base, an acid salt (e.g., hydrochloride salt) or a mixture thereof.
  • acid salt e.g., hydrochloride salt
  • Reference herein to "minocycline” will be understood as encompassing all such forms, unless the context clearly indicates otherwise.
  • Dosages of minocycline salts will be understood to be on the basis of the amount of minocycline free base provided thereby, and thus may be expressed as a minocycline free base equivalent dosage or amount.
  • Minocycline salts are pharmaceutically acceptable in some embodiments.
  • pharmaceutically acceptable refers to a drug, salt, carrier, etc., that can be introduced safely into an animal body (e.g., taken orally and digested, etc.).
  • embodiments of the present invention relate to tetracycline- class antibiotic oral dosage forms and methods of administering them, e.g., for the treatment of acne.
  • the tetracycline-class antibiotic is minocycline or a pharmaceutically acceptable salt thereof and/or the oral dosage form comprises a controUed-release carrier composition.
  • the compositions and oral dosage forms that contain a controUed-release carrier may be referred to herein in a general way as modified-release, controlled-release or extended-release compositions, e.g., to distinguish them from the immediate-release forms also described herein, to which they may be compared.
  • An embodiment provides an oral dosage form, comprising: minocycline or a pharmaceutically acceptable salt thereof; and an amount of a controlled- release carrier composition that is effective to render the oral dosage form pharmacokinetically distinct from MINOCIN® immediate-release minocycline hydrochloride.
  • a controlled-release carrier composition that is effective to render the oral dosage form pharmacokinetically distinct from MINOCIN® immediate-release minocycline hydrochloride.
  • Illustrative controlled-release carrier compositions and methods of selecting such effective amounts and incorporating them into extended-release minocycline oral dosage forms are described in greater detail below.
  • the oral dosage form is pharmacokinetically distinct in such a way that the oral dosage form is not considered to be bioequivalent to MINOCIN® immediate-release minocycline hydrochloride.
  • controlled-release minocycline oral dosage forms provide dosages in a minocycline free base equivalent amount selected from about 45 mg, about 60 mg, about 90 mg and about 135 mg. The selection of a particular dosage may be based on the weight of the patient.
  • Unit dosage forms suitable for administration to a human may be configured to provide a minocycline free base equivalent dosage in the range of about 0.75 mg/kg to about 1.5 mg/kg, e.g., about 1 mg/kg (basis is mg of drug per kilogram of body weight).
  • the controlled-release oral dosage forms described herein may be administered on a once-daily basis, with or without a loading dose.
  • once-daily administration of the controlled- release oral dosage form provides substantially similar or better acne treatment efficacy and/or reduced incidence of at least one adverse effect, as compared to a twice-daily administration of MINOCIN® immediate-release minocycline hydrochloride.
  • the dosing schedule used most frequently for treating acne using currently available immediate- release oral dosage forms is reported to be 100 mg of minocycline (free base equivalent) administered twice daily, see Leyden, J. Cutis 2006; 78 (suppl 4):4-5, and Fleischer, A. et al. Cutis 2006; 78 (suppl 4):21-31.
  • efficacy is substantially similar or better.
  • the compositions described herein contain an amount of a control led-release carrier composition that is effective to render the oral dosage form pharmacokinetically distinct from a comparable composition, such as MINOCIN® immediate-release minocycline hydrochloride.
  • a comparable composition such as MINOCIN® immediate-release minocycline hydrochloride.
  • the amount and type of controlled-release carrier composition may be selected to slow the release of the drug from the oral dosage form after ingestion, thus modifying the pharmacokinetic profile of the composition.
  • a description of representative controlled release carrier materials can be found in the Remington: The Science and Practice of Pharmacy (20 th ed, Lippincott Williams & Wilkens Publishers (2003)), which is incorporated herein by reference in its entirety. Those skilled in the art can formulate controlled-release carrier compositions by routine experimentation informed by the detailed guidance provided herein. Examples 1-12 below describe illustrative minocycline extended-release oral dosage forms.
  • the controlled-release carrier composition comprises one or more slow dissolving carriers and one or more fast dissolving carriers.
  • an embodiment provides an oral dosage form comprising an oral tetracycline-class antibiotic, a fast dissolving carrier and a slow dissolving carrier.
  • the weight ratio of fast dissolving carrier(s) to slow dissolving carrier(s) in the controlled- release carrier composition may be in various ranges, e.g., the range of about 0.3 to about 0.5, the range of about 0.3 to about 0.45, or the range of about 0.36 to about 0.40. Examples of controlled-release carrier compositions are described in U.S. Patent Publication No.
  • the fast dissolving carrier is any binder, vehicle, or excipient that quickly dissolves in an aqueous physiological medium, such as gastric fluid, thereby tending to quickly release the active ingredient. Lactose, its salts and hydrates are good examples of such components. It has been observed that sometimes a portion of the fast dissolving components are formulated in a manner that results in the complete or partial encapsulation or inclusion or coating of these fast-dissolving materials in granules of slow-dissolving materials. These encapsulated materials are excluded from the calculation of the above mentioned ratio of fast-dissolving to slow dissolving components.
  • a slow dissolving carrier is any binder, vehicle, or excipient that dissolves slowly over the course of hours and perhaps a day, thereby slowing the release of the active ingredient.
  • examples of such components are polyvinyl pyrrolidone (e.g., KOLLEDON SR POLYOX), polyvinyl acetate, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL LF, KLUCEL HXF), hydroxypropylmethyl cellulose (e.g., METHOCEL E50 PREMIUM LV, METHOCEL KlOO LV), or waxy or Iipid-based tableting agents such as magnesium stearate or calcium stearate. Outer "enteric" coatings are excluded from this amount when calculating the above-mentioned ratio.
  • a 45 mg (minocycline free base equivalent) unit oral dosage form comprises minocycline hydrochloride and an amount of the controlled- release carrier in the range of about 20% to about 30%, by weight based on the total weight of the unit dosage form.
  • a 45 mg minocycline oral dosage form may comprise about 26 wt. % to about 28 wt. %, e.g., about 27 %, of HYPROMELLOSE USP, Type 2910 (METHOCEL E50 PREMIUM LV).
  • a 90 mg (minocycline free base equivalent) unit oral dosage form comprises minocycline hydrochloride and an amount of the controlled- release carrier in the range of about 20% to about 30%, by weight based on the total weight of the unit dosage form.
  • a 90 mg minocycline oral dosage form may comprise about 26 wt. % to about 28 wt. %, e.g., about 27 %, of HYPROMELLOSE USP, Type 2910 (METHOCEL E50 PREMIUM LV).
  • a 135 mg (minocycline free base equivalent) unit oral dosage form comprises minocycline hydrochloride and an amount of the control led- release> carrier in the range of about 20% to about 30%, by weight based on the total weight of the unit dosage form.
  • a 135 mg minocycline oral dosage form may comprise about 22 wt. % to less than 25 wt. %, e.g., about 23.5 %, of HYPROMELLOSE USP, Type 2910 (METHOCEL E50 PREMIUM LV).
  • the oral dosage forms described herein may be formulated to comprise various excipients, binders, carriers, disintegrants, coatings, etc.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with a pharmaceutical composition as described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain pharmaceutical compositions suitable for use in various forms, e.g., as pills, tablets, powders, granules, dragees, capsules, liquids, sprays, gels, syrups, slurries, suspensions and the like, in bulk or unit dosage forms, for oral ingestion by a patient to be treated.
  • unit dosage forms are described herein; non-limiting examples include a pill, a tablet, a capsule, a gel cap, and the like.
  • suitable excipients are listed below, some of which are mentioned above as having particular dissolution properties (e.g., fast dissolving or slow dissolving).
  • Pharmaceutically acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington: The Science and Practice of Pharmacy (2003), which is hereby incorporated by reference in its entirety.
  • carrier material or “excipient” herein can mean any substance, not itself a therapeutic agent, used as a carrier, diluent, adjuvant, binder, and/or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration.
  • Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
  • Acceptable excipients include lactose, sucrose, starch powder, maize starch or derivatives thereof, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone, and/or polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.
  • suitable excipients for soft gelatin capsules include vegetable oils, waxes, fats, semisolid and liquid polyols.
  • suitable excipients for the preparation of solutions and syrups include, without limitation, water, polyols, sucrose, invert sugar and glucose.
  • the pharmaceutical compositions can additionally include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, buffers, coating agents, or antioxidants.
  • Dissolution or suspension of the active ingredient in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired.
  • oral dosage forms include one or more a sugars (lactose, lactose monohydrate, sucrose, mannitol, or sorbitol); cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); disintegrating agents such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate; colloidal silicon dioxide, magnesium stearate, titanium dioxide, polyethylene glycol, triacetin, carnauba wax, microcrystalline cellulose, provid
  • Coating materials include those available commercially under the tradename OPADRY, e.g., at a level in the range of about 3.5 wt. % to about 3.9 wt. % based on total weight of the oral dosage form.
  • OPADRY e.g., at a level in the range of about 3.5 wt. % to about 3.9 wt. % based on total weight of the oral dosage form.
  • Those skilled in the art can formulate controlled-release oral dosage forms containing one or more of the foregoing ingredients by routine experimentation informed by the detailed guidance provided herein.
  • the pharmacokinetic properties of a drug can affect both the effectiveness and the side effects of treatment.
  • administration of a tetracycline-class antibiotic composition to a suitable patient population as described herein results in one or more of a reduced maximum observed plasma minocycline concentration (C max ), a reduced area under a blood plasma minocycline concentration versus time curve (AUC), and/or an increased time (T ma ⁇ ) of occurrence of the maximum observed plasma minocycline concentration as compared to a comparable composition.
  • the comparable composition is MINOCIN® immediate-release minocycline hydrochloride.
  • Pharmacokinetic properties can be determined by analyzing the plasma of a patient population that has received controlled-release tetracycline-class antibiotic compositions, and comparing them to a comparable patient population that has received the comparable composition, using the appropriate clinical trial methodology and statistical analyses.
  • the pharmacokinetic properties are single- dosage, while in others, they are steady-state.
  • the oral dosage form provides, after administration, at least one in vivo plasma minocycline concentration profile selected from: (a) a single-dosage C max that is about 80% or less of the single-dosage C max of the MINOCIN® immediate-release minocycline hydrochloride; (b) a steady-state C max that is about 80% or less of the steady-state C max of the MINOCIN® immediate-release minocycline hydrochloride; (c) a single-dosage AUC( O-72 ) that is about 80% or less of the single-dosage AUC(o-72) of the MINOCIN® immediate- release minocycline hydrochloride; (d) a steady state AUC(o-72) that is about 80% or less of the steady state AUC(o-72) of the MINOCIN® immediate-release minocycline hydrochloride; (d) a
  • patients may be provided with a single dosage of a composition comprising the controlled-release minocycline, and plasma specimens may be collected from the patient at different time periods relative to the administration of the composition to determine pharmacokinetic profiles.
  • patients may be provided with a dosing regimen across approximately 5 days comprising administering compositions comprising low-dosage controlled-release minocycline.
  • Plasma specimens may then be collected from the patient at different time periods relative to a particular dosage during steady state.
  • the steady state can be determined by monitoring a plasma minocycline concentration profile at specific times of anticipated peak and trough blood levels relative to the administration of a dosage across hours and days and determining when the profile has reached steady state.
  • the in vivo plasma minocycline concentration may be measured one hour after dosing across days, until the concentration no longer significantly varies from day to day.
  • the steady state may be estimated as a specific number of days after the dosing regimen began.
  • steady state may be estimated as six days after the dosing regimen began.
  • steady state is estimated after dosing over about five times the half-life of the drug.
  • Plasma may be analyzed using any appropriate method.
  • blood is collected from a patient. Any suitable amount of blood may be collected. Blood samples may then be centrifuged until separation of red cells from plasma occurs.
  • minocycline analysis is performed using plasma specimens by the bioanalytical division of SFBC Anapharm using the analytical method of SOP ANI 8842.01 entitled "Determination of Minocycline in Human Lithium Heparinized Plasma Over a Concentration Range of 20 to 5000 ng/mL using a High Performance Liquid Chormatographic Method with Tandem Mass Spectrometry Detection and Using MultiPROBE II Automated Extraction," which is hereby incorporated by reference in its entirety.
  • minocycline analysis is performed according to the analytical method validation entitled "Validation of a High Performance Liquid Chormatographic Method Using Tandem Mass Spectrometry Lithium Heparinized Plasma," hereby incorporated by reference in its entirety.
  • samples are analyzed for the content of minocycline by HPLCAJV assay, as described in greater detail below.
  • One pharmacokinetic parameter, C max is the maximum observed plasma concentration.
  • Another pharmacokinetic parameter, AUC is the area under the plasma concentration versus time curve from the time of a specific dosage (which is the first and only dosage during single-dosage analysis and a specific later dosage during steady-state analysis, as described above) to the end of a specific interval.
  • the parameter may be the area under the plasma concentration versus time curve from the time a specific dosage to 24 hours following that dosage (AUC( O-24 )) or to 72 hours following that dosage (AUC(o- 72 >).
  • the AUC from the time of administration until an infinite time later (AUCj nf ) may be extrapolated from the data by any appropriate method.
  • Yet another pharmacokinetic parameter, T max is the time of occurrence of C max relative to the time of the specific dosage (which again is the first and only dosage during single- dosage analysis and the specific later dosage during steady-state analysis).
  • in vivo minocycline concentrations may be measured at various time intervals with respect to a minocycline dosage. In some embodiments, these concentrations are measured at least 10 times within a 24 hour period. In some embodiments, the concentrations are measured pre-dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, 12.5, 13.0, 13.5, 14.0, 15.0, 16.0, 17.0, 18.0 and 20.0 hours post-dose. In some embodiments, the concentrations are measured pre-dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 24.0, 36.0, 48.0, and 72.0 hours post-dose.
  • a patient population undergoes a dosing regimen comprising the administration of a composition comprising a dosage form as described herein, and the reported pharmacokinetic parameters are the average of the pharmacokinetic parameters across patients.
  • the average may be obtained by calculating the parameters for each patient and then averaging across patients.
  • the averaging comprises a least-squares arithmetic mean or a least-squares geometric mean.
  • pharmacokinetic parameters are obtained from crossover studies, wherein the composition comprises an extended-release formulation of minocycline hydrochloride and is compared to a comparable composition comprising an immediate-release formulation of 100 mg dosage of minocycline.
  • the reported pharmacokinetic parameters associated with administration of compositions comprising low-dosage extended-release minocycline may be averaged across both subject groups (such that the parameters associated with such compositions are averaged across all patients regardless of whether such compositions are received first or second).
  • the pharmacokinetic profile of a composition described herein is pharmacokinetically distinct from an immediate-release composition.
  • the pharmacokinetic profile of a composition described herein is pharmacokinetically distinct from a comparable composition.
  • the pharmacokinetic distinctness may be due to, for example, a difference in the C max , AUC(o-72). and/or T max parameters.
  • the parameters may be single-dosage or steady-state.
  • the C max of a composition described herein may be less than about 80% of a comparable composition.
  • the AUC(o-7 2 ) may be less than about 80% of a comparable composition.
  • the T max may be greater than about 125% of a comparable composition.
  • the comparable composition may differ by being of an immediate-release form, e.g., MINOCIN® immediate-release minocycline hydrochloride.
  • the comparable composition may differ by comprising a higher dosage of a tetracycline-class antibiotic (e.g., minocycline).
  • the comparable composition may be an immediate-release form including a higher dosage of the oral tetracycline-class antibiotic.
  • a composition described herein provides a pharmacokinetic profile of one or more of a single-dosage C max that is about 80% or less of the single-dosage C max of the immediate-release dosage form; a steady-state C max that is about 80% or less of the steady-state C max of the immediate-release dosage form; a single-dosage AUQ0-72) that is about 80% or less of the single-dosage AUC(o-72) of the immediate-release dosage form; a steady state AUC( O-72 ) that is about 80% or less of the steady state AUC(o-72) of the immediate-release dosage form; a single-dosage T max that is at least about 125% of the single-dosage T ma ⁇ of the immediate-release dosage form; and a steady state T max that is at least about 125% of the steady state T max of the immediate-release dosage form.
  • the composition described herein provides a pharmacokinetic profile of one or more of a single-do
  • a composition described herein may provide specific pharmacokinetic profiles that are dose-adjusted to a 100-mg dosage.
  • the dose-adjusted pharmacokinetic profile may include a single-dosage C max in the range of about 0.9 ⁇ g/mL to about 1.5 ⁇ g/mL or in the range of about 1.1 ⁇ g/mL to about 1.4 ⁇ g/mL.
  • the dose-adjusted pharmacokinetic profile may include additionally or instead a single-dosage AUC( O-72 ) in the range of about 25 ⁇ g x hr/mL to about 30 ⁇ g x hr/mL or in the range of about 27 ⁇ g x hr/mL to about 29 ⁇ g x hr/mL. These values may indicate that the composition is pharmacokinetically distinct from a comparable composition.
  • the dose-adjusted C max in the range of about 0.9 ⁇ g/mL to about 1.5 ⁇ g/mL or in the range of about 1.1 ⁇ g/mL to about 1.4 ⁇ g/mL may be about 80% or less of the single-dosage C max of the immediate-release dosage form, e.g., MINOCIN® immediate-release minocycline hydrochloride.
  • the dose-adjusted AUC( O-72 ) in the range of about 25 ⁇ g x hr/mL to about 30 ⁇ g x hr/mL or in the range of about about 27 ⁇ g x hr/mL to about 29 ⁇ g x hr/mL may be about 80% or less of the single-dosage AUC( O-72 ) of the immediate-release dosage form, e.g. MINOCIN® immediate-release minocycline hydrochloride.
  • a composition described herein may provide a single-dosage T max in the range of about 3.2 to about 4.5 hours or in the range of about 3.5 to about 4.0 hours. These T max ranges may be about 125% or more of the single-dosage T max of the immediate-release dosage form, e.g. MINOCIN® immediate-release minocycline hydrochloride.
  • a composition described herein may provide specific pharmacokinetic profiles that are dose-adjusted to a 100-mg dosage.
  • the dose-adjusted pharmacokinetic profile may include a steady-state C ma ⁇ in the range of about 2.0 ⁇ g/mL to about 2.8 ⁇ g/mL or in the range of about 2.2 ⁇ g/mL to about 2.6 ⁇ g/mL.
  • the dose-adjusted pharmacokinetic profile may include additionally or instead a steady-state AUC(o-72) in the range of about 25 ⁇ g x hr/mL to about 40 ⁇ g x hr/mL or in the range of about 28 ⁇ g x hr/mL to about 37 ⁇ g x hr/mL.
  • AUC(o-72) in the range of about 25 ⁇ g x hr/mL to about 40 ⁇ g x hr/mL or in the range of about 28 ⁇ g x hr/mL to about 37 ⁇ g x hr/mL.
  • the dose-adjusted C max in the range of about 0.9 ⁇ g/mL to about 1.5 ⁇ g/mL or in the range of about 1.1 ⁇ g/mL to about 1.4 ⁇ g/mL may be about 80% or less of the steady-state C max of the immediate-release dosage form.
  • the dose-adjusted AUC( O- 72) in the range of about 25 ⁇ g x hr/mL to about 30 ⁇ g x hr/mL or in the range of about about 27 ⁇ g x hr/mL to about 29 ⁇ g x hr/mL may be about 80% or less of the steady-state AUC(o- 72 ) of the immediate-release dosage form e.g.
  • a composition described herein may provide a steady-state T max in the range of about 3.2 to about 4.5 hours or in the range of about 3.5 to about 4.0 hours. These T max ranges may be about 125% or more of the steady-state T max of the immediate-release dosage form e.g. MINOCIN® immediate-release minocycline hydrochloride.
  • An embodiment provides a minocycline oral dosage form, comprising minocycline or a pharmaceutically acceptable salt thereof and an amount of a controlled- release carrier composition that is effective to provide an in vitro release rate of the minocycline or pharmaceutically acceptable salt thereof of about 90% in about 4 hours to about 6 hours.
  • In vitro release rate is determined by a standard dissolution test as described above. Thus, during this test, the point in time at which about 90% dissolution of the minocycline oral dosage form is achieved, is in the range of about 4 hours to about 6 hours after commencement of the test.
  • Such an embodiment may be referred to herein as a 4-hour oral dosage formulation or simply as a 4-hour formulation.
  • the amount and type of controlled-release carrier composition that is effective to provide such a release rate is the same as that described elsewhere herein as being effective to render the oral dosage form pharmacokinetically distinct from MINOCIN® immediate-release minocycline hydrochloride.
  • the methods of making and using controlled-release oral dosage forms described herein are applicable to 4-hour formulations.
  • the 4-hour oral dosage formulation comprises a controlled-release carrier composition that comprises at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpryrollidone.
  • the amount of controlled-release carrier composition in the 4-hour formulation may be, for example, in the range of about 20% to about 30%, by weight based on the total weight of the minocycline oral dosage form.
  • various other descriptions provided herein such as minocycline form (e.g., minocycline hydrochloride), dosage (e.g., minocycline free base equivalent dosage in the range of about 0.75 mg/kg to about 1.5 mg/kg), unit dosage size (e.g., about 45 mg, about 60 mg, about 90 mg and about 135 mg), methods of treatment, methods of distribution, methods of making, methods of reducing adverse effects, kits, etc., are not limited to the context in which they may be discussed, but are equally applicable to 4-hour formulations.
  • Administration of a composition as described herein may result in an in vivo plasma minocycline C max as described herein.
  • Administration of the composition may result in an in vivo plasma minocycline AUC as described herein.
  • Administration of the composition may result in an in vivo plasma minocycline T max as described herein.
  • Administration of the composition may result in two selected from the in vivo plasma minocycline C ma ⁇ as described herein, the in vivo plasma minocycline AUC as described herein, and the in vivo plasma minocycline T max as described herein.
  • Administration of the composition may result in an in vivo plasma minocycline C max described herein, an in vivo plasma minocycline AUC as described herein and an in vivo plasma minocycline T max as described herein.
  • a pharmacokinetic profile described herein may be associated with reduced adverse side effects following administration of a composition described herein as compared to those expected and/or obtained by administration of a comparable composition (e.g., MINOCIN® immediate-release minocycline hydrochloride), as described in greater detail below.
  • a comparable composition e.g., MINOCIN® immediate-release minocycline hydrochloride
  • This invention is not bound by theory of operation, but it is believed that the some or all of the adverse effects associated with immediate-release dosage forms may result from dosage practices that produce concentration profiles of the drug in plasma that were believed to be needed to provide efficacy.
  • the administration of the oral dosage forms in accordance with some embodiments described herein produces concentration profiles of the drug that are pharmacokinetically distinct from those obtained by administration of a comparable composition, yet still provide substantially similar or better treatment efficacy and/or reduced incidence of at least one adverse effect.
  • a controlled-release tetracycline-class antibiotic oral dosage form as described herein can be distributed, provided to a patent for self- administration or administered to a patient.
  • the patient is typically suffering from or at risk of suffering from acne or a complication thereof.
  • the acne is acne vulgaris.
  • the acne is acne rosacea.
  • the acne may be one or more of acne conglobata, acne fulminans, gram- negative folliculitis, and pyoderma faciale.
  • the acne may be a severe form of acne, a moderate form of acne, or a mild form of acne.
  • Such distribution, provision or administration of a controlled-release tetracycline-class antibiotic oral dosage form as described herein may be in conjunction with the provision of information regarding actual or potential adverse side effects and/or reductions in adverse effects that may be obtained by administration of a controlled-release tetracycline-class antibiotic oral dosage form as described herein.
  • immediate-release minocycline products have been approved as adjunctive therapy in cases of severe acne, but were not formally studied in FDA trials for that indication, see Leyden, J. Cutis 2006; 78 (suppl 4):4-5.
  • the recommended daily dose of immediate-release minocycline for the treatment of acne ranges from about 2 mg/kg/day to about 4 mg/kg/day.
  • Previous studies have suggested that high dosages are necessary for effective treatment of acne, Pierard-Franchimont et al., Skin Pharmacol. Appl. Skin Physiol. 15(2): 112-119 (2002).
  • oral dosage forms described herein are effective in the treatment of acne.
  • the oral dosage form is more effective than a comparable composition (e.g., MINOCIN® immediate-release minocycline hydrochloride).
  • the comparable composition may comprise higher dosages of the active ingredient and/or an immediate-release formulation.
  • the comparable composition may provide a release rate of greater than 50%, 90% or 95% in about 1, about 2, about 4, or about 6 hours.
  • the comparable composition may provide a release rate of 50%, 90% or 95% in less than about 1 , about 2, about 4, or about 6 hours.
  • the specific dose level of the controlled- release oral dosage forms described herein for any particular patient can depend upon any of a variety of factors including the genetic makeup, body weight, general health, diet, time and route of administration, combination with other drugs and the particular condition being treated, and its severity.
  • low dosages of the active ingredient are provided. These low doses are effective and, in most patients, are associated with reduced side effects as compared to higher dosages.
  • Dosages described herein may involve comparatively low dosages of a tetracycline, minocycline, and/or minocycline hydrochloride.
  • the controlled-release oral dosage forms described herein remain effective in treating acne despite providing a lower AUC as compared to that provided by higher dosages of an immediate-release dosage form such as MINOCIN® immediate-release minocycline hydrochloride.
  • the controlled-release oral dosage forms described herein provide substantially similar or improved acne treatment efficacy as compared to an otherwise comparable composition containing a larger dosage of the active ingredient.
  • once-daily administration of a composition described herein provides substantially similar or better acne treatment efficacy as compared to a twice-daily administration of the immediate- release dosage form.
  • treatment dosages are based on the body weight of the patient, e.g., for minocycline dosages may be in the range of about 0.75 mg/kg to about 1.5 mg/kg, e.g., about 1 milligram of minocycline (free base equivalent) per kilogram of patient body weight. Once-daily dosing is provided in some embodiments.
  • a controlled-release minocycline oral dosage form as described herein on a once-daily basis is effective.
  • the dosing schedule used most frequently for treating acne using currently available immediate-release oral dosage forms is 100 mg of minocycline (free base equivalent) administered twice daily, see Leyden, J. Cutis 2006; 78 (suppl 4):4-5.
  • a controlled-release minocycline oral dosage form as described herein has a single-dosage T max that is about 125% or more of the single-dosage T max of MINOCIN® immediate- release minocycline hydrochloride, e.g., a T max that occurs about an hour later.
  • such once-daily dosing further provides a reduced incidence of at least one adverse effect as compared to a twice-daily administration of a conventional immediate release form, e.g., MINOCIN® immediate-release minocycline hydrochloride.
  • a conventional immediate release form e.g., MINOCIN® immediate-release minocycline hydrochloride.
  • a patient is provided with a composition comprising minocycline hydrochloride, wherein the dosage of minocycline hydrochloride is 45 mg, 60 mg, 90 mg or 135 mg, and the dosage is determined by the weight of the patient.
  • the dosage is chosen such that the administered or provided dosage of minocycline hydrochloride is in the range of about 0.75 mg/kg to about 1.5 mg/kg.
  • the dosage is held constant across days. In other embodiments, the dosage may vary across days. For example, the initial dosages of minocycline may be higher than subsequent dosages.
  • the dosages may be pre-determined or may be determined based on the patient's reaction to the dosage. For example, the dosage may be decreased until the dose is no longer effective, hi other embodiments, the dosage can be increased until the severity of at least one adverse side effect increases. For example, the dosage may be increased until the patient reports experiencing a vestibular side effect.
  • Effective treatment of acne may be characterized in various ways.
  • effective treatment of acne may be characterized as a reduction, and in some embodiments a substantial reduction, in the number of acne lesions.
  • the acne lesions may be defined as at least one of inflammatory and non-inflammatory lesions.
  • Effective treatment of acne may be characterized as a reduction in the severity of acne.
  • Effective treatment of acne may be characterized as a reduction in the duration of an outbreak.
  • a composition described herein may reduce the duration that a lesion will remain after it has formed.
  • Effective treatment of acne may be characterized as a reduced probability of an acne-related symptom.
  • a composition described herein may reduce the probability of developing further lesions.
  • oral dosage forms and methods described herein can be used to treat acne, wherein the acne is acne vulgaris.
  • the acne is acne rosacea.
  • the acne may be one or more of acne conglobata, acne fulminans, gram-negative folliculitis, and pyoderma faciale.
  • the acne may be a severe form of acne, a moderate form of acne, or a mild form of acne, and may include inflammatory and/or non-inflammatory lesions.
  • oral dosage forms and methods described herein can be used to treat inflammatory lesions of acne vulgaris.
  • the acne is at least partially caused by hormonal changes, excessive production of one or more male hormones, or pregnancy.
  • the acne may be caused by a medication, such as a contraceptive pill, ointments for eczema, or medicine for epilepsy.
  • the acne may be caused by a drug, such as androgens, lithium, or barbiturates.
  • a controlled-release tetracycline-class antibiotic oral dosage form as described herein may result in the reduction of one or more adverse side effects associated with administration of a comparable composition (e.g., MINOCIN® immediate-release minocycline hydrochloride) as described in further detail below.
  • the one or more adverse side effects may comprise a side effect associated with acne, treatment using the comparable composition.
  • the comparable composition may comprise higher dosages of the active ingredient and/or an immediate-release formulation.
  • the comparable composition may provide a release rate of greater than 50%, 90% or 95% in about 1 , about 2, about 4, or about 6 hours.
  • the comparable composition may provide a release rate of 50%, 90% or 95% in less than about 1, about 2, about 4, or about 6 hours.
  • a composition described herein reduces one or more adverse side effects while maintaining efficacy as described above. .
  • administration of a controlled-release tetracycline-class antibiotic oral dosage form as described herein may reduce the probability of the adverse side effect occurring. In other embodiments, such administration may reduce the magnitude of at least one adverse side effect. In other embodiments, such administration may reduce the duration of at least one adverse side effect. In some cases, e.g., involving individual patients, such reductions may be in comparison to the side effects that would be expected by one of skill in the art in view of the known side effects of a higher-dosage immediate release form, and thus it is not necessary that the patient actually experience side effects from the immediate release form in order to benefit from such reductions in side effects.
  • Examples of adverse side effects that may be reduced by administration in accordance with certain embodiments include one or more of: ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, vascular disorders, pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and/or anaphylaxis.
  • An adverse side effect may include one or more gastrointestinal disorders, blurred vision, autoimmune syndromes, and/or adverse renal reactions.
  • the gastrointestinal disorder may include anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, pancreatitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, increases in liver enzymes, hepatitis, liver failure, esophagitis and/or esophageal ulcerations.
  • the skin and subcutaneous tissue disorder may include maculopapular, erythematous rashes, exfoliative dermatitis, fixed drug eruptions, balanitis, erythema multiforme, Stevens- Johnson syndrome, or pigmentation of the skin and/or mucous membranes.
  • the adverse renal reaction may be an elevation in BUN and/or acute renal failure.
  • the metabolism and nutritional disorder may be azotemia, hyperphosphatemia, and/or acidosis.
  • An adverse side effect may be a hypersensitivity reaction side effect.
  • the hypersensitivity reaction side effect may be urticaria, angioneurotic edma, polyarthralgia, anaphylaxis, anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus, pulmonary ininf ⁇ ltrates with eosinophilia, and/or transient lupus-like syndrome.
  • An adverse side effect may be a blood side effect.
  • the blood side effect may be hemolytic anemia, thrombocytopenia, neutropenia, and/or eosinophilia.
  • An adverse side may be a central nervous system side effect.
  • the central nervous system side effect may be lightheadedness, dizziness, vertigo, pseudotumor cerebri or benign intracranial hypertension.
  • An adverse side effect may be a brown-black microscopic discoloration of the thyroid glands, soft tissue, bone or teeth, abnormal thyroid function, and/or hepatotoxicity.
  • a controlled-release tetracycline-class antibiotic oral dosage form as described herein can be administered in conjunction with other acne treatments or medications.
  • an extended-release minocycline oral dosage form may include one or more other acne medications, such as an antibiotic and/or retinoid, e.g., retinol, retinoic acid, another oral tetracycline, dapsone, prednisone, and/or estrogen, or they may be administered separately.
  • a controlled- release tetracycline-class antibiotic oral dosage form as described herein can be administered in conjunction with the use of a topical acne treatment product such as a topical antibiotic, a topical retinoid, and/or a cream or facial cleanser product, e.g., a cleanser that contains benzoyl peroxide such as TRIAZ® cleanser pads (available commercially from Medicis Pharmaceutical Corporation, Phoenix, Arizona).
  • a topical acne treatment product such as a topical antibiotic, a topical retinoid, and/or a cream or facial cleanser product, e.g., a cleanser that contains benzoyl peroxide such as TRIAZ® cleanser pads (available commercially from Medicis Pharmaceutical Corporation, Phoenix, Arizona).
  • methods of the present invention include identifying a patient suffering from at least one adverse side effect and/or who is particularly susceptible to at least one adverse side effect associated with a comparable higher-dosage immediate-release composition (such as MINOCIN® immediate-release minocycline hydrochloride) and providing or administering to the patient a controlled- release tetracycline-class antibiotic oral dosage form as described herein.
  • methods of the present invention include identifying a patient who is particularly susceptible to at least one adverse side effect.
  • Methods of use can include the step of administering a therapeutically- effective amount of the oral dosage form to a mammal in need thereof by any suitable route or method of delivery, including those described herein.
  • Actual dosage levels of the compounds in the pharmaceutical compositions may be varied so as to administer an amount of the tetracycline-class antibiotic (e.g., minocycline) that is effective to achieve the desired therapeutic response for a particular patient. Examples of dosages that can be used are described more fully elsewhere herein.
  • Suitable routes of administration include delivery in the form of, e.g., pills, tablets, powders, granules, dragees, capsules, liquids, sprays, gels, syrups, slurries, suspensions and the like, any of which can be in unit dosage form, for oral ingestion by a patient to be treated.
  • the formulation can be in form suitable for bolus administration, for example.
  • Oral administration can be accomplished using fast-melt formulations, for example.
  • the formulations can be included in push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Formulations for oral administration can be in unit dosages suitable for such administration.
  • a composition described herein may be associated with one or more adverse side effects.
  • the one or more side effects may include pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • a composition described herein is administered to a patient.
  • the patient may be informed that the composition may cause one or more adverse side effects.
  • the patient may be informed that the composition may cause one or more of pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • the patient may be provided information that the composition may cause one or more adverse side effects.
  • the patient may be provided information that the composition may cause one or more of pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • a composition described herein is distributed. Information may also be distributed, and may be concomitantly distributed with the composition, indicating that the composition may cause one or more adverse side effects.
  • Information may also be distributed, and may be concomitantly distributed with the composition, indicating that the composition may cause one or more of pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • the present invention relates to a kit.
  • the kit may include one or more unit dosage forms comprising a tetracycline-class antibiotic.
  • the tetracycline-class antibiotic may be minocycline.
  • the tetracycline-class antibiotic may be present in a low dosage.
  • the unit dosage form may be of a controlled-release formulation.
  • the unit dosage forms may be of an oral formulation.
  • the unit dosage forms may comprise tablets.
  • the kit may include a plurality of unit dosage forms.
  • the kit may include information.
  • the information may be directed towards a physician, pharmacist or patient.
  • the information may indicate that the unit dosage form may cause one or more adverse effects.
  • the information may indicate that the unit dosage form is to be administered once per day.
  • the information may indicate that the unit dosage form may cause one or more adverse side effects.
  • the information may indicate that the unit dosage form may cause one or more of pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • the information may comprise instructions to administer the unit dosage form at a dosage of about 0.75 mg/kg to about 1.5 mg/kg. These instructions may be provided in a variety of ways.
  • the information may include a table including a variety of weights or weight ranges and appropriate dosages for each weight or weight range.
  • the information may be provided on a readable medium.
  • the readable medium may comprise a label.
  • the kit may comprise a therapeutic package suitable for commercial sale.
  • the kit may comprise a container.
  • the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual dosages for pressing out of the pack according to a therapeutic schedule.
  • the container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained within a box.
  • the information can be associated with the container, for example, by being: written on a label (e.g., the prescription label or a separate label) adhesively affixed to a bottle containing a composition described herein; included inside a container as a written package insert, such as inside a box which contains unit dose packets; applied directly to the container such as being printed on the wall of a box; or attached as by being tied or taped, for example as an instructional card affixed to the neck of a bottle via a string, cord or other line, lanyard or tether type device.
  • the information may be printed directly on a unit dose pack or blister pack or blister card.
  • one or more of the oral dosage forms, methods and/or kits described herein is provided, with a proviso that the oral dosage form, method and/or kit does not include a composition, oral dosage form or method disclosed in U.S. Patent Publication No. 2006-0293290, published 28 December 2006, which is hereby incorporated by reference in its entirety.
  • an embodiment provides an oral dosage form as described herein, with the proviso that the oral dosage form does not include a 135 mg caplet that consists of 145 mg minocycline hydrochloride, 107.4 mg lactose monohydrate (intragranular), 43.8 mg lactose monohydrate (extragranular), 94 mg HPMC, 3 mg silicon dioxide and 6 mg magnesium stearate.
  • an embodiment provides a method of administering an oral dosage form as described herein, wherein the method does not include administering such a 135 mg caplet.
  • an embodiment provides an oral dosage form as described herein, wherein the oral dosage form does not include a 45 mg caplet that consists of 48.6 mg minocycline hydrochloride, 192.2 mg lactose monohydrate (intragranular), 42.2 mg lactose monohydrate (extragranular), 108 mg HPMC, 3 mg silicon dioxide and 6 mg magnesium stearate.
  • an embodiment provides a method of administering an oral dosage form as described herein, wherein the method does not include administering such a 45 mg caplet.
  • Non-limiting embodiments of the invention include the following:
  • Embodiment 1 An oral dosage form, comprising: minocycline or a pharmaceutically acceptable salt thereof; and an amount of a controlled-release carrier composition that is effective to render said oral dosage form pharmacokinetically distinct from MINOCIN® immediate-release minocycline hydrochloride.
  • Embodiment 2 The oral dosage form of Embodiment 1, wherein a once-daily administration of said oral dosage form provides substantially similar or better acne treatment efficacy and reduced incidence of at least one adverse effect, as compared to a twice-daily administration of said MINOCIN® immediate-release minocycline hydrochloride.
  • Embodiment 3 The oral dosage form of Embodiment 1 or 2, wherein said oral dosage form provides, after administration, at least one in vivo plasma minocycline concentration profile selected from: (a) a single-dosage C ma ⁇ that is about 80% or less of the single-dosage C max of the MINOCIN® immediate-release minocycline hydrochloride;
  • Embodiment 4 The oral dosage form of Embodiment 3, wherein said in vivo plasma minocycline concentration profile is dose-adjusted to a 100 mg dosage and wherein: said single-dosage C ma ⁇ is in the range of about 0.9 ⁇ g/mL to about 1.5 ⁇ g/mL; said single-dosage AUC(o-72) is in the range of about 25 ⁇ g x hr/mL to about 30 ⁇ g x hr/mL; or said single-dosage C ma ⁇ in the range of about 0.9 ⁇ g/mL to about 1.5 ⁇ g/mL and said single-dosage AUC(o-72) is in the range of about 25 ⁇ g x hr/mL to about 30 ⁇ g x hr/mL.
  • Embodiment 5 The oral dosage form of any one of Embodiments 3 to 4, wherein said single-dosage T max in the range of about 3.2 to about 4.5 hours.
  • Embodiment 6 The oral dosage form of Embodiment 5, wherein said single-dosage T ma ⁇ is in the range of about 3.5 to about 4.0 hours.
  • Embodiment 7 The oral dosage form of Embodiment 4, wherein said single-dosage C max is in the range of about 1.1 ⁇ g/mL to about 1.4 ⁇ g/mL.
  • Embodiment 8 The oral dosage form of Embodiment 4, wherein said single-dosage AUC (O ⁇ 2 ) is in the range of about 27 ⁇ g x hr/mL to about 29 ⁇ g x hr/mL.
  • Embodiment 9 The oral dosage form of Embodiment 3, wherein said in vivo plasma minocycline concentration profile is dose-adjusted to a 100 mg dosage and wherein: said steady-state C ma ⁇ is in the range of about 2.0 ⁇ g/mL to about 2.8 ⁇ g/mL; said steady-state AUC(o-24> is in the range of about 25 ⁇ g x hr/mL to about
  • Embodiment 10 The oral dosage form of Embodiment 3 or Embodiment 9, wherein said steady-state T max in the range of about 3.2 to about 4.5 hours.
  • Embodiment 11 The oral dosage form of Embodiment 10, wherein said steady-state T ma ⁇ is in the range of about 3.5 to about 4.0 hours.
  • Embodiment 12 The oral dosage form of Embodiment 9, wherein said steady-state C max is in the range of about 2.2 ⁇ g/mL to about 2.6 ⁇ g/mL.
  • Embodiment 13 The oral dosage form of Embodiment 9, wherein said steady-state AUC(O -72 ) is in the range of about 28 ⁇ g x hr/mL to about 37 ⁇ g x hr/mL.
  • Embodiment 14 The oral dosage form of any one of Embodiments 1 to 13, wherein said minocycline salt is minocycline hydrochloride.
  • Embodiment 15 The oral dosage form of any one of Embodiments 1 to 14, wherein said oral dosage form is in a unit dosage form suitable for administration to a human at a minocycline free base equivalent dosage in the range of about 0.75 mg/kg to about 1.5 mg/kg.
  • Embodiment 16 The oral dosage form of Embodiment 15, wherein said unit dosage form comprises minocycline, hydrochloride in a minocycline free base equivalent amount selected from about 45 mg, about 60 mg, about 90 mg and about 135 mg.
  • Embodiment 17 The oral dosage form of any one of Embodiments 3 to 16, wherein said in vivo plasma minocycline concentration profile is single-dosage
  • Embodiment 18 The oral dosage form of any one of Embodiments 3 to 16, wherein said in vivo plasma minocycline concentration profile is single-dosage
  • Embodiment 19 The oral dosage form of any one of Embodiments 3 to 16, wherein said in vivo plasma minocycline concentration profile is single-dosage
  • Embodiment 20 The oral dosage form of any one of Embodiments 3 to 16, wherein said in vivo plasma minocycline concentration profile is steady-state C max .
  • Embodiment 21 The oral dosage form of any one of Embodiments 3 to 16, wherein said in vivo plasma minocycline concentration profile is steady-state
  • Embodiment 22 The oral dosage form of any one of Embodiments 3 to 16, wherein said in vivo plasma minocycline concentration profile is steady-state T max
  • Embodiment 23 The oral dosage form of any one of Embodiments 3 to 16, wherein said oral dosage form provides, after administration, at least two of said in vivo plasma minocycline concentration profiles.
  • Embodiment 24 The oral dosage form of any one of Embodiments 3 to 16, wherein said oral dosage form provides said single-dosage C max , said single-dosage AUC(o-72) and said single-dosage T max .
  • Embodiment 25 The oral dosage form of any one of Embodiments 3 to 16, wherein said oral dosage form provides said steady-state C max - said steady-state AUC(o-72) and said steady-state T max .
  • Embodiment 26 The oral dosage form of any one of Embodiments 1 to 25, wherein said controlled-release carrier composition comprises at least one selected from hydroxypropylmethylcellulose, hydroxypropyl cellulose, and polyvinylpryrollidone.
  • Embodiment 27 A method of treating acne, comprising administering the oral dosage form of any one of Embodiments 1 to 26 to a subject in need thereof.
  • Embodiment 28 The method of Embodiment 27, comprising administering the oral dosage form to the subject at a minocycline free base equivalent dosage in the range of about 0.75 mg/kg to about 1.5 mg/kg.
  • Embodiment 29 The method of Embodiment 27 or Embodiment 28, comprising administering the oral dosage form to the subject on a once-daily basis.
  • Embodiment 30 The method of any one of Embodiments 27 to 29, further comprising reducing at least one adverse side effect as compared to that expected from administering the MINOCIN® immediate-release minocycline hydrochloride.
  • Embodiment 31 The method of Embodiment 30, wherein reducing at least one adverse side effect comprises reducing the likelihood of experiencing said adverse side effect.
  • Embodiment 32 The method of Embodiment 30, wherein reducing at least one adverse side effect comprises reducing the magnitude of said adverse side effect.
  • Embodiment 33 The method of Embodiment 30, wherein reducing at least one adverse side effect comprises reducing the duration of said adverse side effect.
  • Embodiment 34 The method of any one of Embodiments 27 to 33, further comprising informing the subject that the oral dosage form may cause an adverse effect.
  • Embodiment 35 The method of Embodiment 34, wherein the adverse effect is selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, vascular disorders, pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • the adverse effect is selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, vascular disorders, pseudomembranous
  • Embodiment 36 The method of Embodiment 34, wherein the adverse effect is selected from gastrointestinal disorders, blurred vision, autoimmune syndromes, and adverse renal reactions.
  • Embodiment 37 A method of distributing minocycline, comprising: distributing the oral dosage form of any one of Embodiments 1 to 26; and concomitantly distributing information that the oral dosage form may cause an adverse effect.
  • Embodiment 38 The method of Embodiment 37, wherein the adverse effect is selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, vascular disorders, pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • Embodiment 39 The method of Embodiment 37, wherein the adverse effect is selected from gastrointestinal disorders, blurred vision, autoimmune syndromes, and adverse renal reactions.
  • Embodiment 40 A method of making the oral dosage form of any one of Embodiments 1 to 26, comprising intermixing the minocycline or pharmaceutically acceptable salt thereof and the controlled-release carrier composition to form an admixture.
  • Embodiment 41 The method of Embodiment 40, further comprising forming the admixture into a unit dosage form.
  • Embodiment 42 The method of Embodiment 41, wherein forming the admixture into the unit dosage form comprises compressing the admixture into tablets.
  • Embodiment 43 A method of administering an oral dosage form comprising:
  • administering to a patient an oral dosage form, which oral dosage form comprises: an oral tetracycline-class antibiotic; a fast dissolving carrier; and a slow dissolving carrier; and (ii) providing information to the patient, wherein the information comprises that the administering of-the oral dosage form may cause one or more adverse effects selected from pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • Embodiment 44 The method of Embodiment 43, wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of from 0.3 to 0.5 of fast dissolving carrier to slow dissolving carrier.
  • Embodiment 45 The method of Embodiment 43, wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of from 0.3 to 0.45 of fast dissolving carrier to slow dissolving carrier.
  • Embodiment 46 The method of Embodiment 43, wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of from about 0.36 to 0.40 of fast dissolving carrier to slow dissolving carrier.
  • Embodiment 47 The method of any one of Embodiments 43 to 46, wherein the adverse effect is pseudomembranous colitis.
  • Embodiment 48 The method of any one of Embodiments 43 to 46, wherein the adverse effect is hepatotoxicity.
  • Embodiment 49 The method of any one of Embodiments 43 to 46, wherein the adverse effect is vasculitis.
  • Embodiment 50 The method of any one of Embodiments 43 to 46, wherein the adverse effect is tissue hyperpigmentation.
  • Embodiment 51 The method of any one of Embodiments 43 to 46, wherein the adverse effect is anaphylaxis.
  • Embodiment 52 The method of any one of Embodiments 43 to 51, wherein the patient has been diagnosed with acne vulgaris.
  • Embodiment 53 A method of distributing an oral dosage form, comprising: distributing an oral dosage form comprising an oral tetracycline-class antibiotic, a fast dissolving carrier and a slow dissolving carrier; and concomitantly distributing information that the oral dosage form may cause one or more adverse effects selected from pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • Embodiment 54 The method of Embodiment 53, wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of from 0.3 to 0.5 of fast dissolving carrier to slow dissolving carrier.
  • Embodiment 55 The method of Embodiment 53, wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of from 0.35 to 0.45 of fast dissolving carrier to slow dissolving carrier.
  • Embodiment 56 The method of Embodiment 53, wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of from about 0.36 to 0.40 of fast dissolving carrier to slow dissolving carrier.
  • Embodiment 57 The method of any one of Embodiments 53 to 56, wherein the adverse effect is pseudomembranous colitis.
  • Embodiment 58 The method of any one of Embodiments 53 to 56, wherein the adverse effect is hepatotoxicity.
  • Embodiment 59 The method of any one of Embodiments 53 to 56, wherein the adverse effect is vasculitis.
  • Embodiment 60 The method of any one of Embodiments 53 to 56, wherein the adverse effect is tissue hyperpigmentation.
  • Embodiment 61 The method of any one of Embodiments 53 to 56, wherein the adverse effect is anaphylaxis.
  • Embodiment 62 A method of administering an oral dosage form comprising:
  • oral dosage form which oral dosage form comprises: an oral tetracycline-class antibiotic; a fast dissolving carrier; and a slow dissolving carrier; wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of 0.3 to 0.5 of fast dissolving carrier to slow dissolving carrier; and
  • Embodiment 63 The method of Embodiment 62, wherein the weight ratio of fast dissolving carrier to slow dissolving carrier is 0.35 to 0.45.
  • Embodiment 64 The method of Embodiment 62, wherein the weight ratio of fast dissolving carrier to slow dissolving carrier is about 0.36 to 0.40.
  • Embodiment 65 The method of any one of Embodiments 62 to 64, wherein the one or more adverse effects is/are selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, and vascular disorders.
  • the one or more adverse effects is/are selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, and vascular disorders.
  • Embodiment 66 The method of any one of Embodiments 62 to 64, wherein the one or more adverse effects is/are selected from gastrointestinal disorders, blurred vision, autoimmune syndromes, and adverse renal reactions.
  • Embodiment 67 The method of any one of Embodiments 62 to 66, wherein the patient has been diagnosed with acne vulgaris.
  • Embodiment 68 A method of distributing an oral dosage form, comprising: distributing an oral dosage form comprising an oral tetracycline-class antibiotic, a fast dissolving carrier and a slow dissolving carrier, wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of 0.3 to 0.5 of fast dissolving carrier to slow dissolving carrier; and concomitantly distributing information that the oral dosage form may cause one or more adverse effects.
  • Embodiment 69 The method of Embodiment 68, wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of 0.35 to 0.45 of fast dissolving carrier to slow dissolving carrier.
  • Embodiment 70 The method of Embodiment 68, wherein the fast dissolving carrier and the slow dissolving carrier are at a weight ratio of about 0.36 to 0.40 of fast dissolving carrier to slow dissolving carrier.
  • Embodiment 71 The method of any one of Embodiments 68 to 70, wherein the one or more adverse effects is/are selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, and vascular disorders.
  • the one or more adverse effects is/are selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, and vascular disorders.
  • Embodiment 72 The method of any one of Embodiments 68 to 70, wherein the one or more adverse effects is/are selected from gastrointestinal disorders, blurred vision, autoimmune syndromes, and adverse renal reactions.
  • Embodiment 73 A minocycline oral dosage form, comprising minocycline or a pharmaceutically acceptable salt thereof and an amount of a controlled- release carrier composition that is effective to provide an in vitro release rate of the minocycline or pharmaceutically acceptable salt thereof of about 90 % in about 4 hours to about 6 hours.
  • Embodiment 74 The minocycline oral dosage form of Embodiment 73, wherein said controUed-release carrier composition comprises at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpryrollidone.
  • Embodiment 75 The minocycline oral dosage form of Embodiment 73 or Embodiment 74, wherein said amount of said contxolled-release carrier composition is in the range of about 20% to about 30%, by weight based on the total weight of the minocycline oral dosage form.
  • Embodiment 76 The minocycline oral dosage form of any one of Embodiments 73 to 75, wherein the minocycline salt comprises minocycline hydrochloride.
  • Embodiment 77 The minocycline oral dosage form of any one of Embodiments 73 to 76, wherein said oral dosage form is in a unit dosage form suitable for administration to a human at a minocycline free base equivalent dosage in the range of about 0.75 mg/kg to about 1.5 mg/kg.
  • Embodiment 78 The minocycline oral dosage form of Embodiment
  • said unit dosage form comprises minocycline hydrochloride in a minocycline free base equivalent amount selected from about 45 mg, about 60 mg, about 90 mg and about 135 mg.
  • Embodiment 79 The minocycline oral dosage form of Embodiment
  • said unit dosage form comprises minocycline hydrochloride in a minocycline free base equivalent amount of about 45 mg and about 26% to about 28% of said controlled-release carrier composition, by weight based on the total weight of the minocycline oral dosage form.
  • Embodiment 80 The minocycline oral dosage form of Embodiment 78, wherein said unit dosage form comprises minocycline hydrochloride in a minocycline free base equivalent amount of about 90 mg and about 26% to about 28% of said controlled-release carrier, by weight based on the total weight of the minocycline oral dosage form.
  • Embodiment 81 The minocycline oral dosage form of Embodiment 78, wherein said unit dosage form comprises minocycline hydrochloride in a minocycline free base equivalent amount of about 135 mg and about 22% to less than 25% of said controlled-release carrier, by weight based on the total weight of the minocycline oral dosage form.
  • Embodiment 82 A method of treating acne, comprising administering the minocycline oral dosage form of any one of Embodiments 73 to 81 to a subject in need thereof.
  • Embodiment 83 The method of Embodiment 82, comprising administering the minocycline oral dosage form to the subject at a minocycline free base equivalent dosage in the range of about 0.75 mg/kg to about 1.5 mg/kg.
  • Embodiment 84 The method of Embodiment 82 or 83, comprising administering the minocycline oral dosage form to the subject on a once-daily basis
  • Embodiment 85 The method of any one of Embodiments 82 to 84, further comprising eliminating or reducing the magnitude of at least one adverse side effect as compared to that obtained from administering substantially the same dosage of MINOCIN® immediate-release minocycline hydrochloride.
  • Embodiment 86 The method of any one of Embodiments 82 to 85, further comprising informing the subject that the oral dosage form may cause an adverse effect.
  • Embodiment 87 The method of Embodiment 86, wherein the adverse effect is selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, vascular disorders, pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • the adverse effect is selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, vascular disorders, pseudomembr
  • Embodiment 88 The method of Embodiment 86, wherein the adverse effect is selected from gastrointestinal disorders, blurred vision, autoimmune syndromes, and adverse renal reactions.
  • Embodiment 89 A method of distributing minocycline, comprising: distributing the minocycline oral dosage form of any one of Embodiments
  • Embodiment 90 The method of Embodiment 89, wherein the adverse effect is selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, vascular disorders, pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • Embodiment 91 The method of Embodiment 89, wherein the adverse effect is selected from gastrointestinal disorders, blurred vision, autoimmune syndromes, and adverse renal reactions.
  • Embodiment 92 A method of making the minocycline oral dosage form of any one of Embodiments 73 to 81, comprising intermixing the minocycline salt and the controlled-release carrier composition to form an admixture.
  • Embodiment 93 The method of Embodiment 92, further comprising forming the admixture into a unit dosage form.
  • Embodiment 94 The method of Embodiment 93, wherein forming the admixture into the unit dosage form comprises compressing the admixture into tablets.
  • Embodiment 95 A kit comprising: the minocycline oral dosage form of any one of Embodiments 1 to 26 or 73 to 81; and information that the oral dosage form may cause one or more adverse effects.
  • Embodiment 96 The kit of Embodiment 95, wherein the adverse effect is selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, vascular disorders, pseudomembranous colitis, hepatotoxicity, vasculitis, tissue hyperpigmentation, and anaphylaxis.
  • Embodiment 97 The kit of Embodiment 95, wherein the adverse effect is selected from gastrointestinal disorders, blurred vision, autoimmune syndromes, and adverse renal reactions.
  • Embodiment 98 The kit of any one of Embodiments 95 to 97, further comprising instructions for administering the oral dosage form at a minocycline free base equivalent dosage of about 0.75 mg/kg to about 1.5 mg/kg.
  • Embodiment 99 The kit of any one of Embodiments 95 to 98, further comprising instructions for administering the oral dosage form on a once daily basis.
  • Embodiment 100 A kit comprising: (i) an oral dosage form comprising: an oral tetracycline-class antibiotic; a fast dissolving carrier; and a slow dissolving carrier; wherein the fast dissolving carrier and slow dissolving carrier are at a weight ratio of 0.3 to 0.5 of fast dissolving carrier to slow dissolving carrier; and
  • Embodiment 101 The kit of Embodiment 100, wherein the ratio of fast dissolving carrier to slow dissolving carrier is 0.35 to 0.45.
  • Embodiment 102 The kit of Embodiment 100, wherein the ratio of fast dissolving carrier to slow dissolving carrier is about 0.36 to 0.40.
  • Embodiment 103 The kit of any one of Embodiments 100 to 102, wherein the one or more adverse effects is/are selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, and vascular disorders.
  • the one or more adverse effects is/are selected from ear and labyrinth disorders, eye disorders, gastrointestinal disorders, immune system disorders, infections and infestations, laboratory blood abnormalities, metabolism and nutritional disorders, musculoskeletal and connective disorders, nervous system disorders, psychiatric disorders, renal and urinary disorders, reproductive system and breast disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, and vascular disorders.
  • Embodiment 104 The kit of any one of Embodiments 100 to 102, wherein the one or more adverse effects is/are selected from gastrointestinal disorders, blurred vision, autoimmune syndromes, and adverse renal reactions.
  • Embodiment 105 The kit of any one of Embodiments 100 to 104, further comprising instructions for administering the oral dosage form at a dosage of about 0.75 mg/kg to about 1.5 mg/kg.
  • Embodiment 106 The kit of any one of Embodiments 100 to 105, further comprising instructions for administering the oral dosage form on a once-daily basis.
  • a batch of 45 mg minocycline hydrochloride extended release tablets (4-hour formulation) is prepared.
  • the tablets include 45 mg (minocycline free base equivalent) of the active ingredient minocycline hydrochloride, 108 mg of the matrix- forming polymer Methocel E50 Premium LV (hydroxypropyl methylcellulose), 197 mg intragranular of the diluent Fast Flo (lactose monohydrate), 41.0 mg extragranular of the diluent Fast Flo (lactose monohydrate), 3.0 mg of silicon oxide and 6.0 mg of the lubricant magnesium stearate
  • Tablet formation includes high shear granulation followed by wet milling and fluid bed drying.
  • the quantity of water used to achieve the wet granulation end point is 34% w/w of the starting materials (dry powders). Purified water is removed during drying and therefore is not present in the final tablet.
  • the spray rate at which the granulating liquid is delivered is 5,000 g/minute.
  • the formulation is then dry milled and blended with extragranular excipients before being compressed into tablets and subsequently film coated.
  • the tablets deliver approximately 90% of the active ingredient minocycline hydrochloride as free base over a 4-hour period and are suitable for use in the once-daily treatment of acne vulgaris.
  • a batch of 90 mg minocycline hydrochloride extended release tablets (4-hour formulation) is prepared.
  • the tablets include 90 mg (minocycline free base equivalent) of the active ingredient minocycline hydrochloride, 108 mg of the matrix- forming polymer Methocel E50 Premium LV (hydroxypropyl methylcellulose), 152 mg intragranular of the diluent Fast Flo (lactose monohydrate), 41.0 mg extragranular of the diluent Fast Flo (lactose monohydrate), 3.0 mg of silicon oxide and 6.0 mg of the lubricant magnesium stearate [0206] Tablet formation includes high shear granulation followed by wet milling and fluid bed drying.
  • the quantity of water used to achieve the wet granulation end point is 34% w/w of the starting materials (dry powders). Purified water is removed during drying and therefore is not present in the final tablet.
  • the spray rate at which the granulating liquid is delivered is 5,000 g/minute.
  • the formulation is then dry milled and blended with extragranular excipients before being compressed into tablets and subsequently film coated.
  • the tablets deliver approximately 90% of the active ingredient minocycline hydrochloride as free base over a 4-hour period and are suitable for use in the once-daily treatment of acne vulgaris.
  • a batch of 135 mg minocycline hydrochloride extended release tablets (4-hour formulation) is prepared.
  • the tablets include 135 mg (minocycline free base equivalent) of the active ingredient minocycline hydrochloride, 94 mg of the matrix- forming polymer Methocel E50 Premium LV (hydroxypropyl methylcellulose), 121 mg intragranular of the diluent Fast Flo (lactose monohydrate), 41.0 mg extragranular of the diluent Fast Flo (lactose monohydrate), 3.0 mg of silicon oxide and 6.0 mg of the lubricant magnesium stearate
  • Tablet formation includes high shear granulation followed by wet milling and fluid bed drying.
  • the quantity of water used to achieve the wet granulation end point is 34% w/w of the starting materials (dry powders). Purified water is removed during drying and therefore is not present in the final tablet.
  • the spray rate at which the granulating liquid is delivered is 5,000 g/minute.
  • the formulation is then dry milled and blended, with extragranular excipients before being compressed into tablets and subsequently film coated.
  • the tablets deliver approximately 90% of the active ingredient minocycline hydrochloride as free base over a 4-hour period and are suitable for use in the once-daily treatment of acne vulgaris.
  • a batch of 150 mg minocycline hydrochloride extended release tablets (4-hour formulation) is prepared.
  • the tablets include 150 mg (minocycline free base equivalent) of the active ingredient minocycline hydrochloride, 94 mg of the matrix- forming polymer Methocel E50 Premium LV (hydroxypropyl methylcellulose), 138 mg of the diluent Fast Flo (lactose monohydrate), 3.0 mg of silicon oxide and 6.0 mg of the lubricant magnesium stearate
  • Tablet formation includes high shear granulation followed by wet milling and fluid bed drying.
  • the quantity of water used to achieve the wet granulation end point is 34% w/w of the starting materials (dry powders). Purified water is removed during drying and therefore is not present in the final tablet.
  • the spray rate at which the granulating liquid is delivered is 5,000 g/minute.
  • the formulation is then dry milled and blended with extragranular excipients before being compressed into tablets and subsequently film coated.
  • the tablets deliver approximately 90% of the active ingredient minocycline hydrochloride as free base over a 4-hour period and are suitable for use in the once-daily treatment of acne vulgaris.
  • a batch of 150 mg minocycline hydrochloride extended release tablets is prepared.
  • the tablets include 36.41% of the active ingredient minocycline hydrochloride, 28.16% of the matrix-forming polymer Methocel E50 Premium LV (hydroxypropyl methylcellulose), 20.39% intragranular of the diluent Fast Flo (lactose monohydrate), 10.68% extragranular of the diluent Fast Flo (lactose monohydrate), 0.97% of the glidants Cab-O-Sil (colloidal silicon oxide), 0.49% of the lubricant magnesium stearate, and 2.91% of the non-functional film coat OpaDry II.
  • a batch of 150 mg minocycline hydrochloride extended release tablets (4-hour formulation) is prepared.
  • the tablets include 36.41% of the active ingredient minocycline hydrochloride, 22.82% of the matrix-forming polymer Methocel E50 Premium LV (hydroxypropyl methylcellulose), 25.73% intragranular of the diluent Fast Flo (lactose monohydrate), 10.68% extragranular of the diluent Fast Flo (lactose monohydrate), 0.97% of the glidants Cab-O-Sil (colloidal silicon oxide), 0.49% of the lubricant magnesium stearate, and 2.91% of the non-functional film coat OpaDry II.
  • the tablets are formed using appropriate tablet-making methods. Purified water is removed during drying and therefore is not present in the. final tablet.
  • a batch of 200 mg minocycline hydrochloride extended release tablet (4-hour formulation) is prepared.
  • the tablets include 48.54% of the active ingredient minocycline hydrochloride, 22.82% of the matrix-forming polymer Methocel E50 Premium LV (hydroxypropyl methylcellulose), 13.59% intragranular of the diluent Fast Flo (lactose monohydrate), 10.19% extragranular of the diluent Fast Flo (lactose monohydrate), 0.97% of the glidants Cab-O-Sil (colloidal silicon oxide), 0.97% of the lubricant magnesium stearate, and 2.91% of the non-functional film coat Opa Dry II.
  • the tablets are formed using appropriate tablet-making methods. Purified water is removed during drying and therefore is not present in the final tablets.
  • a batch of 180 mg minocycline hydrochloride extended release tablets (4-hour formulation) is prepared.
  • the tablets include 43.69% of the active ingredient minocycline hydrochloride, 22.82% of the matrix-forming polymer Methocel E50 Premium LV (hydroxypropyl methylcellulose), 18.45% intragranular of the diluent Fast Flo (lactose monohydrate), 10.19% extragranular of the diluent Fast Flo (lactose monohydrate), 0.97% of the glidants Cab-O-Sil (colloidal silicon oxide), 0.97% of the lubricant magnesium stearate, and 2.91% of the non-functional film coat Opa Dry II.
  • the tablets are formed using appropriate tablet-making methods. Purified water is removed during drying and therefore is not present in the final tablet.
  • a batch of 135 mg minocycline hydrochloride extended release tablets (4-hour formulation) is prepared.
  • the tablets include 32.77% of the active ingredient minocycline hydrochloride, 22.82% of the matrix-forming polymer Methocel E50 Premium LV (hydroxypropyl methylcellulose), 13.59% intragranular of the diluent Fast Flo (lactose monohydrate), 22.82% extragranular of the diluent Fast Flo (lactose monohydrate), 0.73% of the glidants Cab-O-Sil (colloidal silicon oxide), 0.73% of the lubricant magnesium stearate, and 2.91% of the non-functional film coat Opa Dry II.
  • the tablets are formed using appropriate tablet-making methods. Purified water is removed during drying and therefore is not present in the final tablet.
  • a batch of 90 mg minocycline hydrochloride extended release tablets (4-hour formulation) are prepared.
  • the tablets include 32.77% of the active ingredient minocycline hydrochloride, 26.21% of the matrix- forming polymer Methocel E50 Premium LV (hydroxypropyl methylcellulose), 36.89% intragranular of the diluent Fast Flo (lactose monohydrate), 10.68% extragranular of the diluent Fast Flo (lactose monohydrate), 0.73% of the glidants Cab-O-Sil (colloidal silicon oxide), 0.73% of the lubricant magnesium stearate, and 2.91% of the non-functional film coat Opa Dry II.
  • the tablets are formed using appropriate tablet-making methods. Purified water is removed during drying and therefore is not present in the final tablet.
  • a batch of 45 mg minocycline hydrochloride extended release tablets (4-hour formulation) is prepared.
  • the tablets include 10.92% of the active ingredient minocycline hydrochloride, 26.21% of the matrix-forming polymer Methocel E50 Premium LV (hydroxypropyl methylcellulose), 47.28% intragranular of the diluent Fast Flo (lactose monohydrate), 10.92% extragranular of the diluent Fast Flo (lactose monohydrate), 0.73% of the glidants Cab-O-Sil (colloidal silicon oxide), 0.49% of the lubricant magnesium stearate, and 2.91% of the non-functional film coat Opa Dry II.
  • the tablets are formed using appropriate tablet-making methods. Purified water is removed during drying and therefore is not present in the final tablet.
  • the dissolution properties of the tablets are measured under various storage conditions as shown below:
  • a purpose of this single-dose, four-way crossover, dose proportionality study is to determine the pharmacokinetics of minocycline after giving increasing doses to normal healthy subjects under fasted conditions. These data are evaluated statistically to determine the dose proportionality of the different strengths of the controlled-release (CR) minocycline unit dosage formulations and to compare the minocycline bioavailability of the these controlled-release formulations to that of commercially available immediate- release MINOCIN® capsules.
  • CR controlled-release
  • the study is performed as a single-dose four-way crossover, dose proportionality study using increasing doses of minocycline with an adequate washout period (7 days) between subsequent periods of the study.
  • An equal number of subjects are randomly assigned to each of four dosing sequences (ABCD, BCDA, CDAB, DABC) to receive the study treatments, 2 X 45 mg caplets (A), 1 X 90 mg caplet (B), 1 X 135 mg caplet (C) and 1 X 100 mg MINOCIN® capsule (D).
  • Venous blood samples are collected over a 72-hour period of time post drug administration. Medical care of the volunteers is assured by the presence of a physician for at least 4 hours post dose and the physician is on-call throughout the blood-sampling period. Professional medical personnel are on site during the entire study confinement period. Subjects are confined in the clinical facility for at least 10 hours before dosing and for 24 hours after dosing. Subjects are discharged after the 24-hour blood sample and return as outpatients for the remaining blood samples. Standardized meals are served and no caffeine, alcohol, or grapefruit-containing foods or beverages are allowed to be consumed 24 hours before dosing or throughout study confinement.
  • GCP Good Clinical Practice
  • the study drugs are administered per randomization code together with 240 mL of tepid water and a mouth check is performed.
  • Blood samples (1 x 7 mL) are drawn from an antecubital or forearm vein into sodium heparin vacuum tubes and are obtained according to Table 2.
  • Plasma samples are obtained for the pharmacokinetic samples. Blood samples are centrifuged until separation of red cells from plasma occurrs. Plasma is transferred into a polypropylene tube and placed into a freezer within one hour of sample collection. Plasma samples are stored at a temperature at or below -20° ⁇ 5° C until transferred to the analytical laboratory for analysis.
  • sample storage freezer temperature rises beyond -15° C for short periods of time during the study. These deviations are caused by frequent placement of samples into the freezer or by sample preparation for shipment. None of the frozen samples thaws during these times.
  • Samples are analyzed for the content of minocycline by a fully- validated HPLC/UV assay.
  • Calibration standards and controls are prepared by spiking human, interference-free, plasma with the minocycline HCl reference material. Calibration standards are prepared to contain minocycline concentrations of 25.0, 50.0, 100, 250, 500, 750, 1000, 2500, and 5000 ng/mL. Quality control samples are prepared to contain concentrations of 40.0 ng/mL, 800 ng/mL, and 4000 ng/mL.
  • the assay method involvs protein precipitation with perchloric acid followed by column switching and chromatographic separation of minocycline and the internal standard, demeclocycline, on an RP 18 column. Detection and peak quantification are based on UV absorbance at 351 nm. Samples are analyzed in runs that consist of a control sample, control blanks with and without internal standard one set of calibration standards, two sets of quality control samples, and typically the samples from two subjects, both periods.
  • the peak height response ratio (analyte-to-internal) for each calibration standard is plotted as a function of concentration.
  • a linear regression is calculated by the method of weighted least-squares using the inverse of concentration (1/x) as a weighting factor.
  • a calculated concentration is determined for each standard quality control sample and subject sample from the calibration line.
  • the analyte concentrations in samples and controls are estimated from the calibration line by use of the equation:
  • the coefficient of variation for the calculated concentrations for the quality control samples ranges from 4.9% to 7.9%.
  • the apparent bias (% deviation of the mean from known concentration) for the calculated concentrations for the quality control samples ranges from -5.7% to +2.0%.
  • the coefficient of variation for the back-calculated concentrations of the calibration standards ranges from 2.0% to 6.1%.
  • the bias for the back-calculated concentrations of the calibration standards ranges from —3.2% to +2.4%.
  • the lower limit of quantification of the assay is established at 25.0 ng/mL. Any sample whose calculated concentration is below this limit is reported as less than this lower limit.
  • the assay is linear over the concentration range of 25.0 ng/mL to 5000 ng/mL.
  • Pharmacokinetic parameters are calculated using the times of sample collection corrected for any reported deviations in collection time. Graphical presentations of individual subject results also use the corrected times of sample collection. Graphical presentations of mean results use the scheduled times of sample collection.
  • Peak concentration (C max ) is the observed maximum value during the collection period of 0 to 72 hours.
  • the time to peak concentration (T max ) is the time at which Cmax is observed (or first observed, if the peak value occurred at more than one time).
  • the apparent first-order elimination rate constant (Ke) is estimated as the negative value of the slope of the regression line for the terminal log-linear concentration-time values. A minimum of three terminal values are used to obtain an estimate. The values included in the regression analyses are determined by examination of the individual subject plots of natural logarithm of concentration against time. Elimination half-life (TYz) is estimated as log e (2)/Ke.
  • the statistical model contains main effects of sequence, subject nested within sequence, treatment and period.
  • F-ratios for testing main effects are constructed using the mean square term for the effect as the numerator and the mean square error term from the ANOVA as the. denominator.
  • Pair-wise comparisons of interest are those between each of the three controlled-release compositions comprising minocycline hydrochloride at various strengths (45 mg, 90 mg and 135 mg) and MINOCIN® capsules for assessing relative bioavailability.
  • Of interest for evaluating the dose-proportionality of the three controlled- release compositions are the three pair-wise comparisons 45 mg vs. 90 mg, 45 mg vs. 135 mg and 90 mg vs. 135 mg.
  • the intra-subject coefficient of variation is estimated from the mean square error term (MSE) of the In-transformed (loge) results as:
  • X T , X R are the Test and Reference least-squares means in each comparison of interest, respectively.
  • Se is the standard error of the estimated difference between means from the SAS estimate statement.
  • intervals are computed for the "true” mean treatment differences, expressed as a percent of the reference mean for the comparison, and true geometric mean ratios (from logarithmic transformation).
  • Tables 7-12 show pair- wise comparisons of the pharmacokinetic variables and show 90% confidence intervals on the ratios of the variables.
  • Ratio calculated as the 45-mg least-squares mean divided by the 135-mg least-squares mean. None of the comparisons are detected as statistically significant by ANOVA ( ⁇ 0.05).
  • Ratio calculated as the 90-mg least-squares mean divided by the 135-mg least-squares mean. None of the comparisons are detected as statistically significant by ANOVA ( ⁇ 0.05).
  • FIGs 1-2 show the time dependence of the plasma concentrations.
  • Each of the three controlled-release caplets produces statistically significantly lower areas and C max than does the MINOCIN® capsule. None of the confidence intervals on the geometric mean C max ratios of the controlled-release compositions to the MINOCIN® capsule are within the bioequivalence acceptable region of 0.80 to 1.25.
  • the mean time of peak (T ma ⁇ ) of the controlled-release compositions is approximately 1 hour later than the mean for the MINOCIN® capsule, a difference which is detected as statistically significant (p ⁇ 0.05).
  • a purpose of this study is to determine the relative bioavailability of minocycline from controlled-release 135 mg minocycline HCl caplets after administration of single doses to normal healthy subjects under fed and fasted conditions. These data are evaluated statistically to determine if the product demonstrates a food effect.
  • volunteers Before entering the study, volunteers undergo a physical examination including clinical laboratory screening and electrocardiogram, to verify inclusion criteria. Subjects are at least 18 years of age, have a body weight within 15% of the appropriate range as defined in the 1983 Metropolitan Life Insurance tables, and weigh at least 110 pounds. A total of 24 non-smoking subjects (12 men and 12 women) are included in this study, of which all 24 finish the study according to the protocol.
  • the study is performed as a single-dose (one 135 mg CR caplet), two- way crossover study with an adequate washout period (7 days) between the two periods of the study and with an equal number of subjects randomly assigned to receive the study test drug in a fasted state (Treatment A) and after receiving the FDA high-fat Breakfast (Treatment B).
  • Venous blood samples are collected over a 72-hour period of time post drug administration. Medical care of the volunteers is assured by the presence of a physician for at least 4 hours post dose and the physician is on-call throughout the blood-sampling period. Professional medical personnel are on site during the entire study confinement period. Subjects are confined in the clinical facility for at least 10 hours before dosing and for 24 hours after dosing. Subjects are discharged after the 24-hour blood sample and return as outpatients for the remaining blood samples. Standardized meals are served and no caffeine, alcohol, or grapefruit-containing foods or beverages are allowed to be consumed 24 hours before dosing or throughout study confinement.
  • GCP Good Clinical Practice
  • the study drugs are administered per randomization code together with 240 ml of tepid water and a mouth check is performed.
  • Plasma samples are centrifuged until separation of red cells from plasma occurrs. Plasma is transferred into a polypropylene tube and placed into a freezer within one hour of sample collection. Plasma samples are stored at a temperature at or below -20 ⁇ 5 0 C until transferred to the analytical laboratory for analysis.
  • Ratio calculated as the Fed least-squares mean divided by the Fasted least-squares mean. None of the comparisons are detected as statistically significant by ANOVA ( ⁇ 0.05).
  • a purpose of this study is to determine the bioequivalence of Minocycline HCl formulations after administration of single doses to normal healthy males under fed and fasting conditions. These data are evaluated statistically.
  • volunteers Before entering the study, volunteers a physical examination, including clinical laboratory screening and electrocardiogram, to verify inclusion criteria. Prior to study start, volunteers are informed about the aim, design, risks and preparations of the study in writing, and are offered the opportunity to ask any questions. Subjects declare their consent and the voluntary nature of participation by signing an informed consent form. A total of 24 non-smoking male subjects are included in this study, of which 24 finish the study according to the protocol. The mean age is 29.3 years with a range of 19 to 45. The mean height is 70.8 inches and the mean weight is 182.6 pounds.
  • the study is performed as a single-dose three-way (2 X 75 mg capsules or 1 X 150 mg tablet), crossover bioequivalence study with an adequate washout period (7 days) between the three periods of the study.
  • Venous blood samples are collected over a 48-hour period of time post drug administration. Medical care of the volunteers is assured by the presence of a physician for at least 4 hours post dose and the physician is on-call throughout the blood-sampling period. Professional medical personnel are on site during the entire study confinement period. Subjects are confined in the clinical facility for at least 10 hours before dosing and for 24 hours after dosing. Subjects are discharged after the 24-hour blood sample and returned for outpatient draws at 36, and 48 hours post administration. Standardized meals are served and no caffeine, alcohol, or grapefruit-containing foods or beverages are allowed to be consumed 24 hours before dosing or throughout study confinement.
  • GCP Good Clinical Practice
  • Treatments A and B provide two prototype versions (Prototype 1 and Prototype 2) of controlled-release minocycline tablets (150 mg).
  • Treatment C provides DYNACIN® immediate-release minocycline tablets (2 X 75 mg).
  • the study is performed in a comparative, single dose, three-treatment (Test Fed, Reference Fasted & Test Fasted), three-period, crossover study with an adequate washout period (7 days) between the three phases of the study. Subjects numbered 1-12 received Prototype 1 tablets while subjects 13-24 received Prototype 2 tablets.
  • the study drugs are administered per randomization code together with 240 ml of tepid water and a mouth check is performed.
  • Plasma samples are centrifuged until separation of red cells from plasma occurs. Plasma is transferred split into a polypropylene tube and placed into a freezer within one hour of sample collection. Plasma samples are stored at a temperature at or below -20° ⁇ 5° C until transferred to the analytical laboratory for analysis.
  • Pharmacokinetic parameters are calculated using the actual rather than the scheduled times of sample collection. Graphical presentations of individual subject results also use the exact times of sample collection. Graphical presentations of mean results use the scheduled times of sample collection.
  • Peak concentration (C max ) is the observed maximum value during the collection period of 0 to 48 hours.
  • the time to peak concentration (T max ) is the time at which C max is observed (or first observed, if the peak value occurs at more than one time).
  • the apparent first-order elimination rate constant (Ke) is estimated as the negative value of the slope of the regression line for the terminal log-linear concentration-time values. A minimum of six terminal values is used to obtain an estimate. The values included in the regression analyses are determined by examination of the individual subject plots of natural logarithm of concentration against time. Elimination half-life (T' ⁇ ) is estimated as log e (2)/Ke.
  • the statistical model contains main effects of sequence, subject nested within sequence treatment, and period.
  • F-ratios for testing main effects are constructed using the mean square error term for the effect as the numerator and the mean square error term from the ANOVA as the denominator.
  • the F-ratio to test for sequence effects is constructed using the type III mean square term for sequence as the numerator and type III mean square for subjects nested within sequence as the denominator.
  • Pairwise comparisons of interest are controlled-release minocycline 150 mg tablets (Test Fasted) vs. DYNACIN® 75 mg capsules (Reference Fasted) for determining bioequivalence and Test Fed vs. Test Fasted for assessing the effects of food on the generic product. These comparisons are conducted on the 12 subjects (subjects 1 - 12) who are randomized with Prototype 1 (Test) of minocycline and also on the 12 subjects (subjects 13 - 24) who are randomized with Prototype 2 (Test).
  • X ⁇ , X R are the Test-Fasted and Reference-Fasted (Test-Fed and Test- Fasted for food- effect comparison) least-squares means, respectively.
  • Se is the standard error of the estimated difference between means from the SAS estimate statement.
  • intervals are computed for the "true” mean treatment differences, expressed as a percent of the reference mean, and true geometric mean ratios (from logarithmic transformation).
  • Prototype 1 has a statistically significantly (p ⁇ 0.05) lower extent of absorption than the DYNACIN® product.
  • the mean test-to-reference area ratios are less than 0.78 and mean peak concentration ratio is 0.73.
  • the time to peak for Prototype 1 is statistically significantly longer than that for the Reference product (3.58 hours compared to 2.25 hours).
  • Food increases both the area and C ma ⁇ for Prototype 1 and slightly delays the time to peak. However, the differences between dosing Prototype 1 with or without food are not detected as statistically significant (p ⁇ 0.05).
  • Prototype 2 has a statistically significantly (p ⁇ 0.05) lower extent of absorption than the DYNACIN® product.
  • the mean test-to-reference area ratios are less than 0.72 and peak concentration ratio is 0.63.
  • the time to peak for Prototype 2 is statistically significantly longer than that for the Reference product (3.58 hours compared to 2.25 hours).
  • Food increases the extent (area ratios greater than 1.14) and delays the rate (T max ratio 1.23) of absorption from Prototype 2. The differences between the fed and fasted results are statistically significant (p ⁇ 0.05).
  • a purpose of this study is to determine the pharmacokinetics of two minocycline formulations after administration of multiple doses to normal, healthy subjects. These data are evaluated statistically to determine the relative bioavailability at steady state between Controlled-Release (CR) Minocycline HCl Caplets and commercially available MINOCIN® (minocycline HCl) Capsules.
  • CR Controlled-Release
  • MINOCIN® Minocycline HCl
  • the study is a randomized 2-way crossover study in 28 healthy males and females to evaluate the pharmacokinetics of minocycline during 6 days of once daily treatment with Controlled-Release Minocycline HCl Caplets, 135 mg (Test product).
  • the reference product is commercially available MINOCIN® (minocycline HCl) Capsules, 100 mg (Lederle) administered every 12 hours for 6 days. Each dose is taken at approximately the same time each day with or without food, except for the morning dose on Day 6 of each period which is taken in a fasting state.
  • Subjects self-administer the medication on an outpatient basis for the afternoon capsule doses on Day 1 and Day 4, and for all doses on Days 2 and 3. On all other days subjects are dosed at the clinic in conjunction with other study-related activities.
  • Each subject receives treatment with either the Test or the Reference products in each of the 2 study periods, in randomized sequence.
  • the first dose of the second period is administered 20 days after the first dose of Period 1.
  • Blood samples for minocycline analysis are drawn pre-dose on Day 1 , Day 4, and Day 5 of each period. Sampling on Day 6 is pre-dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, 12.5, 13.0, 13.5, 14.0, 15.0, 16.0, 17.0, 18.0 and 20.0 hours post-dose.
  • subjects are discharged from the research facility after a 24-hour post-dose sample is obtained.
  • Plasma concentrations are determined by a validated and sensitive bioanalytical method. The analytical data are utilized to compare the formulations in regard to plasma concentrations at each collection, Cmax, Tmax, and AUC for each dose.
  • Subjects are recruited from a population of healthy male and female adults. Good physical health is determined by medical history, physical examination, including electrocardiogram (ECG), and clinical laboratory tests, conducted within 2 weeks of study dosing.
  • ECG electrocardiogram
  • Subjects are assigned upon enrollment to a sequence of treatments according to a predetermined randomization schedule.
  • the study drugs are administered by trained clinical personnel on the mornings of Day 1, Day 4, Day 5, and Day 6, and on the evenings of Day 5 and Day 6. All other doses are self-administered by the subjects at home.
  • the drug is administered orally with 240 mL of tepid water.
  • Subjects are confined to the clinical site in each period from the evening before Day 1 until after the Day 1 morning dose, and from the evening of Day 5 until 24 hours after the morning dose of Day 6.
  • Each subject is counted only once per treatment in the body system's total using the most severe adverse event. Only the greatest severity for a subject is counted in each adverse event's total. Subjects may be counted more than once per treatment in the total number of subjects with AEs.
  • Plasma specimens are collected for minocycline analysis pre-dose on Day 1, Day 4, and Day 5 of each period. Sampling on Day 6 is pre-dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, 12.5, 13.0, 13.5, 14.0, 15.0, 16.0, 17.0, 18.0 and 20.0 hours post- dose. On Day 7, subjects are discharged from the research facility after a 24-hour post-dose sample is obtained. Subjects return to the clinic each morning on Days 8 and 9 (at 48 and 72 hours post-dose, respectively) for additional sampling.
  • Each of these parameters are analyzed using an analysis of variance mode! with terms for subject, subject within sequence, period, and treatment.
  • the sequence effect is tested against the variance for subjects within sequence; all other effects are tested against the residual variance of the model.
  • Least squares means for each treatment, and the difference between the treatment least squares means are calculated.
  • AUC(o-24), C max , and C m j n the parameters are also analyzed after log transformation. Ninety percent 2-sided confidence intervals are constructed on the treatment differences of the untransformed parameters, and on the ratio of geometric means for AUC( O-24 ), C max , and C m j n .
  • the plasma minocycline concentrations are plotted versus sampling point for each individual subject and period as well as for the means by treatment.
  • the achievement of steady state is investigated by performing an analysis of variance with effects of period, day, and period-day interaction for each treatment separately, using only the pre-dose minocycline concentrations on Days 4, 5, 6, and 7.
  • the least squares mean AUC(o-24) at Day 6 for the Test product is 33.32 ⁇ g ⁇ hr/mL, and the least squares mean Cmax at Day 6 is 2.63 ⁇ g/mL. These are to be compared with the respective dose-adjusted values of 46.35 ⁇ g ⁇ hr/mL and 2.92 ⁇ g/mL for the Reference product.
  • the ratio of geometric means is 72% for AUC(o-24), 90% for C max , and 49% for C mm .
  • CI conf ⁇ dence interval
  • P values are from analysis of variance with effects of treatment.
  • the mean AUC(o-24) at Day 6 for the Test product is 28.4 ⁇ gxhr/mL, and the least squares mean C ma ⁇ at Day 6 is 2.20 ⁇ g/mL.
  • the respective dose- adjusted values for the Reference product are 54.1 ⁇ gxhr/mL and 3.45 ⁇ g/mL.
  • the ratio of geometric means is 52% for AUC ( o- 2 4), 63% for C max> and 34% for C m ⁇ n .
  • the value of T ma ⁇ for the Test product is 3.62 hours compared to 1.96 hours for the Reference product.
  • the difference between treatments is statistically significant for all PK parameters in Period 1, showing the Test product to be less bioavailable and more slowly absorbed than the Reference product.
  • Mean plasma minocycline concentrations are plotted versus time in Figures 9-10. The dose-adjusted curves show that the Reference product is less bioavailable, and the Test product more bioavailable, in Period 2 compared to Period 1.
  • the mean AUC(O -24) at Day 6 for the Test product is 38.6 ⁇ gxhr/mL, and the least squares mean C max at Day 6 is 3.07 ⁇ g/mL.
  • the respective dose- adjusted values for the Reference product are 38.3 ⁇ g ⁇ hr/mL and 2.38 ⁇ g/mL.
  • the ratio of geometric means is 99% for AUC( O-24 ), 128% for C max , and 70% for C min .
  • the value of T max for the Test product is 3.07 hours compared to 4.04 hours for the Reference product.
  • the difference between treatments is statistically significant only for C max and PTF in Period 2, with the Reference product showing a higher C max than the Test product.
  • the Period 2 results are qualitatively different from the Period 1 results in this study.
  • the least squares mean AUC ( o- 24 > at Day 6 for the Test product is 33.32 ⁇ g*hr/mL
  • the least squares mean C max at Day 6 is 2.63 ⁇ g/mL.
  • Period 1 the value of T max for the Test product is 3.62 hours compared to 1.96 hours for the Reference product. The difference between treatments is statistically significant for all PK parameters in Period 1, showing the Test product to be less bioavailable and more slowly absorbed than the Reference product.
  • Period 2 the mean AUC(o-24> at Day 6 for the Test product is 38.6 ⁇ gxhr/mL, and the least squares mean C max at Day 6 is 3.07 ⁇ g/mL.
  • the respective dose-adjusted values for the Reference product are 38.3 ⁇ g ⁇ hr/mL and 2.38 ⁇ g/mL.
  • the ratio of geometric means is 99% for AUC( O-24 ), 128% for C max , and 70% for C mm .
  • Period 2 the value of T ma ⁇ for the Test product is 3.07 hours compared to 4.04 hours for the Reference product. The difference between treatments is statistically significant only for C max and PTF in Period 2, with the Reference product showing a higher C max than the Test product. Thus, the Period 2 results are qualitatively different from the Period 1 results in this study. In Period 2, the Reference product is found to be less bioavailable than in Period 1, and the Test product is found to be slightly more bioavailable in Period 2 than in Period 1.
  • Example 16 A multi-center, 12-week, randomized, double-blinded, placebo-controlled, dose-ranging study examines the effects of controlled-release minocycline in the treatment of moderate to severe facial acne vulgaris.
  • the study includes 250 subjects from up to 18 study centers in the United States. Subjects are between 12 to 30 years old at the time of enrollment, weigh between 39.1 kg and 102.3 kg (86-225 Ib) and are diagnosed with moderate to severe facial acne vulgaris. They are required to have at least 20 and no more than 100 inflammatory facial lesions and less than 5 facial nodules or cysts. Females of childbearing potential have a negative urine pregnancy test result (25 ⁇ g/mL sensitivity), are practicing contraception, and are willing to continue on the contraceptive for the duration of the study.
  • Subjects or a parent/guardian provide informed consent, The main criteria for exclusion are known sensitivity to minocycline or any of the components; females who are pregnant; males with facial hair; use of supplements containing aluminum, calcium, iron, or magnesium, or vitamin A; or a prior history of complicating illnesses or medications.
  • Subjects randomly are assigned 1 of 3 active treatments (1 , 2, or 3 mg/kg daily) or placebo according to the dosing schedule in Table 33.
  • the study drug is administered once daily in the morning throughout the 84-day study. Randomization is stratified based on each subject's weight to ensure that all treatment groups contain equal numbers of subjects in each weight category.
  • the primary efficacy endpoint is the reduction in the number and percentage of inflammatory lesions (papules, pustules, nodules, cysts) from baseline (day 1) to day 84.
  • Secondary efficacy endpoints include the reduction in inflammatory lesions at interim visits (days 28 and 56), changes in noninflammatory (open and closed comedones) and total (inflammatory and noninflammatory) lesion counts, and changes in the Investigator's Static Global Evaluation of acne severity.
  • Safety assessments are based on the incidence of adverse drug events (ADEs) reported at each post-baseline visit (days 28, 54, 84) and at telephone contacts on days 7 and 91 as well as ADEs recorded in each subject's daily diary during the first 5 days of treatment. Complete blood counts and serum chemistries are monitored at baseline and at the end of the study for evidence of clinically significant changes.
  • ADEs adverse drug events
  • Statistical analyses are performed using SAS® PC Version 6.12. Subject demographics are summarized using descriptive statistics. Interval data are compared between treatment groups using 2-way analysis of variance (treatment and center) with interaction. Categorical data are compared between groups using Cochran-Mantel-Haenszel statistics, adjusted for center.
  • the primary and secondary efficacy analyses are performed in the intent- to-treat (ITT) population, which is defined as all randomized subjects who received the study drug. Last observation carried forward is employed. The absolute lesion count, the change from baseline, and the percentage change from baseline are analyzed using the 2-way analysis of variance (treatment and center) with interaction. The dichotomized Investigator's Static Global Evaluation defines a treatment success as a score of 3 (clear) or 4 (almost clear), and treatment groups are compared using Cochran-Mantel-Haenszel statistics. A Cochran- Mantel-Haenszel analysis also is performed to compare the proportion of subjects who experience an improvement of 2 or more points from baseline to day 84.
  • ITT intent- to-treat
  • the decrease in the number of lesions from baseline to day 84 ranges from -18.3 in the control led-release- minocycline 3-mg/kg treatment group to -23.7 in the 2-mg/kg treatment group compared with -7.2 in the placebo group.
  • Percentage change from baseline to day 84 ranges from -46.6% in the controlled-release-minocycline 3-mg/kg treatment group to -56.8% in the 1-mg/kg treatment group compared with -39.4% in the placebo group.
  • No dose-dependent effect is observed; the percentage decrease in the number of inflammatory lesions in the controlled- release-minocycline 1-mg/kg group is equal to or greater than that observed with 2 mg/kg or 3 mg/kg.
  • Baseline noninflammatory lesion counts ranges from 36.9 in the controlled-release minocycline 3-mg/kg treatment group to 44.6 in the 2-mg/kg treatment group, and total (inflammatory and noninflammatory) lesion counts ranges from 76.0 in the 3-mg/kg treatment group to 91.6 in the 2-mg/kg treatment group.
  • dose groups or from placebo There are no statistically significant differences among the dose groups or from placebo for both noninflammatory and total lesion counts.
  • the number of noninflammatory and total lesions decreases over the treatment period in all 3 dose groups, though the changes are smaller. There are no significant dose-related effects.
  • Treatment-Related Treatment-Emergent Adverse Drug Events Occurring in ⁇ 5% of Subjects (Intent-to-Treat Population)*
  • Intent-to-treat population is ⁇ 5% of subjects in any treatment group.
  • Acute vestibular adverse events including nausea, vomiting, dizziness, vertigo, and ringing in the ears, are more commonly reported during the first 5 days of treatment.
  • AVAEs Acute vestibular adverse events
  • the incidence for the 1-mg/kg dose group is less than half the incidence for the higher-dose groups, and overall differences among the groups are not statistically significant.
  • Lower incidences are seen at each subsequent reporting period throughout the 84-day study; additionally, during this time, differences among the dose and placebo groups at any time point during treatment are not statistically different.
  • AVAE includes >1 of the following symptoms: nausea, vomiting, dizziness, vertigo, and ringing in the ears.
  • Severe ADEs are reported by 1 subject (2%) in the control led-release- minocycline 1-mg/kg treatment group and 2 subjects (3%) each in the 2- and 3-mgfkg treatment groups.
  • One subject (2%) in the placebo group also reports a severe ADE.
  • the severe ADEs include one report of severe headache in each of the 3 dose groups, one report of severe urticaria and severe pruritus in the 2-mg/kg treatment group, one report of severe vomiting in the 3-mg/kg treatment group, and one report each of severe fatigue and severe pruritus in the placebo group.
  • a dose-ranging phase 2 study is undertaken to determine the optimal dosing regimen of the new controlled-release-minocycline formulation.
  • the study compares once-daily doses of controlled-release minocycline 1, 2, and 3 mg/kg with placebo in a 12- week treatment protocol. (See Stewart et al., Cutis. 2006; 78(suppl 4): 11-20, which is herein incorporated by reference in its entirety.)
  • the phase 2 study is a multicenter, 12-week, randomized, double-blinded, placebo-controlled dose-ranging study.
  • the 2 phase 3 studies which are identical in design, are independent, 12-week, randomized, double-blinded, placebo-controlled studies of controlled-release-minocycline tablets given in a 1 -mg/kg daily-dosing regimen. Study drug is administered once daily in the morning from study days 1 to 84 in the phase 2 and phase 3 studies.
  • a total of 59 subjects (male and female) aged 12 to 30 years with moderate to severe facial acne vulgaris are given controlled-release minocycline 1 mg/kg in the phase 2 study.
  • subjects are required to have at least 20 and no more than 100 inflammatory facial lesions and less than 5 facial nodules or cysts.
  • This group of subjects plus the 55 subjects given placebo in the phase 2 study are included in the pooled safety and efficacy analysis described here.
  • Nine hundred twenty-four subjects with moderate to severe facial acne vulgaris are enrolled in the two phase 3 studies, which are conducted at 30 treatment centers in the United States.
  • Subjects include males and females aged at least 12 years at the time of enrollment with moderate to severe facial acne.
  • subjects are required to have at least 25 and no more than 75 inflammatory facial lesions, no more than 2 facial nodules or cysts, and an Evaluator's Global Severity Assessment (EGSA) of moderate or severe facial acne (Table 39).
  • EGSA Global Severity Assessment
  • Exclusion criteria for the phase 2 and phase 3 studies are similar and include history of AVAEs such as vertigo, lightheadedness, nausea, or vomiting within 30 days prior to enrollment; history or current risk of hepatic dysfunction; history or current risk of renal dysfunction, systemic lupus erythematosus, or-in the phase 3 study only-a positive test result for antinuclear antibodies at screening; history of alcohol or drug dependency; baseline safety laboratory values outside of the reference range for liver function tests that are determined to be clinically significant; or use of oral isotretinoin within 6 months, oral antibiotics (eg, tetracyclines, erythromycin) within 4 weeks, systemic corticosteroids within 4 weeks, topical retinoid or retinol-containing products for facial acne within 2 weeks, topical antibiotics for facial acne within 2 weeks, topical corticosteroids applied to the face within 2 weeks, topical benzoyl peroxide for facial acne within 2 weeks, or topical over-the-counter remedies (e.
  • the primary efficacy assessment for the pooled analysis is the inflammatory lesion count conducted by the investigator at each study visit.
  • Primary efficacy assessments for the phase 3 studies include the investigator-conducted inflammatory lesion count at each study visit as well as EGSA.
  • Secondary efficacy assessments include noninflammatory and total (inflammatory and noninflammatory) lesion counts. Descriptive statistics are used to summarize baseline characteristics of subjects in the phase 2 and phase 3 studies. For continuous variables such as age, height, and weight, as well as comparisons among the treatment groups and analysis centers, statistical analyses are conducted using 2-way analysis of variance that includes treatment group and analysis center factors. Treatment groups are compared using the Cochran-Mantel-Haenszel test, stratified by center. Efficacy data for subjects who do not complete the study are imputed from the time of termination through study day 84 using last observation carried forward methodology.
  • the common primary efficacy endpoint for the phase 2 and phase 3 studies is the reduction in inflammatory lesion counts from baseline to day 84, which is analyzed as the change in absolute lesion count as well as the percentage change from baseline.
  • An additional primary efficacy endpoint for the phase 3 studies is EGSA, which is based on inflammatory lesions only and defined as the proportion of subjects who achieve success (score of 0 (clear) or 1 (almost clear)).
  • Secondary efficacy endpoints include reduction from baseline in both noninflammatory and total (inflammatory and noninflammatory) lesion counts at days 28, 56, and 84.
  • a total of 1038 subjects are included in the intent-to-treat populations for the pooled safety and efficacy analyses; 674 are given controlled-release minocycline 1 mg/kg and 364 are given placebo. Approximately 89% of subjects complete the 84-day treatment phase. The most frequent reasons for premature withdrawal in the controlled- release-minocycline group are lost to follow-up (3.3%) and adverse experiences (3.0%); the most frequent reasons for premature withdrawal in the placebo group are lost to follow-up (4.1%) and withdrawal of consent (4.9%).
  • Subject baseline demographic characteristics and the pooled population of the 3 studies are shown in Table 41.
  • the mean age of the pooled population is 19.6 (19.4 years in the controlled-release-minocycline group and 20.1 years in the placebo group).
  • the mean ages of the individual treatment groups in the phase 3 studies are similar to those of the overall population.
  • Subjects in the phase 2 study are, on average, younger than those in the phase 3 studies. More than 60% of the pooled subjects are younger than 18 years. Approximately 57% of subjects in the pooled population are male, 58.0% of the controlled- release-minocycline group is male, and 54.4% of the placebo group is male.
  • phase 3 studies reflects the pooled population; however, in the phase 2 population, the 1 mg/g controlled-release-minocycline treatment group is 64.4% male and the placebo group is 45.5% male. In the pooled population, 73.9% of subjects are white, 10.3% are black, and 12.1 % are Hispanic. A greater percentage of the subjects in the phase 2 study than in the phase 3 studies are white.
  • MP-0104-01 , MP-0104-04 and MP-0104-05 are clinical study numbers.
  • f CRM indicates controlled-release minocycline; PLBO, placebo.
  • the treatment difference (change from baseline) is statistically significant (P ⁇ 0.001) by both parametric and nonparametric techniques with no treatment-by-center effects.
  • the percentage change in lesion counts is 32.0% in the controlled-release-minocycline treatment group versus 22.8% in the placebo group at day 28; 40.8% versus 30, respectively, at day 56; and 45.5% versus 32.4% respectively, at day 84.
  • MP-0104-01 , MP-0104-04 and MP-0104-05 are clinical study numbers.
  • ⁇ CRM indicates controlled-release minocycline; PLBO, placebo; NA, not available.
  • the second primary endpoint in the phase 3 studies is EGSA dichotomized as success or failure based on inflammatory lesions only (Table 43).
  • the proportion of subjects with treatment success increases over the course of the study in both groups; at all time points in both studies, the proportion is greater in the controlled- release-minocycline treatment group compared with the placebo group.
  • the pooled data reflects the results of the individual studies.
  • the proportion of subjects with treatment success increases from 6% at day 28 to 16.6% at day 84 in the controlled-release-minocycline treatment group, and from 0.6% at day 28 to 8.7% at day 84 in the placebo group.
  • MP-0104-04 and MP-0104-05 are clinical study numbers.
  • f CRM indicates controlled-release minocycline; PLBO, placebo.
  • Weight-based dosing results in subjects receiving a range of 0.75 to 1.50 mg/kg of controlled-release minocycline. To further confirm that this dosing strategy of approximately 1 mg/kg daily is correct, a subset analysis of 472 subjects who complete all 84 days of treatment is performed of the mean reduction of inflammatory lesion counts from baseline at 4 dose quartiles. No substantial differences in lesion count reductions are seen in subjects given 0.75 to 0.98 (45.8% reduction), 0.98 to 1.23 (49.6% reduction), 1.23 to 1.37 (48.8% reduction), and 1.37 to 1.50 (45.6% reduction) mg/kg daily.
  • MP-0104-01, MP-0104-04, and MP-0104-05 are clinical study numbers.
  • r CRM indicates controlled-release minocycline; PLBO, placebo. * Pooled data from phase 3 subjects only. 5 Noninferiority analyses include only phase 3 subjects.
  • Total (inflammatory and noninflammatory) lesion count data are presented in Table 45. Mean total tesion counts at baseline are similar between treatment groups in each study and among the 3 studies. In the pooled data, baseline mean total lesion counts are 84.1 in the controlled-release-minocycline treatment group and 83.9 in the placebo group. In all 3 studies, the absolute and percentage changes in the controlled-release-minocycline treatment group are greater compared with the placebo group. These results are reflected in the pooled data. The mean absolute change from baseline at day 84 is 26.8 in the control led-release- minocycline treatment group compared with 19.2 in the placebo group. The percentage change from baseline to day 84 in total lesion count is 32.9% in the control led-release- minocycline treatment group and 22.1 % in the placebo group. The treatment difference is statistically significant (P ⁇ .001).
  • MP-0104-01, MP-0104-04 and MP-0104-05 are clinical study numbers.
  • CRM indicates extended-release minocycline; PLBO, placebo; NA, not available.
  • Table 46 presents the number and percentage of subjects (at least 1% of subjects in the dose groups) with treatment emergent ADEs in the pooled population.
  • the most commonly reported treatment-emergent events in the controlled-release-minocycline treatment group are headache (22.6%), nausea (9.5%), fatigue (9.2%), dizziness (8.8%), diarrhea (5.2%), and pruritus (4.6%).
  • ADEs The incidence of these ADEs is similar in the placebo group (22.8%, 1 1.3%, 6.6%, 4.7%, 5.8%, and 4.4%, for the 6 conditions, respectively). The majority of ADEs are mild in severity. Severe treatment- emergent ADEs are reported by 20 subjects (3%) given controlled-release minocycline and by 7 subjects (2%) given placebo. There are no reports of skin discoloration or hyperpigmentation in any of the phase 2 or phase 3 studies.
  • CRM indicates controlled-release minocycline
  • PLBO placebo. Includes only subjects randomized to CRM 1 mg/kg.
  • ADEs possibly related to vestibular function and these events are analyzed separately because minocycline is known to be associated with AVAEs.
  • AVAEs are reported more frequently during the first 5 days of treatment in the phase 2 and phase 3 studies. Possible AVAEs in the first 5 days of treatment for each study are shown in Table 47. AVAEs are reported with approximately the same frequency (7.9%- 16.4%) in the placebo group as the dose group (9.0%- 10.5%).
  • MP-0104-01, MP-0104-04 and MP-0104-05 are clinical study numbers.
  • CRM indicates extended-release minocycline
  • ADEs that lead to treatment discontinuation: pruritus (7), urticaria (7), rash (3), aggravated acne (1), and fatigue (2).
  • Other ADEs are gastrointestinal tract pain, diarrhea, nausea, headache, arthralgia, facial swelling, dizziness, migraine, insomnia, mood alteration, upper respiratory tract infection, neck pain, hypoesthesia, paresthesia, and dermatitis medicamentosa, ADEs such as urticaria, rash, dermatitis, and pruritus occur in a small number of subjects but account for a disproportionate number of discontinuations.
  • Pruritus occurs with about the same frequency in the dose and placebo groups, while skin eruptions occur slightly more often in the controlled-release-minocycline treatment group. Only one report of urticaria is considered severe, and none of the pruritus reports are severe.
  • One possible explanation for the incidence of pruritus in both groups is that the trials are conducted during the winter months, when skin dryness is exacerbated by central heating and the seasonal low humidity. This explanation may account for some cases of skin eruptions, with the exception of urticaria. For the subjects who discontinue because of urticaria, the discontinuations generally occur within the first 2 to 3 weeks of therapy and resolved after treatment is discontinued.
  • the controlled-release minocycline used in this study is a modified formulation of minocycline with lower C max and T max , lowering the amount and rate of drug crossing the blood- brain barrier into the central nervous system, thus lowering the incidence of AVAEs while maintaining desired minocycline efficacy.
  • These pharmacokinetic studies confirm that the modified formulation of minocycline has the desired pharmacokinetic properties; the subsequent phase 2 dose-finding study demonstrate that about 1 mg/kg is an effective dose, with potential for desired improvement in AVAEs.
  • the placebo-controlled phase 3 studies show that control led-release-minocycline administered daily for 12 weeks at a dose of approximately 1 mg/g is safe and effective in the treatment of inflammatory lesions of acne vulgaris.
  • 31.050 kg of hydroxypropyl methylcellulose Hypromellose Type 2910, Methocel E50 Premium LV
  • de-agglomerated lactose monohydrate #316 Fast-Flo
  • the resulting pre- blend is then wet granulated by spraying 34.212 kg of purified water targeting 5000 g/min addition rate with the chopper and impeller on.
  • the granulation is wet massed using the impeller and chopper.
  • the resulting wet-massed material is wet-sized through a comminutor mill.
  • the resulting wet-massed granulation is then dried in a fluid bed dryer at a inlet temperature of 65 degrees Celsius until a loss on drying (LOD) of 1.5% to 2.5% (target 2.0%).
  • LOD loss on drying
  • the resultant dried granulation is sized through a comminutor mill and collected in a tote.
  • This blend is then passed through a comminutor mill and added to the tote.
  • the material in the tote is then blended. This process is then repeated until all three granulation/blend sublots have been separately manufactured.
  • AU three blends are then charged to a tote and mixed. This produces the final blend used to form the tablet formulation.
  • the final blend tablet formulation is then compressed on a rotary tablet press using caplet shaped tooling (0.2343" x 0.6250) with a target weight of 400 mg.
  • the caplets are then de-dusted and passed through a metal detector.
  • the tablets are then coated in three 1 15 kg sub-lots, to a target weight gain of 14.0 mg/caplet with Opadry II Yellow Coating Solution (18% solids) in a 48" coating pan.

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Abstract

L'invention concerne des formes posologiques orales de la minocycline contenant un support à libération contrôlée, qui sont utiles pour le traitement de l'acné.
PCT/US2007/008086 2007-04-02 2007-04-02 Formes posologiques orales de minocycline pour le traitement de l'acné WO2008121107A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9084802B2 (en) 2010-05-12 2015-07-21 Rempex Pharmaceuticals, Inc. Tetracycline compositions
US9918998B2 (en) 2015-03-23 2018-03-20 BioPharmX, Inc. Pharmaceutical tetracycline composition for dermatological use
US11103517B2 (en) 2015-04-07 2021-08-31 Dr. Reddy's Laboratories Ltd. Pharmaceutical compositions for minocycline

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418565A2 (fr) * 1989-09-21 1991-03-27 American Cyanamid Company Système du type "une fois par jour" pour délivrance pulsée de minocyline
WO2002080932A1 (fr) * 2001-04-05 2002-10-17 Collagenex Pharmaceuticals, Inc. Methodes de traitement de l'acne
US20030199480A1 (en) * 2002-04-12 2003-10-23 David Hayes Modified release preparation
WO2003088906A2 (fr) * 2002-04-16 2003-10-30 Collagenex Pharmaceuticals, Inc. Procedes pour traiter simultanement de la keratite rosacee et de l'acne rosacee
WO2004012700A2 (fr) * 2002-08-05 2004-02-12 Torrent Pharmaceuticals Limited Nouvelle forme galenique
US20040115261A1 (en) * 2001-04-05 2004-06-17 Ashley Robert A. Controlled delivery of tetracycline compounds and tetracycline derivatives
US20040127471A1 (en) * 2002-09-17 2004-07-01 Barry Reisberg Methods of treating age associated memory impairment (AAMI), mild cognitive impairment (MCI), and dementias with cell cycle inhibitors
US20050148552A1 (en) * 2003-11-06 2005-07-07 Ryan Maria E. Methods of treating eczema
GB2414668A (en) * 2004-06-03 2005-12-07 Dexcel Ltd Sustained release delivery system for tetracycline compounds
US20060293290A1 (en) * 2005-06-24 2006-12-28 Medicis Pharmaceutical Corporation Method for the treatment of acne

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418565A2 (fr) * 1989-09-21 1991-03-27 American Cyanamid Company Système du type "une fois par jour" pour délivrance pulsée de minocyline
WO2002080932A1 (fr) * 2001-04-05 2002-10-17 Collagenex Pharmaceuticals, Inc. Methodes de traitement de l'acne
US20040115261A1 (en) * 2001-04-05 2004-06-17 Ashley Robert A. Controlled delivery of tetracycline compounds and tetracycline derivatives
US20030199480A1 (en) * 2002-04-12 2003-10-23 David Hayes Modified release preparation
WO2003088906A2 (fr) * 2002-04-16 2003-10-30 Collagenex Pharmaceuticals, Inc. Procedes pour traiter simultanement de la keratite rosacee et de l'acne rosacee
WO2004012700A2 (fr) * 2002-08-05 2004-02-12 Torrent Pharmaceuticals Limited Nouvelle forme galenique
US20040127471A1 (en) * 2002-09-17 2004-07-01 Barry Reisberg Methods of treating age associated memory impairment (AAMI), mild cognitive impairment (MCI), and dementias with cell cycle inhibitors
US20050148552A1 (en) * 2003-11-06 2005-07-07 Ryan Maria E. Methods of treating eczema
GB2414668A (en) * 2004-06-03 2005-12-07 Dexcel Ltd Sustained release delivery system for tetracycline compounds
US20060293290A1 (en) * 2005-06-24 2006-12-28 Medicis Pharmaceutical Corporation Method for the treatment of acne

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9084802B2 (en) 2010-05-12 2015-07-21 Rempex Pharmaceuticals, Inc. Tetracycline compositions
US9278105B2 (en) 2010-05-12 2016-03-08 Rempex Pharmaceuticals, Inc. Tetracycline compositions
US9744179B2 (en) 2010-05-12 2017-08-29 Rempex Pharmaceuticals, Inc. Tetracycline compositions
US11944634B2 (en) 2010-05-12 2024-04-02 Melinta Subsidiary Corp. Tetracycline compositions
US12161656B2 (en) 2010-05-12 2024-12-10 Melinta Subsidiary Corp. Tetracycline compositions
US9918998B2 (en) 2015-03-23 2018-03-20 BioPharmX, Inc. Pharmaceutical tetracycline composition for dermatological use
US10391108B2 (en) 2015-03-23 2019-08-27 BioPharmX, Inc. Pharmaceutical tetracycline composition for dermatological use
US10881672B2 (en) 2015-03-23 2021-01-05 BioPharmX, Inc. Pharmaceutical tetracycline composition for dermatological use
US11103517B2 (en) 2015-04-07 2021-08-31 Dr. Reddy's Laboratories Ltd. Pharmaceutical compositions for minocycline

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