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WO2000048589A1 - Forme posologique orale solide contenant de l'heparine ou un heparinoide combinee a un support - Google Patents

Forme posologique orale solide contenant de l'heparine ou un heparinoide combinee a un support Download PDF

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Publication number
WO2000048589A1
WO2000048589A1 PCT/US2000/004559 US0004559W WO0048589A1 WO 2000048589 A1 WO2000048589 A1 WO 2000048589A1 US 0004559 W US0004559 W US 0004559W WO 0048589 A1 WO0048589 A1 WO 0048589A1
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WO
WIPO (PCT)
Prior art keywords
heparin
snac
tablets
dosage form
carrier
Prior art date
Application number
PCT/US2000/004559
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English (en)
Inventor
Kenneth Iain Cumming
Mary L. Martin
Original Assignee
Emisphere Holdings, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Emisphere Holdings, Inc. filed Critical Emisphere Holdings, Inc.
Priority to AU32409/00A priority Critical patent/AU3240900A/en
Publication of WO2000048589A1 publication Critical patent/WO2000048589A1/fr

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

Definitions

  • the present invention relates to a solid oral dosage form containing a carrier in combination with a Heparin or a heparinoid.
  • the invention relates to a solid oral dosage form comprising a Heparin or a heparinoid as an active ingredient in combination with a carrier such that the carrier enhances the bioavailability and/or the absorption of the active ingredient.
  • the epithelial cells lining the lumenal side of the GIT are a major barrier to drug delivery following oral administration.
  • transport pathways which can be exploited to facilitate drug delivery and transport: the transceilular, paracellular, carrier-mediated and transcytotic transport pathways.
  • the ability of a drug, such as a conventional drug, a peptide, a protein, a macromolecule or a nano- or microparticulate system, to "interact" with one or more of these transport pathways may result in increased delivery of that drug from the GIT to the underlying circulation.
  • Certain drugs utilise transport systems for nutrients which are located in the apical cell membranes (carrier mediated route). Macromolecules may also be transported across the cells in endocytosed vesicles (transcytosis route). However, many drugs are transported across the intestinal epithelium by passive diffusion either through cells (transceilular route) or between cells (paracellular). Most orally administered drugs are absorbed by passive transport. Drugs which are lipophilic permeate the epithelium by the transceilular route whereas drugs that are hydrophilic are restricted to the paracellular route. Paracellular pathways occupy less than 0.1% of the total surface area of the intestinal epithelium.
  • US 5,650,386 and WO96/30036 disclose modified amino acid compounds useful for the effective administration, including oral administration, of a variety of active agents including heparin.
  • US 5,650,386 and WO96/30036 are hereby incorporated in their entirety.
  • the modified amino acid compounds disclosed include the two carriers which are referred herein as SNAC and SNAD and whose chemical identities are given below: SNAC 8-(salicyloylamino)octanoic acid
  • SNAC and SNAD have been shown to promote the oral absorption of heparin in a number of animal models, e.g., rats and primates, and SNAC has been shown to promote the oral absorption of heparin in man, giving measurable changes in APTT and anti-FXa activity.
  • the combination carrier/heparin in these studies have been administered in an aqueous solution containing, e.g., 25% propylene giycol as a cosolvent and possibly as an enhancer.
  • the carriers SNAC and SNAD have a very bitter taste and tolerability issues were observed when the aqueous solutions were administered to man.
  • a taste-masked solution has been developed in order to improve tolerability and was subsequently dosed in a human biostudy, at a dose of 2.25g SNAC in 30 mis of taste-masked solution, with increasing doses of heparin from 30,000 to 150,000 iu. No adverse events were reported in the study.
  • the pharmacokinetic profiles observed show a very rapid increase in APTT and anti-FXa activity which declines very rapidly (elimination 1 ⁇ A calculated from the biostudy in man was 1.45 - 1.63 hours compared to 2.45 hours for the dose administered s.c). Daily dosing of every 5 hours will therefore be required for the oral solution which may give rise to possible tolerability issues and patient compliance problems.
  • Solid oral dosage form which would facilitate the administration of a drug together with the carrier is desirable.
  • the advantages of solid oral dosage forms over other dosage forms include ease of manufacture, the ability to formulate different controlled release and extended release formulations and ease of administration. Administration of drugs in solution form does not readily facilitate control of the profile of drug concentration in the bloodstream.
  • Solid oral dosage forms are versatile and may be modified, for example, to maximise the extent and duration of drug release and to release a drug according to a therapeuticaliy desirable release profile. There may also be advantages relating to convenience of administration increasing patient compliance and to cost of manufacture associated with solid oral dosage forms.
  • a carrier with a heparin drug is more effective when a solid oral dosage form is designed to present the drug and carrier concurrently to the GI tract, the drug and carrier preferably being in solubilized forms, in a manner that allows the carrier to facilitate the absorption of therapeuticaliy effective amounts of the drug in an animal, preferably a human.
  • solid oral dosage forms comprising a heparin drug in combination with a carrier are provided according to the present invention.
  • the solid oral dosage form targets both the carrier and the heparin drug for release in the lower GI tract. More preferably, the solid oral dosage form substantially prevents precipitation of the carrier in the regions of the GI track in which the pH is low.
  • the solid oral dosage forms according to the invention have a number of advantages, including 1 ) protection for the carrier from precipitation at low pH, 2) release of both carrier and drug at a pH of approximately 6.5 or greater to allow for solulibilzation of the carrier; 3) flexibility in extent and duration of both the drug and carrier release; 4) ability to decrease the dosing frequency; 5) ability to effectively taste mask and 6) production of a more stable product compared to a liquid product.
  • the present invention provides a solid oral dosage form containing a heparin drug in admixture with a carrier such that the dosage form protects the carrier from precipitation during transit through the low pH regions of the GI track, thus enabling concurrent presentation of the heparin drug and the carrier in the GI track to facilitate the absorbtion and/or enhance the bioavailability of the heparin drug.
  • the carrier is selected from the group consisting of SNAC, SNAD, pharmaceutically acceptable salts thereof, esters thereof and combinations thereof.
  • Figure 1 shows the dissolution profile of SNAC from SNAC/Heparin IR (tablets D) and SR tablets G (SR component added extragranularly) and SR tablets H (SR component added intragranularly at pH 1.2 and pH 7.4 according to Example 3;
  • Figure 2 shows the dissolution profile of Heparin from SNAC/Heparin IR (tablets).
  • Figure 3 shows a plot of Anti-Xa Activity (IU/ml) versus time following oral administration of the following formulations to dogs as described in Example 4: a) three uncoated solid oral dosage tablets each containing 450 mg Heparin USP and 1.1g SNAC as given in Example 2; b) three coated (Eudragit S) solid oral dosage tablets each containing 450 mg Heparin USP and 1.1g SNAC as given in Example 2; 3) 7.5 ml of a 20% PG aqueous solution containing 450 mg Heparin and 1.1 SNAC; and 4) 7.5 ml of an aqueous solution containing 450 mg Heparin and 1.1 SNAC;
  • Figure 4 shows the dissolution profiles of SNAD and Heparin USP at pH 1.2 and pH 7.4 from SNAD/Heparin IR tablets (Tablet P formulation as shown in Example 5);
  • Figure 5 shows the mean antifactor Xa levels versus time following administration of the following treatments to dogs as described in Example 7: 1) Uncoated USP heparin tablet (90,000 IU + 550 mg SNAD); two tablets/dog; 2) LMW Heparin solution (90,000 IU + 550 mg SNAD in water); 10 ml/dog; 3) Uncoated LMW heparin tablet (90,000 IU + 550 mg SNAD); two tablets/dog; 4) LMW heparin subcutaneous (5000 IU in 0.5 ml saline); 5) LMW Heparin solution (90,000 IU + 1100 mg SNAD in water); 10 ml/dog; and 6) Uncoated LMW heparin tablets (90,000 IU + 1100 mg SNAD); 3 tablets/dog.
  • carrier refers to SNAC or SNAD, pharmaceutically acceptable salts thereof, esters thereof and combinations thereof.
  • the carrier is SNAC or SNAD or a sodium salt thereof.
  • drug or "heparin drug” includes heparins, such as Heparin USP, low molecular weight heparins (LMWH), unfractionated heparins, heparin fragments and heparinoids, pharmaceutically acceptable salts thereof and combinations thereof.
  • heparin drug also includes nano- or microparticulate drug delivery systems in which a drug is entrapped, encapsulated by, associated with, or attached to a nano- or microparticle.
  • the drug itself may be in the form of nano-, micro- or larger particles in crystalline or amorphous form.
  • a "therapeuticaliy effective amount of a drug” refers to an amount of drug that elicits a therapeuticaliy useful response in an animal.
  • a "therapeuticaliy effective amount of a carrier” refers to an amount of carrier that allows for uptake of therapeuticaliy effective amounts of the drug via oral administration
  • a solid oral dosage form according to the present invention may be a tablet or may be a multiparticulate.
  • tablette includes, but is not limited to, immediate release (IR) tablets, sustained release (SR) tablets, matrix tablets, multilayer tablets, multilayer matrix tablets extended release tablets, delayed release tablets and pulsed release tablets any or all of which may optionally be coated with one or more coating materials, including polymer coating materials, such as enteric coatings, rate-controlling coatings, semi-permeable coatings and the like.
  • tablette also includes osmotic delivery systems in which a drug compound is combined with an osmagent (and optionally other excipients) and coated with a semi-permeable membrane, the semi-permeable membrane defining an orifice through which the drug compound may be released.
  • Tablet solid oral dosage forms particularly useful in the practice of the invention include those selected from the group consisting of IR tablets, SR tablets, coated IR tablets, matrix tablets, coated matrix tablets, multilayer tablets, coated multilayer tablets, multilayer matrix tablets and coated multilayer matrix tablets.
  • multiparticulate means a plurality of discrete particles, pellets, mini-tablets and mixtures or combinations thereof. If desired, the multiparticulate may be coated with a layer containing rate controlling polymer material. Alternatively, the multiparticulate and one or more auxiliary excipient materials can be compressed into tablet form. Such a tablet may optionally be coated with a controlled release polymer so as to provide additional controlled release properties.
  • the drug may be present in any amount which is sufficient to elicit a therapeutic effect and, where applicable, may be present either substantially in the form of one optically pure enantiomer or as a mixture, racemic or otherwise, of enantiomers.
  • the drug compound is suitably present in any amount sufficient to elicit a therapeutic effect.
  • the actual amount of drug compound used will depend on the potency of the drug compound in question.
  • the carrier is suitably present in any amount sufficient to allow for uptake of therapeuticaliy effective amounts of the drug via oral administration.
  • the drug and the carrier are present in a ratio of from 100: 1 to 1 :100 (drug : carrier), preferably 10:1 to 1:10.
  • the actual ratio of drug to carrier used will depend on the potency of the drug compound and the enhancing activity of the carrier.
  • a solid oral dosage form according to the invention comprises a drug and a carrier in admixture compressed into a tablet.
  • a solid oral dosage form according to the invention comprises a drug, a carrier and a rate controlling polymer material in admixture compressed into a tablet.
  • rate controlling polymer material includes hydrophilic polymers, hydrophobic polymers and mixtures of hydrophilic and/or hydrophobic polymers that are capable of controlling or retarding the release of the drug compound from a solid oral dosage form of the present invention.
  • Suitable rate controlling polymer materials include those selected from the group consisting of hydroxyalkyl cellulose such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose; poly(ethylene) oxide; alkyl cellulose such as ethyl cellulose and methyl cellulose; carboxymethyl cellulose, hydrophilic cellulose derivatives; polyethylene glycol; polyvinylpyrrolidone; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; polyvinyl acetate phthalate; hydroxypropylmethyl cellulose phthalate; hydroxypropylmethyl cellulose acetate succinate; polyvinyl acetaldiethylamino acetate; poly(alkylmethacrylate) and poly (vinyl acetate).
  • suitable hydrophobic polymers include polymers and/or copolymers derived from acrylic or methacrylic acid and their respective esters, zein, waxes, shellac and hydrogenated vegetable oils. Particularly useful in the practice of the present invention are poly acrylic acid, poly acrylate, poly methacrylic acid and poly methacrylate polymers such as those sold under the Eudragit tradename (Rohm GmbH, Darmstadt, Germany) specifically Eudragit ® L, Eudragit ® S, Eudragit ® RL, Eudragit ® RS coating materials and mixtures thereof.
  • a solid oral dosage form according to the invention comprises a multilayer table.
  • a multilayer tablet may comprise a first layer containing a drug and a carrier in an instant release form and a second layer containing a drug and a carrier in a sustained, extended, controlled or modified release form.
  • a multilayer tablet may comprise a first layer containing a drug and a second layer containing a carrier.
  • Each layer may independently comprise further excipients chosen to modify the release of the drug or the carrier.
  • the drug and the carrier may be released from the respective first and second layers at rates which are the same or different.
  • each layer of the multilayer tablet may comprise both drug and carrier in the same or different amounts.
  • a fourth embodiment a solid oral dosage form according to the invention comprises a drug and a carrier in admixture in the form of a multiparticulate.
  • the drug and carrier may be contained in the same or different populations of particles, pellets or mini-tablets making up the multiparticulate.
  • capsules such as hard or soft gelatin capsules can suitably be used to contain the multiparticulate.
  • a multiparticulate solid oral dosage form according to the invention may comprise a blend of two or more populations of particles, pellets or mini- tablets having different in vitro and/or in vivo release characteristics.
  • a multiparticulate oral dosage form may comprise a blend of an immediate release component and a delayed release component contained in a suitable capsule.
  • a controlled release coating may be applied to the final dosage form (tablet, multilayer tablet etc.).
  • the controlled release coating may typically comprise a rate controlling polymer material as defined above.
  • the dissolution characteristics of such a coating material may be pH dependent or independent of pH.
  • the various embodiments of the solid oral dosage forms of the invention may further comprise auxiliary excipients such as for example diluents, lubricants, disintegrants, plasticisers, anti-tack agents, opacifying agents, pigments, flavourings and such like.
  • auxiliary excipients such as for example diluents, lubricants, disintegrants, plasticisers, anti-tack agents, opacifying agents, pigments, flavourings and such like.
  • Suitable diluents include for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing.
  • examples of diluents include microcrystalline cellulose such as that sold under the Trademark Avicel (FMC Corp., Philedelphia, PA) for example AvicelTM pH101 , AvicelTM pH102 and AvicelTM pH112; lactose such as lactose monohydrate, lactose anhydrous and Pharmatose DCL21; dibasic calcium phosphate such as Emcompress; mannitol; starch; sorbitol; sucrose; and glucose.
  • Avicel FMC Corp., Philedelphia, PA
  • Suitable lubricants including agents that act on the flowability of the powder to be compressed are, for example, colloidal silicon dioxide such as AerosilTM 200; talc; stearic acid, magnesium stearate, and calcium stearate.
  • Suitable disintegrants include for example lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate and combinations and mixtures thereof.
  • Example 1 SNAC and Heparin USP in-vitro precipitation experiments
  • Mechanisms for SNAC/SNAD enhancement of Heparin absorption in the GI tract have been suggested. These mechanisms include microparticle formation upon exposure to acidic conditions and structure activity relationships between SNAC/SNAD and Heparin or heparinoids. It has been speculated that SNAC and/or SNAD may form a co-precipitate with Heparin or a heparinoid on transit through the GI tract and this co- precipitated complex may play a role in the increased Heparin/heparinoid absorption.
  • SNAC is the sodium salt of a weak acid with a pKa of 5.01. At low pH, the solubility of SNAC decreases and the SNAC precipitates as the SNAC free acid form.
  • Heparin is also the sodium salt of an acid, heparinic acid, and in acid conditions the Heparin sodium may be converted to the less soluble heparinic acid which may also precipitate out of solution. The activity of Heparin in acid conditions may decrease also as a result of desulphonation.
  • the SNAC/Heparin solutions investigated were equivalent to solutions dosed in the biostudies (75mg/ml SNAC with 1 ,000IU/ml and 3,000IU/ml Heparin in 30ml of 20% aq. propylene glycol (PG) and 150mg/ml SNAC with 428IU/ml Heparin in 70mi of 20% aq. PG). These solutions were chosen to examine both the effect of increasing the Heparin dose and keeping the SNAC dose and concentration constant and to examine the effect of increasing the dose and concentration of SNAC and keeping the dose of Heparin constant. Corresponding solutions of SNAC (75mg/ml in 30ml of 20% aq. PG) and Heparin (333IU/ml, 1 ,000IU/ml and 3,000IU/ml in 30ml of 20% aq. PG) were also examined to assess the behaviour of the individual components of these solutions in the various pH environments.
  • a sample of the suspension formed after dilution with GIF was diluted (1 :10) with isotonic phosphate buffers pH 6.2, pH 6.8 and pH 7.4. The resulting solution/suspension was then recovered and characterised as described above. When a suspension was observed after dilution, a Millipore pump and 0.45 ⁇ m filter were used to separate the precipitate which was dried under vacuum and the weight of the dried precipitate was recorded.
  • Particle size analysis of suspension was carried out using a Malvern Mastersizer. The suspension to be analysed was dispersed in filtered H 2 O in the stirred small volume cell. A 300mm lens was used and a 3OHD presentation. The particle size analysis was repeated in triplicate. DSC analysis was carried out using a Perkin Elmer DSC 7. Approximately 5mg of the sample to be analysed was weighed into an aluminum pan and scanned between 40°C and 230°C at a scanning rate of 10°C/min, in an atmosphere of N 2 . XRD analysis was carried out using a Siemens XRD. A powdered sample was placed on a glass slide and the XRD pattern was measured between 5° and 35° two theta at a rate of 0.05 sec.
  • SNAC analysis was carried out using a HPLC method.
  • the HPLC conditions were as follows: column-TCD 137 Hypersil BDS C18 5 ⁇ (50 x 4.6mm), wavelength- 244nm, flow rate-2ml/min, temperature-ambient, injection volume-50 ⁇ m, run time-20 minutes.
  • Two mobile phases A and B were used for gradient.
  • the mobile phase A was 900mls d.H 2 O, 100mls Acetonitrile, 2.5ml 1N HCI, 2ml Acetic acid.
  • the mobile phase B was 300mls d.H 2 O, 700mls Acetonitrile, 3mls Acetic acid.
  • the diluting solvent used was a ratio of Mobile phase B to d.H 2 O of 3:2.
  • the Heparin analysis was carried out using an anti-FXa assay kit, Coatest® supplied by Chromogenix.
  • the Heparin is analysed as a complex [Heparin AT] with excess Antithrombin.
  • the amount of FXa neutralised by the complex [Heparin AT] is proportional to the amount of complex and hence Heparin.
  • the remaining FXa hydrolyses the chromogenic substrate S-2222 thus liberating the chromophoric group, pNA.
  • the colour is then read photometrically at 405nm and the remaining FXa can be determined thus allowing the amount of Heparin to be calculated.
  • aqueous solution of 20% PG containing SNAC without Heparin was initially investigated to determine the effect of the various pH environments on SNAC in solution.
  • the dose and concentration of SNAC in solution were 2.25g SNAC and 75mg/ml SNAC, respectively.
  • the SNAC in solution interact with the acid medium to form the less soluble free acid form of SNAC which would be precipitated from solution.
  • the precipitation of SNAC acid from solution resulted in an increase in the solution pH and neutralisation of the solution.
  • the higher percentage of SNAC sodium remaining in solution for the solutions diluted with simulated GIF may be attributed to the presence of NaCI in GIF which provides additional Na + counterions to keep SNAC in solution.
  • Higher concentrated SNAC solutions would increase the concentration of SNAC in the diluted solution and therefore a greater degree of SNAC conversion to the free acid form and a higher increase in the pH of the resulting solution.
  • DSC and XRD analysis identified the precipitate as the free acid form of SNAC.
  • DSC analysis of the precipitate displayed a sharp endotherm at 115°C which was similar to the endotherm previously known for the SNAC free acid form.
  • the XRD pattern displayed by the precipitate was crystalline and similar to the XRD pattern recorded for crystalline SNAC acid.
  • SEM analysis of the precipitate displayed orthorhombic crystals similar in shape to those previously observed for SNAC free acid.
  • the median particle size (D50%) and particle size distribution of the precipitate from the simulated GIF and the 0.1 N HCI solution were similar, D50% of 31.87 ⁇ m and 38.82 ⁇ m respectively.
  • SNAC precipitation in the in vitro medium studied did not result in the formation of colloidal/nanoparticles giving increased surface area for dissolution or absorption enhancement.
  • Aqueous solutions of SNAC (75mg/ml) and Hepa ⁇ n (30.000IU and 90,000IU) Aqueous PG solutions containing Heparin and SNAC were investigated to assess the effect of the various pH environments on solutions containing the combinations.
  • the solutions analysed were 30ml in volume, containing 75mg/ml SNAC with 1 ,000IU/ml and 3,000IU/ml Heparin.
  • a precipitate was formed when the solutions were diluted with simulated GIF.
  • the SNAC/Heparin solution with the lower level of Heparin (1 ,000IU/ml) the presence of Heparin in solution did not influence the neutralisation of GIF by SNAC sodium as shown in Table 1 and Table 3.
  • the solubility of SNAC appeared to be influenced by the slight differences in pH resulting from the different levels of Heparin in solution. As expected the percentage SNAC in solution was higher in solutions with a more alkaline pH as shown in Table 3 and 4. The percentages of recovered precipitate were lower than expected for all SNAC solutions; this may be due to incomplete recovery of precipitate.
  • DSC and XRD analysis identified the precipitate formed by the addition of the SNAC/Heparin solutions to the simulated GIF as the free acid form of SNAC.
  • the DSC analysis of the precipitate displayed an endothermic peak, with an onset around 115°C similar to that of the SNAC free acid.
  • the XRD patterns of the precipitates were similar to that of SNAC free acid crystals.
  • SEM analysis showed that the precipitate for SNAC/Heparin solutions was similar in shape to the precipitate formed from solutions of SNAC alone and the SNAC free acid crystals. There was no evidence of co-precipitate formation between SNAC and Heparin.
  • Particle size analysis of the precipitates showed that median particle size (D50%) of 30-64 ⁇ m. Again, there was no evidence of the formation of colloidal/nanoparticles giving increased surface area for dissolution or abso ⁇ tion enhancement by precipitation of SNAC form solution in the acidic medium of the stomach.
  • a solution containing Heparin (30.000IU in 70mls) and SNAC at a higher concentration and dose (150mg/ml or 10.5g in 70mls) was investigated to see the effect of increasing the dose and concentration of SNAC upon SNAC and Heparin solubility in different pH environments.
  • this solution was diluted with simulated GIF, a precipitate was formed.
  • the pH of the supernatant formed was close to the pH of the original SNAC/Heparin solution, which indicated complete neutralisation of the simulated GIF by the SNAC/Heparin solution (Table 6).
  • the increase in the concentration of SNAC results in a greatly degree of conversion of SNAC to the insoluble SNAC free acid form thus reducing the hydrogen ion concentration and causing an increase in pH to a more alkaline value close to than of the original solution at which the remaining SNAC stays in solution.
  • the increased Heparin response can be attributed to the increased dose and concentration of Heparin in solution with SNAC.
  • the heparin dosed remained in solution throughout the GI tract and was unaffected by the GI tract pH environments.
  • the heparin in-vivo response also increased by increasing the level of SNAC in solution.
  • the dosage form of the drug should be targeted at the lower GI tract (pH 6.8 - 7.4) where the SNAC solubility in solution is optimum.
  • the solid oral dosage forms according to this invention achieve this goal.
  • Example 2 Formulation of SNAC/Heparin USP solid oral dosage forms using direct compression
  • SNAC sodium salt (lyophilised; Emisphere Technologies, Inc.) was milled prior to tabletting in order to reduce particle size and size distribution and to improve its flow properties.
  • Heparin sodium USP was supplied from Scientific Protein Laboratories containing 184.3 USP units per milligram,.
  • the mean particle size, D50%, of heparin and the milled SNAC particles were 122.37 ⁇ 28.76 ⁇ m and 49.68 ⁇ 8.9 ⁇ m, respectively.
  • the milled lyophilised SNAC was used to prepare tablets containing 365mg SNAC to 150mg of Heparin per tablet; these tablets were designed so that three tablets would give the required dose of 1.1 g of SNAC to 450mg of Heparin per dog. Tabletting was carried out using the Fette E1 single station tablet press (E3028) with a selection of punches, such as 13mm round and 13X8mm oval punch. SNAC sodium and heparin were blended with three other tablet excipients in the following composition as detailed in Table 10.
  • Tabletting was carried out on the Fette E1 (E3028), using the 13mm round punches.
  • the approximate die fill was 6mm, with a compression force of 42/3 and on target hardness of 50 - 70N.
  • heparin was included with SNAC, the compressibility of SNAC was compromised resulting in bigger tablets which were friable.
  • the water, isopropyl alcohol and diethyl phthalate were added to a stainless steel vessel and the mixer was switched on at 10Orpm for 15 minutes to ensure that a uniform solution was obtained.
  • Eudragit S12.5 was added gradually to the solvent mixture and mixing was continued for a further 10 minutes at a speed of 125rpm.
  • Talc was then added to the solvent mixture and the mixing was continued for a further 20 minutes at 150 rpm.
  • the tablets, both coated and uncoated, were assayed for potency of SNAC and heparin (n 6).
  • the disintegration of tablets was monitored in water at 37°C.
  • the uncoated tablets were found to disintegrate within 5 minutes in water at 37°C, while the coated tablets did not disintegrate within the first 30 minutes but had fully disintegrated after 2 hours in water at 37°C.
  • Dissolution testing was carried out at both pH 1.2 and pH 7.4. Both SNAC and heparin release were monitored. For the uncoated tablets, heparin release was faster than SNAC release at pH 1.2, with 54% of Heparin released after 15 minutes and up to 94% released after 1 hour compared with 16% of SNAC released after 15 mins and up to 19% released after 1 hour. The release of Heparin and SNAC was similar at pH 7.4 with 82% heparin released compared to 76% of SNAC after 15 minutes. Heparin release at pH 1.2 was slower than that at pH 7.4, especially at the early time points of 15 mins and 30 mins. For SNAC, release at pH 1.2 was very slow with only 19% release after 1 hour.
  • SNAC release was complete after 1 hour.
  • heparin in vitro release was low ( ⁇ 10%) at pH 1.2 after 2 hours while no SNAC was detectable at pH1.2 during the two hour dissolution.
  • pH 7.4 the release of heparin was higher than SNAC at the early time point of 15 mins with 33% of Heparin released and 18% of SNAC released after 15 mins.
  • the release of Heparin was complete and SNAC release was nearly complete at 90%.
  • SNAC and heparin were released at pH 1.2 but both were released at pH 7.4 showing that the enteric coating was effective.
  • Example 3 Formulation of SNAC/Heparin USP solid oral dosage forms using aqueous granulation
  • Granulation was investigated to improve the particle size, flow properties, density compressibility of the SNAC/Heparin material and ultimately allow the production of good quality SNAC/Heparin tablets.
  • SNAC and SNAC/Heparin granules were produced by aqueous granulation.
  • the SNAC/Heparin ratios in the granules investigated were 2.25g SNAC to 90,000 IU Heparin and 2.25g SNAC to 150,000 IU Heparin which were equivalent to the concentrations in the taste-masked solutions used for dosing in man.
  • Granule yield, density, flow properties and water content were measured and selected granular material was tabletted.
  • Aqueous granulation of SNAC and Heparin prior to tabletting enabled SNAOHeparin tablets of good quality to be produced.
  • Granules and tablets were assayed for SNAC potency, SNAC release at pH 1.2 and 7.4 and residual moisture content. Heparin potency and Heparin release at pH 1.2 and 7.4 was also determined for the SNAC.Heparin tablets. Disintegration testing of the tablets was also carried out in water at 37°C.
  • the dried material was sieved through a 355 ⁇ m sieve to separate fine material from the granules.
  • the sieve apertures selected were larger that those normally used in granulation (0.315mm) to facilitate the manual sieving of the granular material.
  • the aerosil 200 was bag blended with the SNAC granules or the SNAC:Heparin granules, the magnesium stearate was then added and bag blended.
  • the tablet weight was set at approximately 500mg and the tablet hardness was set as reported. Tabletting was carried out on the Manesty E2 single station using the 12mm round punch and die set.
  • SNAC analysis was carried out using a HPLC method as described in Example 1.
  • SNAC and Heparin potency of the granules and tablets were measured.
  • Dissolution testing of SNAC and Heparin from granules and tablets was undertaken at 37°C in simulated gastric fluid pH 1.2 and isotonic phosphate buffer pH 7.4.
  • Disintegration testing of tablets was measured in water at 37°C.
  • Karl Fisher titration was used to determine percentage water content in the granules and tablets.
  • Heparin molecular weight was determined by aqueous Gel Permeation Chromatography (GPC) analysis. Differential Scanning Calorimetry (DSC) was conducted using a Perkin Elmer 7 Series thermal analysis systems.
  • GPC Gel Permeation Chromatography
  • the granulation of pure SNAC sodium was investigated with and without the inclusion of PVP as a binding agent.
  • a binder, PVP 26-28 was added to the granulate mix as a 10% aqueous PVP solution and as a dry powder.
  • the formulation of these granules is outlined in Table 12.
  • the SNAC sodium granules Batch 1 prepared by adding PVP solution to the granular material did not granulate well.
  • the granulating liquid was poorly dispersed through the granular mix and hard granules were formed. Overwetting the granular mixture can also result in granule hardness.
  • the Batch 2 granules were prepared by blending PVP as a dry powder with the SNAC sodium powder prior to the addition of the granulating liquid.
  • the volume of granulating liquid was also reduced in an attempt to reduce granule hardness but hard granules were still produced.
  • the SNAC granules Batch 4 produced without the inclusion of PVP were also hard.
  • Granule hardness may be due to the solubility of SNAC in the granulation fluid. Strong bonds may form as a result of fusion or recrystallisation of SNAC particles upon drying. Because addition of the binder PVP would further increase granule cohesive forces and granule hardness, a binder was omitted from the granular formulation.
  • the granules produced displayed reduced hardness.
  • the apparent density of Batch 3 granules (0.4381 g/ml) was greater than the triturated SNAC sodium starting material (0.2451 g/ml). Therefore, these SNAC granules were expected to exhibit better compressibility than the SNAC starting material and hence to produce less friable tablets.
  • the Batch 3 granules were tabletted to produce SNAC tablets.
  • SNAC:Heparin granules were prepared for inclusion in SNAOHeparin IR tablets.
  • the ratios of SNAC sodium to Heparin in the granules prepared were 2.25g SNAC sodium to 90.000IU Heparin (Table 13) and 2.25g SNAC sodium to 150.000IU Heparin (Table 14).
  • Explotab was added to each of the granular mixes to reduce granular hardness.
  • the SNAC: Heparin granules prepared with 7.45% Explotab (Batch 5 and Batch 6) were very hard. The increased hardness of the Hardness was reduced in the Batch 7 granules by increasing :ne oercs-tage Explotab in the granular mix from 7.45% to 9.09%.
  • the Batc ⁇ 7 granules exmor e good flow properties.
  • the apparent density of the SNAC/Hepann granules was not e-ected by the presence of Heparin.
  • Batch 8 granules were prepared using a 1 :1 water/ethanol granulating licuid. However, a greater volume of granulating fluid was required to reach the granulation en ⁇ oc—: and the water content in the dried Batch 8 granules was still high ( .93 ⁇
  • the granules with a ratio 2.25g SNAC to 150,000 IU Heparin required a lower level of water to reach the granulation er.c oint point (Table 14) compared to the granules with a ratio of 2. 5g SNAC to " '.OOO IU Heparin (Table 13).
  • the reduced level of water may be due to the reduced prop r ⁇ on of hygroscopic SNAC in the granular mix.
  • SNAC Heparin granules with Hydroxypropyl methyl cellulose, Methocel, a water soluble polymer was selected as the controlled release component of these tablets. Methocel partially hydrates upon contact with an aqueous medium to form a gel layer which controls the rate of release of drug from the tablet by a diffusion and/or erosion mechanism. The rate of release of the drug can be varied by varying the grade of Methocel used.
  • Methocel K100LV was selected for inclusion in the formulation of SNAOHeparin granules. The formulation details are listed in Table 15. -32-
  • Formulation of the SNAC sodium tablets prepared from SNAC Batch 3 is shown in Table 16.
  • the tablet blend compressed well and the resulting tablets were smooth and showed no sign of capping or chipping.
  • SNAC:Heparin IR tablets were prepared with a ratio of 2.25g SNAC sodium to 90.000IU Heparin from the Batch 9 granules and with a ratio of 2.25g SNAC sodium to 150.000IU Heparin from the Batch 10 and Batch 1 1 granules.
  • the formulation of the tablets are summarised in Table 17.
  • Heparin SR tablets were prepared by compression of granules containing an SR component Methocel (Batch 14). SR tablets were also prepared using IR granulates (Batch 11) and adding Methocel K100LV to the tablet blend, extragranularly as shown in Table 18.
  • Molecular weight of Heparin in granules The average molecular weight (Mw) and the number average molecular weight (Mn) of Heparin in granules with a 2.25g SNAC to Heparin 90,000 ratio (Batch 7) and 2.25g SNAC to Heparin 150,000 ratio (Batch 10) was determined and compared to the Heparin starting material. Mw, Mp and Mn values of Heparin present in the SNAC:Heparin granules (Batch 7 and Batch 10) were slightly greater than for the Heparin reference material as shown in Table 19. The increased Heparin molecular weight during the granulation process may be a result of a complex formation with one of the components in the granular mix.
  • the Heparin release from the IR tablets reached 80% at 30 minutes in a dissolution medium of pH 7.4, and fluctuated around this level over the 4 hour testing period.
  • the 80% level of Heparin released may be due to the variability of the assay method rather than incomplete release of Heparin from the IR tablet.
  • Two other batches of IR tablets tested (Tablets B and C) displayed 100% Heparin release after 30 minutes at pH 7.4.
  • the SR tablets displayed a sustained release profile with the Tablet H tablets giving a more gradual release profile for Heparin than the Tablet G tablets.
  • the Tablet H tablets released SNAC and Heparin gradually over a 4 hour period with the release of Heparin being faster as shown in Figures 1 and 2.
  • the release profiles of SNAC and Heparin from the IR tablets at pH 7.4 were similar to those of the uncoated IR tablets dosed in the Dog Biostudy (Examples 2 and 4 herein).
  • the Heparin release from the IR tablets prepared in this study at pH 1.2 was approximately 40% after 4 hours compared to 100% release from the uncoated IR tablets dosed in the Dog Biostudy after 2 hours.
  • the difference in the level of Heparin release from the IR tablets prepared in this study and the biostudy uncoated IR tablets may be due to the method of tablet manufacture, the material used in tablet manufacture and the quality of the tablets produced.
  • the biostudy IR tablets (Example 2 herein) produced by direct compression were friable.
  • the aqueous granulation process would produce a more intimate mixture of Heparin with SNAC than direct compression. Therefore, the retarded release of Heparin from the IR tablets at pH 1.2 may be due to the hydrophobic nature of SNAC at pH 1.2 preventing the dissolution of Heparin from the tablet matrix.
  • the uncoated IR tablets dosed in the dog biostudy were friable and therefore Heparin contact with the dissolution medium would be increased allowing 100% Heparin release at 2 hours.
  • the reduced Heparin release at pH 1.2 may also be due to possible complex formation between Heparin and one of the components in the granular mix as indicated by molecular weight gain in the GPC analysis which reduced the Heparin dissolution rate at pH 1.2.
  • Example 4 Administration of SNAC/Heparin USP solid oral dosage forms to dogs
  • the APTT response was low in all the studied legs with a delay in Xa and APTT response following administration of coated tablets in comparison to the uncoated tablets and the solution formulation. Comparable areas under the plasma heparin concentration versus time curves were achieved for the uncoated tablets and the two dosing solutions. In contrast, the enteric coated tablets yielded about twice the AUC of the other groups. It may be that maintaining the SNAC and heparin in physical proximity prior to entry into the intestine (targeting the SNAC and heparin to the lower GI tract) was beneficial in this respect.
  • Example 5 Formulation of SNAD/Heparin USP solid oral dosage forms using aqueous granulation
  • a binder PVP was added to the SNAD/Heparin granule mix in an attempt to reduce the amount of water required to reach the granulation endpoint and hence soften granules.
  • Avicel and Explotab were added to the SNAD/Heparin granules to reduce granule hardness.
  • Avicel was the selected diluent due to its poor aqueous solubility which was hoped to reduce the formation of crystalline solid bridges on drying and soften the granules. Explotab was added to the granule to aid disintegration of the granules in the dissolution medium. The volume of water required to reach the granulation endpoint was reduced but otherwise there was no evident difference in granule quality or yield.
  • a SR component Methocel K100LV
  • Methocel K100LV was added to the SNAD/Heparin granules to obtain a gradual release of SNAD and Heparin from the granules.
  • the amount of water required to reach the granulation endpoint was increased possibly due to hydration of the Methocel during granulation and yield achieved was similar to that obtained for the IR granulates.
  • Avicel was added to the granular blend as a diluent to reduce granule hardness. Avicel was selected due to its poor aqueous solubility which would reduce the formation of solid bridges and maintain the inherent SR characteristics of Methocel (hydration and gel formation) which can be undermined by water soluble excipients.
  • the addition of Avicel to the granules did decrease the volume of water required to reach the granulation end point and the hardness of the granules produced. However the total yield of granules was reduced.
  • SNAD/Heparin tablet blends were prepared SNAD/Heparin granules and 0.5% Mag. Stearate and with 4% Explotab and 15% Pharmatose. Both blends produced good quality tablets of adequate tablet hardness. The level of external lubricant appeared to be insufficient and tablets adhered to the lower punch during manufacture. Tablets blends were also prepared from SNAD/Heparin granules with 5% Explotab intragranularly and 0.5% Mag. Stearate. There were no problems noted while tabletting the blend and no sticking to the lower punch was noted. The improved lubrication of this blend was attributed to the higher percentage of excipients in the table blend. -39-
  • the disintegration times were measured for tablets without a disintegrant and with Explotab intra and intergranularly. The disintegration times were similar for the three tablet batches between 13-15 minutes.
  • SNAD/Heparin granules containing Methocel were tabletted with 0.5% Mag. Stearate.
  • a second batch of SNAD/Heparin granules containing Methocel and Avicel intragranularly with 0.5% Mag. Stearate and with extra 10% Methocel intergranularly were tabletted. Good quality tablets were produced with no evidence of sticking to the punches during manufacture, as was observed for batches of IR tablets.
  • the addition of Methocel to the granules reduced the granule tackiness upon compression.
  • the SNAD/Heparin IR tablets (Tablet P) were coated with Eudragit S and Eudragit L enteric coatings.
  • the coating solution used was an organic solution and the formulation details are given in Table 25:
  • SNAD and Heparin showed parallel release from the uncoated IR tablets in a pH7.4 dissolution medium. Near complete release of both SNAD and Heparin was measured after one hour as is shown in Figure 4 for Tablet P. Heparin is highly soluble ( ⁇ 600mg/ml) and appears to have a fast dissolution rate. The saturated solubility of SNAD is relatively high ( ⁇ 359mg/ml), however, it appears to have a low intrinsic dissolution rate resulting in a slower release profile than expected for these IR tablets. An intimate mixture of SNAD and Heparin material may be formed by aqueous granulation and the Heparin release from these tablets may be limited by the slow dissolution of the SNAD material due to this intimate mixture.
  • the SNAD and Heparin release at pH7.4 were comparable to the release profiles for the SNAC Heparin tablets (Example 2) dosed in previous dog biostudy (Example 4). These SNAC/Heparin tablets were produced by direct compression. The release of SNAC at pH1.2 was greater than that of the SNAD material and Heparin release was higher from the SNAC/Heparin tablets possibly due to the extra granulation step in these tablets and the poorer dissolution rate of the SNAD material.
  • Example 6 Formulation of SNAD/LMWH solid oral dosage forms using aqueous granulation
  • Heparin (LMWH or LMW heparin) was supplied by Pamaparin (potency 91IU/mg).
  • SNAD analysis was carried out using a HPLC method and LWMH analysis was carried out using and anti-FXa assay kit, , Coatest® supplied by Chromogenix.
  • Granulation was SNAD with LMWH was investigated in the absence and presence of excipients as shown in Table 26, including the presence of a wetting agent (SLS).
  • SLS wetting agent
  • Batches 24-27 produced large quantities of hard granules.
  • the size distribution of Batch 28 granules was much improved with a much higher % of granules less than 355 ⁇ m.
  • Tablets were prepared from the granules produced in above.
  • the required amounts of Explotab, Aerosil and magnesium stearate as shown in Table 27 were bag blended and tablets were produced on a Manesty hand operated tablet press using 12.5mm round punches.
  • SNAD LMWH tablets were formulated for use in the dog biostudy of Example 7 for determination of the pharmacokinetics of LMWH in dogs. Two strengths of tablets were prepared with ratios of SNAD : LMWH of 550mg : 90, 000IU and 1100mg : 90.000IU. The tablets containing the higher strength of SNAD was formulated as a three tablet dose, while the tablets containing the lower strength of SNAD were formulated as a two tablet dose.
  • the SNAD (1100mg):LMWH (90,000IU) granules were formulated at 499.7mg/g SNAD, 449.3 mg/g LMWH, 50.0 mg/g Explotab, and 1.0 mg/g SLS for a total weight per unit of 1000 mg.
  • SNAD, LMWH and Explotab were bag blended for 3 minutes and transferred to a Kenwood mixer.
  • the SLS was dissolved in 5mls of deionised water and this was added to the Kenwood using a syringe. Deionised H 2 0 was subsequently added until the granulation end-point was reached (total 32mls).
  • the granulate was transferred to an oven and tray dried for 16 hours at 70°C.
  • the granulate was weighed after drying and passed through a 630 ⁇ m sieve on an oscillating granulator. Granule flow properties were assessed to determine the suitability of the granules for tabletting. The granules were analysed for SNAD and LMWH potency content.
  • the SNAD (550mg):LMWH (90.000IU) granules were formulated at 355.6 mg/g SNAD, 593.4 mg/g LMWH, 50.0 mg/g Explotab, and 1.0 mg/g SLS for a total weight per unit of 1000mg.
  • SNAD, LMWH and Explotab were bag blended for 3 minutes and transferred to a Kenwood mixer.
  • the SLS was dissolved in 5mls of deionised water and this was added to the Kenwood using a syringe. Deionised H 2 0 was subsequently added until the granulation end-point was reached (total 46mls).
  • the granulate was transferred to an oven and tray dried for 18 hours at 70°C.
  • the granulate was weighed after drying and passed through a 630 ⁇ m screen on an oscillating granulator. Granule flow properties were assessed to determine the suitability of the granules for tabletting. The granules were analysed for SNAD and LMWH potency content.
  • the tablet blend for SNAD (1100mg):LMWH (90.000IU) consisted of (w/w%) 87% granules, 7% SNAD, 5% Explotab, 0.5% Aerosil, and 0.5% Mg Stearate.
  • the Aerosil was blended with some of the SNAD and sieved through a 1000 ⁇ m sieve into the remaining SNAD.
  • Extra SNAD (7%) was included in the formulation extragranularly to make up for the apparent SNAD shortage in the granules indicated by SNAD potency analysis.
  • SNAD : LMWH granules and Explotab were added to the mix and all components were bag blended for 3 minutes. Magnesium stearate was then added followed by bag blending for another minute.
  • Tabletting was carried out on a 16 station piccola tablet press with two punches operating fitted with 13mm round concave punches.
  • the resulting tablets were round khaki green tablets with dark green and white flecks which were well compressed and shiny in appearance.
  • the potency of both SNAD and LMWH in the tablets were determined.
  • tablet weight uniformity, hardness and disintegration time were determined.
  • the tablet blend for SNAD (550mg):LMWH (90.000IU) consisted of (w/w%) 94% granules, 5% SNAD, 5% Explotab, 0.5% Aerosil, and 0.5% Mg Stearate and the tablets were formed similarly to the SNAD(1100mg) strength given above.
  • the granules were formulated into tablet blends which displayed good flow properties and greater apparent densities than the SNAD starting material (0.26gcm 3 ).
  • the tablet blends were compressed to form good quality tablets which showed no tendency towards capping or chipping.
  • the SNAD (1100mg) tablets fell within 96.5 - 104.1% of the target tablet weight range, while the SNAD (550mg) tablets fell within 98.9 - 100.9% of the target tablet weight range.
  • the SNAD potency of both batches of tablets were >94% of the theoretical potency. Disintegration times for both tablet batches were both ⁇ 13 minutes in deionised water.
  • the SNAD (1100mg) tablets were administered in a three tablet dose to beagle dogs to provide a total dose of 1100mg of SNAD and 90, 000IU of LMWH.
  • the SNAD (550mg) tablets were administered in a two tablet dose to beagle dogs to provide a total dose of 550mg of SNAD and 90, 000IU of LMWH.

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Abstract

L'invention concerne une forme posologique orale solide contenant un médicament du type héparine mélangé à un support pour permettre à cette forme posologique d'empêcher la précipitation du vecteur durant son transit dans les régions à faible pH du tube digestif ; ce procédé permet ainsi, d'une part, le cheminement simultané du médicament d'héparine et du vecteur dans le tube digestif et facilite, d'autre part, l'absorption et/ou améliore la biodisponibilité du médicament du type héparine. Le vecteur est choisi dans le groupe composé des SNAC, des SNAD, de sels et d'esters de ceux-ci ainsi que de combinaisons de ces derniers, pharmaceutiquement acceptables.
PCT/US2000/004559 1999-02-22 2000-02-22 Forme posologique orale solide contenant de l'heparine ou un heparinoide combinee a un support WO2000048589A1 (fr)

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