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WO1992001446A1 - Formulations a liberation entretenue - Google Patents

Formulations a liberation entretenue Download PDF

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Publication number
WO1992001446A1
WO1992001446A1 PCT/GB1991/001153 GB9101153W WO9201446A1 WO 1992001446 A1 WO1992001446 A1 WO 1992001446A1 GB 9101153 W GB9101153 W GB 9101153W WO 9201446 A1 WO9201446 A1 WO 9201446A1
Authority
WO
WIPO (PCT)
Prior art keywords
wax
formulation
coating
granules
water soluble
Prior art date
Application number
PCT/GB1991/001153
Other languages
English (en)
Inventor
Brian William Barry
Bryan Arthur Mulley
Peter York
Original Assignee
Aps Research Limited
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
Priority claimed from GB909016005A external-priority patent/GB9016005D0/en
Priority claimed from GB919103421A external-priority patent/GB9103421D0/en
Application filed by Aps Research Limited filed Critical Aps Research Limited
Publication of WO1992001446A1 publication Critical patent/WO1992001446A1/fr

Links

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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • This invention relates to sustained-release formulations of water soluble drugs, especially highly water soluble drugs.
  • a method for preparing the formulations is also provided.
  • Some medical conditions are best treated by administration of a pharmaceutical which is formulated to allow the active substance or ingredient to act as quickly as possible.
  • a formulation may comprise an injectable solution or a readily dissolvable tablet or capsule. This type of formulation is useful, for instance, for treating acute pain, such as headaches, or pain associated with sudden trauma, such as an accident.
  • a pharmaceutical in such a way as to sustain its action over an extended period of time.
  • This type of administration is useful, for example, for treating chronic pain, such as that associated with rheumatic or arthritic conditions, or for the treatment of a chronic cardiovascular condition. It can be achieved by repeated administration of an immediate-release tablet or capsule at frequent intervals, for instance every four hours. However, this is generally inconvenient, especially during the night, when it is often necessary to awaken a patient to administer the tablet or capsule. In addition, such multiple dosing may lead to undesirable fluctuations in the plasma concentration of the active substance. It has previously been proposed to produce ⁇ formulation which will release the active substance therein at a controlled rate such that the amount available in the body to treat the condition is
  • sustained-release formulations are generally known as "sustained-release formulations. "
  • sustained-release formulations are already known, but there is no generally applicable method by which such formulations can be designed. Each formulation is dependent on the particular active substance incorporated therein. In designing a formulation, it is generally necessary to take into account many factors, including the rates of absorption and clearance of the active substance, the interaction of the active substance with the excipients and/or coatings to be used in the formulation, the solubility of the active substance and of the excipients and/or coatings, and the effects on the bioavailability of the active substance which may be caused by the excipients and/or coatings. It is, however, not possible readily to predict whether any particular formulation will provide the desired sustained-release, and it is generally found necessary to carry out considerable experimentation to produce a sustained-release formulation having the desire ⁇ properties.
  • soluble as used herein is to be understood as referring to substances which are soluble in up to 100 parts of water.
  • highly water soluble drugs include isosorbide-5- mononitrate, chlorpheniramine maleate, dextropropoxyphene HCl, dihydrocodeine tartrate,oxprenolol HCl, pheniramine maleate, promethazme HCl, salbutamol sulphate and morphine sulphate.
  • Isosorbide-5-mononitrate for example, is a vasodilator and is useful for the treatment of angina pectoris. Immediate-release and sustained-release formulations of this drug have previously been developed. Sustained-release formulations currently available in the United Kingdom include those sold under the names Imdur and Elantan LA.
  • a sustained-release formulation of a water soluble or highly water soluble drug comprising sufficient granules to provide a predetermined dose or number of doses, each of said granules comprising said water soluble or highly water soluble drug and having a coating of a pharmaceutical wax or wax-like material over substantially its whole surface.
  • the pharmaceutical wax or wax-like material acts as a DMCA, and is typically a long chain alcohol, acid or ester, a paraffin wax, such as a hard paraffin wax or cetyl ester wax, or a silicone wax.
  • the pharmaceutical wax preferably comprises a long chain alcohol, most preferably cetostearyl alcohol. Such materials are pharmaceutically acceptable for oral administration.
  • At least a proportion of the aforesaid granules are further provided with a coating of a polymer or other non-wax material deposited from an aqueous suspension or solution and covering substantially the whole surface thereof.
  • the invention further provides a method for preparing these sustained-release formulations and which comprises:-
  • step iv) coating at least a proportion of the granules with the said suspension or solution.
  • the coating of step iv) is applied in several stages, each layer of the coating being allowed to dry before the next layer is applied. In the following description, all parts and percentages are by weight unless otherwise indicated.
  • Table I Effect of coatings and coating loading on release o isosorbide - 5 - mononitrate.
  • each of the granules will have a diameter of between 0.5 and 2.5 mm, preferably between 0.7 and 1.2 mm.
  • Each of the granules has a coating of a pharmaceutical wax covering substantially the whole of its surface.
  • each of the coated granules will have a diameter of between 0.5 and 2.5 mm, preferably between 0.7 and 1.2 mm.
  • a suitable polymer coating for example, comprises a water insoluble but water swellable acrylic polymer and a water soluble hydroxylated cellulose derivative.
  • the weight of this polymer coating will usually be from 2 to 25% of the weight of the underlying granule. Preferably, the weight of this coating is from 2 to 10% of the weight of the granule.
  • the formulations of this invention are characterised by the presence of granules which bear a coating of a pharmaceutical wax. It is to be understood that some or all of the granules may also have a further coating of a polymer or other non-wax material. As will be readily appreciated, by varying the proportion of granules with a further coating it is possible to produce a range of formulations with different release profiles. It is within the ability of persons skilled in the art, through routine trial and experimentation, to determine the proportions of such coated: non-coated granules needed to achieve particular release characteristics.
  • the formulations also preferably contain a bulking agent such as microcrystalline cellulose.
  • a bulking agent such as microcrystalline cellulose.
  • microcrystalline cellulose This is a well known form of cellulose which is partially depolymerised.
  • a particularly suitable microcrystalline cellulose is sold under the name Avicel (a registered trade mark) .
  • Avicel a registered trade mark
  • other conventional bulking agents may also be used, as will be readily apparent to those skilled in the art.
  • the formulations may also contain a diluent, such as lactose.
  • a capillary-active agent such as sodium carboxymethylcellulose, which is sold under the name Ac-Di-Sol (a registered trade mark), may additionally be included. These components are used in conventional amounts.
  • the formulations of this invention may also contain colouring agents, sweetening agents and flavouring agents.
  • a polymer ccr.ting when present, preferably comprises about 30 parts of a hydroxylated cellulose derivative. If too much is present, the coating may become too sticky and the rate of release may become too high. If too little is present, the rate of release may be too low.
  • a particularly suitable hydroxylated cellulose derivative is hydroxypropylmethyl cellulose having a degree of substitution of 28 to 30% of methoxy groups and 7 to 12% of hydroxy groups. However, other equivalent materials such as hydroxypropyl, hydroxyethyl or hydroxymethyl celluloses can be used.
  • the acrylic polymer component of the polymer coating is preferably neutral and may comprise a homopolymer or a copolymer, for instance of acrylic acid esters or methacrylic acid esters.
  • the acrylic polymer is provided as an aqueous dispersion.
  • a particularly suitable acrylic polymer is sold under the name Eudragit (a registered trade mark), which comprises a copolymer of acrylic and methacrylic acid esters and which is usually supplied as an aqueous dispersion containing approximately 30% solids.
  • the formulations of this invention can typically be prepared in the following manner.
  • the pharmacologically active substance i.e. a water soluble or highly water soluble drug
  • other constituents such as a bulking agent and a diluent.
  • the blending is conveniently performed by mixing the components in a dry blender.
  • Some water is next added to produce a slightly cohesive product.
  • This is then extruded, chopped into suitable lengths, spheronised and dried to produce the desired granules.
  • These are then coated, suitably in a coating pan, with a molten pharmaceutical wax and left to cool so that individually coated granules are produced.
  • a further coating of a polymer or other non-wax material is ihen applied to the granules.
  • a suitable coating is prepared, for example, by forming a solution of a hydroxylated cellulose derivative and mixing it with a dispersion of an acrylic polymer. The aqueous mixture is then used to coat the dried granules, prepared as described above, and these are subsequently dried to produce coated granules.
  • the coated granules are then sieved to ensure that they are in the correct size range.
  • the resulting formulations of this invention may be supplied loose with a means for dispensing a measured amount, for instance to be sprinkled on food. Alternatively, they may be provided in sachets containing measured amounts. More preferably, however, the formulations are placed in measured amounts in readily soluble capsules.
  • the capsule may be any of those already known in the art, and may, for instance, comprise a thin gelatin skin. Preferably, the capsule contains a sufficient amount to provide a conventional dose of the pharmacologically active substance.
  • the granules may, if desired, be formed into tablets using conventional tabletting machinery.
  • the 24-hour blood level profile should ideally consist of a period following the administration of a dose where the plasma level rises rapidly to an effective range, is maintained there for about 16 hours and is followed by an essentially drug free period (i.e. a low or zero drug concentration) before the next dose. Since the half- life is about 4 hours, release from the dose form should be completed well before the end of the 16-hour peak phase. Assuming that a suitable active pharmacological blood level is around 400 ng/ml and the inactive phase begins at about 100 ng/ml, this corresponds to a period after complete release from the formulation of about two half-lives, i.e. 8-9 hours. The following account describes the development of a multi-particulate coated bead formulation in capsules, mixed with fast-release beads, which meets these requirements when assessed in vitro by dissolution measurements.
  • Microcrystalline cellulose - Avicel PH101 (lot 710161).
  • Pellets were rotated in a Manesty 16 inch copper coating pa together with 15* w/w cetostearyl alcohol B.P. (Evans, lo 8BY9547) .
  • hot air gun was employed to raise the temperatur in the pan to -55°C to allow the cetostearyl alcohol to melt
  • the pellets became coated with the liquid wax as they rotated
  • the heat source was then removed and, as the wax cooled i formed a smooth coat around individual pellets. The pellet were left to cool whilst being rotated in the pan.
  • a portion of the cetostearyl alcohol coated pellets was give an additional coat of 20* w/w Eudragit NE 30D (calculated wit respect to uncoated pellet dry weight) .
  • the pellets were rotated in the copper coating pan and the Eudragit NE 30 (Rohm Pha ⁇ na, lot 12-88-1276) was applied as a 30* aqueou dispersion in four equal portions. After each portion ha been added, and that stage of the coating procedure completed, the pellets were removed from the pan and placed i an oven at 35°C for approxiinately 3 hours to ensure that eac layer of the coating had dried completely before the next on was added. When the final layer of the coat had been applie the pellets were left to dry overnight in the oven at 35°C. - 1 4 -
  • the dose of isosorbide - 5 - mononitrate was 0mg per capsule. 7 (28mg) of the dose was contained in pellets coated with 1 cetostearyl alcohol + 20% Eudragit and 30% (12mg) of the dose w contained in pellets coated with 15* cetostearyl alcohol only.
  • the dose of isosorbide - 5 - mononitrate was 40mg per capsule. 8
  • Hewlett Packard diode array spectrophotometer Model HP451A lcm flow cell.
  • Drug/lactose mixture (IS-5-MN 40mg) was dissolved in water (IL) .
  • Imdur 60mg was found to contain 6i.7mg of IS-5-MN and Elantan LA50 47.0mg, uncorrected for capsule weight content in both cases. Excipients in these formulations were thus considered unlikely to interfere with dissolution studies.
  • Dissolution tests were carried out on formulations 1 and 2 using an automated U.S.P. dissolution system. Imdur and Elantan LA50 were tested by the same method.
  • Dissolution profiles are shown in Figures 1 to 5 normalised to 100* release at 12 hours.
  • Figure 3 shows the dissolution profiles of the two types of coated pellets which were mixed to produce Formulations 1 and
  • the dissolution data in Section 3.3 were used to predict vivo blood level-time profiles using the pharmacokinetic da recorded by Major et al (Clin.Pharmacol Ther. 1984, 35, 64 659) and graphical and computer methods. Predictions from t in vitro measurements were then compared with in vivo profil published for Elantan LA50 in The American Journal Cardiology, 1988 and in the Schwarz product literatu booklet, and for Imdur from the Astra booklet. Predictio for OSAT formulations 1 and 2 (pellet combinations 70:30 a 80:20) formulations were also made but these await comparis with volunteer studies.
  • Figure 6 shows two experimental in vivo profiles from th American Journal of Cardiology and the Schwarz bookle (although these are multidose studies cumulation is likely t be negligible) . They are in good agreement.
  • the compute predicted curve was obtained by assuming an initial infusio over ⁇ hr of 19.6mg of drug followed by 30.4mg infused ove 7.6hr at 4mg/hr (from the dissolution results).
  • the othe predicted curve was derived by a graphical technique with a initial input as for the computer method, followed by amount each hour calculated from the dissolution data. Dru remaining for release after 8 hours (5 per cent) was assume to be absorbed by 12 hours. Both predicted curves were fairl close to the experimental data, the computer method being th better. It is possible that the kinetic parameters for th subjects in Major's study were somewhat different from th subjects in the other two experimental reports thus partl accounting for the differences. For development purposes th agreement is reasonably satisfactory. - 22 -
  • the dry ingredients were mixed together and distilled water added slowly until a thic paste formed.
  • the paste was then pressed into plastic moulds and allowed to air dry for approximately 12hrs before ejecting the formed pellets.
  • a known quantity of pellets (approx 2g) was rotated in a small copper coating pan together with 20% w/w wax*.
  • a hot air gun was employed to raise the temperature of the pan to allow the wax to melt.
  • the pellets became coated with liquid wax as they rotated.
  • the heat source was then removed and as the wax cooled it formed a smooth coat around individual particles.
  • a known quantity of pellets (approx 2g) were rotated in a small copper coating pan.
  • An aqueous dispersion of Eudragit (NE30D) was added dropwise in small portions, drying was assisted by a gentle stream of cool air directed into the pan. At regular intervals the pellets were removed and weighed until the desired level of coating was reached.
  • the dissolution medium was assayed by measuring the change in its absorbance at a specific wavelength.
  • absorption Deaks were identified for each drug, and the peaks at 274nm (for oxprenolol hydrochloride) and 284nm (for dihydrocodiene tartrate) were chosen as suitable for the purpose because they both exhibit a linear increase in absorbance with increasing drug concentration.
  • the mass of pellets used for each test was such that at
  • drug concentration in the dissolution fluid was approximately 25mg/l and 50mg/l for oxprenolol hydrochloride (Example 2) and dihydrocodeine tartrate (Example 3), respectively.
  • Oxprenolol hydrochloride Stearyl alcohol (Figu-e 9) (Example 2) Tristearin ( Figure Q ) Cetostearyl alcohol ( Figure 11 Witepsol E85 ( Figure 12) Dynasan 118 ( Figure 13)
  • the Eudragit NE30D coat on some oxprenolol hydrochloride and dihydrocodeine tartrate pellets appeared irregular and poorly formed. No spikes of recrystallised drug were observed penetrating from the core though the Eudragit NE30D coat.
  • the Eudragit NE30D coat on some of the oxprenolol hydrochloride and dihydrocodeine tartrate pellets appeared to be of a higher quality in that it was smoother and more evenly formed.
  • Drying cf the Eudragit-coated pellets was initially performed by passing a stream of warm air over the pellets as they rotated in the coating pan. However, as the pellets dried they became extremely " ⁇ 0 adhesive and formed large agglomerates. It was found that if a stream of cool air was used it prevented this and also provided an acceptable drying rate.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

Formulations à libération entretenue d'un produit médicamenteux soluble ou très soluble dans l'eau, comprenant un nombre suffisant de granules pour produire un dosage ou un nombre de doses prédéterminé. Chacun des granules est constitué dudit produit médicamenteux soluble ou très soluble dans l'eau et comporte un revêtement en matière pharmaceutique cireuse ou similaire qui recouvre pratiquement la totalité de sa surface. De plus, les granules comportent éventuellement un revêtement constitué par un polymère ou une autre matière non cireuse, déposé à partir d'une suspension ou d'une solution aqueuse. L'invention décrit également un procédé de préparation de ces formulations.
PCT/GB1991/001153 1990-07-20 1991-07-12 Formulations a liberation entretenue WO1992001446A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB909016005A GB9016005D0 (en) 1990-07-20 1990-07-20 Sustained-release formulations
GB9016005.2 1990-07-20
GB919103421A GB9103421D0 (en) 1991-02-19 1991-02-19 Sustained-release formulations
GB9103421.5 1991-02-19

Publications (1)

Publication Number Publication Date
WO1992001446A1 true WO1992001446A1 (fr) 1992-02-06

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PCT/GB1991/001153 WO1992001446A1 (fr) 1990-07-20 1991-07-12 Formulations a liberation entretenue

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4313726A1 (de) * 1993-04-27 1994-11-03 Byk Nederland Bv Feste Darreichungsform
EP0636370A1 (fr) * 1993-07-01 1995-02-01 Euro-Celtique S.A. Compositions à libération prolongée à base de morphine
GB2281204A (en) * 1993-07-27 1995-03-01 Euro Celtique Sa Sustained release morphine compositions
GB2284760A (en) * 1993-11-23 1995-06-21 Euro Celtique Sa Sustained release morphine compositions
GB2288117A (en) * 1994-03-01 1995-10-11 Euro Celtique Sa Sustained release morphine
EP0742008A1 (fr) * 1995-05-11 1996-11-13 Euro-Celtique S.A. Compositions pharmaceutiques à libération contrÔlée
US5591452A (en) * 1993-05-10 1997-01-07 Euro-Celtique, S.A. Controlled release formulation
US5672360A (en) * 1993-11-23 1997-09-30 Purdue Pharma, L.P. Method of treating pain by administering 24 hour oral opioid formulations
US5807574A (en) * 1995-04-03 1998-09-15 Abbott Laboratories Homogeneous mixtures of low temperature-melting drugs and additives for controlled release
NL1005948C2 (nl) * 1997-05-01 1998-11-09 Inst Voor Agrotech Onderzoek Omhulde stof met gecontroleerde afgifte.
US5833891A (en) * 1996-10-09 1998-11-10 The University Of Kansas Methods for a particle precipitation and coating using near-critical and supercritical antisolvents
WO1998049910A1 (fr) * 1997-05-01 1998-11-12 Instituut Voor Agrotechnologisch Onderzoek (Ato-Dlo) Substance encapsulee a liberation regulee
US5874029A (en) * 1996-10-09 1999-02-23 The University Of Kansas Methods for particle micronization and nanonization by recrystallization from organic solutions sprayed into a compressed antisolvent
US5958459A (en) * 1991-12-24 1999-09-28 Purdue Pharma L.P. Opioid formulations having extended controlled released
US5968551A (en) * 1991-12-24 1999-10-19 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US6399096B1 (en) 1995-09-22 2002-06-04 Euro-Celtique S.A. Pharmaceutical formulation
FR2837100A1 (fr) * 2002-03-18 2003-09-19 Flamel Tech Sa Comprimes a bases de microcapsules a liberation modifiee
US7510727B2 (en) 1994-11-04 2009-03-31 Purdue Pharma L.P. Melt-extrusion multiparticulates
US7514100B2 (en) 2000-10-30 2009-04-07 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8110226B2 (en) 2007-07-20 2012-02-07 Mylan Pharmaceuticals Inc. Drug formulations having inert sealed cores
US8486452B2 (en) 2007-07-20 2013-07-16 Mylan Pharmaceuticals Inc. Stabilized tolterodine tartrate formulations
US20140271758A1 (en) * 2013-03-14 2014-09-18 Syngenta Crop Protection Llc Overcoated powder particles
US8975273B2 (en) 1999-10-29 2015-03-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9655894B2 (en) 2001-05-02 2017-05-23 Purdue Pharma L.P. Once-A day oxycodone formulations
US9814684B2 (en) 2002-04-09 2017-11-14 Flamel Ireland Limited Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations

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WO1989002738A1 (fr) * 1987-09-22 1989-04-06 Aps Research Limited Preparation de nifedipine a liberation soutenue
JPH01287019A (ja) * 1988-05-12 1989-11-17 Tanabe Seiyaku Co Ltd 徐放性製剤

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Cited By (73)

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Publication number Priority date Publication date Assignee Title
US7270831B2 (en) 1991-12-24 2007-09-18 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US5968551A (en) * 1991-12-24 1999-10-19 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US5958459A (en) * 1991-12-24 1999-09-28 Purdue Pharma L.P. Opioid formulations having extended controlled released
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