WO1992001446A1 - Sustained-release formulations - Google Patents

Sustained-release formulations 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
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WIPO (PCT)
Prior art keywords
wax
formulation
coating
granules
water soluble
Prior art date
Application number
PCT/GB1991/001153
Other languages
French (fr)
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/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5015Organic compounds, e.g. fats, sugars
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5073Microcapsules 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5084Mixtures 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.

Abstract

Sustained-release formulations of a water soluble or highly water soluble drug comprising sufficient granules to provide a predetermined dose or number of doses. Each of the granules comprises said water soluble or highly water soluble drug and has a coating of a pharmaceutical wax or wax-like material over substantially its whole surface. The granules are optionally further provided with a coating of a polymer or other non-wax material deposited from an aqueous suspension or solution. A method for preparing the formulations is also provided.

Description

SUSTAINED-RELEASE FORMULATIONS
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. Such 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.
Other medical conditions are best treated by administration of 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 α 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
Figure imgf000004_0001
-
maintained at *a relatively constant level over an extended period of time. Particularly suitable periods are twelve hours and twenty-four hours, since such formulations need only be taken once or twice a day to maintain an effective treatment of the condition. Such formulations are generally known as "sustained-release formulations. "
Many 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 desireα properties.
Additional difficulties arise when the pharmacologically active substance to be administered is soluble or highly soluble in water and other aqueous solutions. The term "soluble" as used herein is to be understood as referring to substances which are soluble in up to 100 parts of water. Examples of 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.
Problems experienced in the development of sustained-release formulations of drugs such as isosorbide-5-mononitrate stem largely from their aforementioned high solubility. Attempts to coat beads or pellets (hereinafter referred to as "granules") of the drug with the usual polymers in aqueous solvents have resulted in products in which there is rapid migration of the drug from within the porous granules to the surface of the coating. It appears that some recrystallisation occurs while the coat is drying and this produces fine needles that penetrate the coating, thereby destroying its integrity and causing rapid release of the drug. The present inventors have surprisingly found that such effects can be avoided by first applying to the granules a coating (i.e. a sub-coat) of a drug migration controlling agent (DMCA) .
According LO the present invention there is provided 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 (hereinafter referred to simply as wax) 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.
In a preferred embodiment of the invention, 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:-
i) forming granules comprising the water soluble or highly water soluble drug;
ii) providing each of the said granules with a coating of a pharmaceutical wax or wax-like material,• and optionally
iii) forming an aqueous suspension or solution comprising a polymer or other non-wax material; and
iv) coating at least a proportion of the granules with the said suspension or solution. Most preferably, 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.
This invention is based on the twin discoveries that:
1 ) There is a tendency for a very soluble drug to migrate rapidly to the surface of a coating composed of the usual polymers, and
2) This can be overcome by the application of an initial coating of a pharmaceutical wax. The wax coating inhibits drug migration, but does not prevent water penetrating into the granules to dissolve the drug once the preparation is administered to a patient.
A range of "waxes" were evaluated for their value in controlling the release of water soluble or highly water soluble drugs. The actual drug used in these tests was isosorbide-5-mononitrate. The results obtained are shown in Table I below. itepsol H15 was clearly seen to be the least suitable for this drug, because even with 10% loading all of the drug was released after only 3 hours. Hard paraffin gave better results, but the long chain alcohols (and cetostearyl alcohol in particular) were found to be the most effective of the materials tested with ιsosorbide-5-mononitrate because they give most control over the release of this particular drug.
Table I : Effect of coatings and coating loading on release o isosorbide - 5 - mononitrate.
Figure imgf000008_0001
Witepsol grade = Witepsol H15 Eudragit = Eudragit NE 30D
SUBSTITUTESHEET It will be appreciated that the precise diameter and composition of the granules comprising the water soluble or highly water soluble drug will depend on the actual drug concerned and the time over which the formulation is designed to work. Generally, however, 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.
Turning now to the embodiment wherein at least a proportion of the granules are provided with a further coating of a polymer or other non-wax material, to some extent the diameter of the coated granules and the composition and amount of this further coating will each depend on the time over which the formulation is designed to work. Typically, however, 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. Typically, for every 100 parts of the water insoluble but water swellable acrylic polymer present in the coating, there will be from 20 to 70 parts of the water soluble hydroxy.1-v-i-ed 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.
In addition to the pharmacologically active substance, i.e. a water soluble or highly water soluble drug, the formulations also preferably contain a bulking agent such as 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) . However, 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. If desired, 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. Preferably, 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, is blended with 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.
If desired, a further coating of a polymer or other non-wax material is ihen applied to the granules. In the case of polymer coated 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. Preferably, 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.
It has thus surprisingly been found that the presence of a coating of a pharmaceutical wax, most preferably cetostearyl alcohol, assists in the formulation for sustained-release administration of water soluble or highly water soluble drugs. Examples of such drugs include those mentioned above. The present invention will now be illustrated by the following Examples and which refer to formulations of representative highly water soluble drugs. The Examples are by way of illustration only; they do not necessarily represent fully optimised formulations. The formulations described below v;^re developed using the OSAT system developed by the inventors at the University of Bradford.
EXAMPLE 1
A review of the literature on isosorbide-5- mononitrate suggests that 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.
- 12 -
OSλT FORMULATIONS 1 and 2
1 ) PELLET MANUFACTURE
Isosorbide - 5 -mononitrate mixture 42* *800g Microcrystalline cellulose 58* 1120g Water (to bind) 1000ml
100* 1920g
* Isosorbide - 5 - mononitrate diluted 60:40 with lactos (lot 258 P054).
Microcrystalline cellulose - Avicel PH101 (lot 710161).
* Equivalent to 480g isosorbide - 5 - mononitrate.
The dry ingredients were mixed together using a Hobart mixer Water was added in portions until the components began to bin and the mixture was of a suitable consistency for extrusion The mixture was extruded using an Alexanderwerk extruder t produce lmm slugs which were then spheronised for 1 minute i a Caleva spheroniser. The resulting pellets were drie overnight at room temperature. The pellets were sieved an those with diameters between 0.7 and 2.0mm were collected. 2 ) PELLET COSTING
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 wer rotated in the copper coating pan and the Eudragit NE 30 (Rohm Phaπna, 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 -
3j FORMULATIONS - for dissolution studies
Formulation 1
Pellets (cetostearyl alcohol + Eudragit coated) 151mg - 28mg IS-5- Pellets (cetostearyl alcohol coated) 55mg = 12mg IS-5-
206ng - 40mg IS-5-
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.
Formulation 2
Pellets (cetostearyl alcohol + Eudragit coated) 173mg — 32mg IS-5- Pellets (cetostearyl alcohol coated) 37mg — 8mg IS-5-
210mg 0πg IS-5-
The dose of isosorbide - 5 - mononitrate was 40mg per capsule. 8
(32mg) of the dose was contained in pellets coated with 1 cetostearyl alcohol +20% Eudragit and 20% (8mg) of the dose w contained in pellets coated with 15% cetostearyl alcohol only.
Commercial Formulations
Imdur
60mg sustained release tablet
Astra Pharmaceuticals Limited
PL0017/0226
PA9/36/1
Lot OC-66
Elantan * LA50
50mg sustained release capsule
Schwarz Pharmaceuticals Limited
PL4438/0015
PA271/1/3
Lot 70375
DISSOLUTION TESTING
1 ) ϋ.V. Calibration measurements
Apparatus:
Hewlett Packard diode array spectrophotometer. Model HP451A lcm flow cell.
Drug/lactose mixture (IS-5-MN 40mg) was dissolved in water (IL) . The absorption spectrum was measured between 190 and 820nm at 37°C with distilled water as the reference. One peak was observed at 196nm (d = 0.890).
Interference by lactose in the solution was found to be negligible. The other insoluble components were assumed to be non-interfering.
Using this reference datum in the dissolution studies at 12 hours (complete dissolution) , 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. 2 i Test Conditions
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.
Apparatus:
Caleva Dissolution apparatus model 6ST Watson Marlow pump
Hewlett Packard diode array spectrophotometer model HP451A with 7 cell transport acquisition lcm flow cells
Hewlett Packard twin disc drive model HP9121.
Conditions
- 5 -
Figure imgf000019_0001
3 ) Results
Dissolution profiles are shown in Figures 1 to 5 normalised to 100* release at 12 hours.
Fiσυre 1
Formulation 1
Figure 2
Formulation 2
Figure 3
Pellets coated with cetostearyl alcohol
Pellets coated with cetostearyl alcohol and Eudragit NE30D
Figure 4
Imdur Elantan LA50
Figure 5
Formulation 1 Formulation 2 Imdur Elantan LA50
Figure 3 shows the dissolution profiles of the two types of coated pellets which were mixed to produce Formulations 1 and
2. By changing the proportion of each type of pellet in the mixture, the dissolution characteristics of the dose were changed to produce formulations which gave the required dissolution profiles (Figures 1 and 2) .
SUBSTITUTESHEET The dissolution profile of the sustained release capsule Elantan LA50 (Figure 4) was considered to be a suitable model with which to compare the profiles of Formulations 1 and 2 as this product has been shown to achieve accepted therapeutic levels of isosorbide - 5 - mononitrate in the blood. Figure 5 showed a comparison of the dissolution profiles of Formulations 1 and 2 with the commercial products Elantan LA50 and Imdur. Formulation 1 gave a profile closest to that of Elantan LA50.
SUBSTITUTESHEET — IN — — VITRO ^ -— — I —N VIVO SIMULA —T ^I—ON ^—S
1 ) Methods and data sources
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.
2) RESULTS AND DISCU8SION:
A. Elantan LA
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 subiects in the other two experimental reports thus partl accounting for the differences. For development purposes th agreement is reasonably satisfactory. - 22 -
Imdur
The in vitro - in vivo comparison is shown in Figure 7 Computer data were generated from an input over the first hal hour of 19.3mg followed by infusion of 40.7mg at 6mg/hr fo 6.8 hours. This release pattern was estimated from th dissolution data although it was actually slower in the 5- hour period. Agreement with the in vivo data is reasonabl over the first 12 hours but there is a large discrepancy at 2 hours. The Astra data only shows a single point after 1 hours and this may be inaccurate for some unknown reason.
C. ) OSAT Formulations 1 and 2
Predictions were obtained as before by the graphical and computer methods. For the computer prediction 15.2mg was assumed infused over the first half hour followed by 25 mg at 3.0 mg/hr over 8.33 hours for formulation 1 (70:30 pellet ratio) and 10.8 mg followed by 29.2 mg over 9.7 hours (also 3.0 mg/hr) for formulation 2. Results are shown in Figure 8.
The prediction probably indicates a drug free period of about 6 hours. If a longer period is required a pellet ratio of 60:40 could be considered, or possibly a slightly faster release for the
Eudragit-coated fraction.
EXAMPLES 2 and 3 ) PELLET MANUFACTURE
All pellets were manufactured on a bench scale according to the following formula.
Drug 2.0g
Avicel PH101 2.0g
Distilled water as required.
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.
2 ) PELLET COATING Wax coating
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.
[*approx 15% w/w wax coating achieved. ] Eudragit coating
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.
3) DISSOLUTION TESTING Assay method
To follow drug release from the pellets, the dissolution medium was assayed by measuring the change in its absorbance at a specific wavelength. Several 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. Interference from Avicel PH101, the excipient used in pellet manufacture, was shown to be negligible. l») TEST CONDITIONS
Dissolution tests were performed using an automated
U.S.P. dissolution system.
The mass of pellets used for each test was such that at
100% release, drug concentration in the dissolution fluid was approximately 25mg/l and 50mg/l for oxprenolol hydrochloride (Example 2) and dihydrocodeine tartrate (Example 3), respectively.
APPARATUS
Caleva dissolution apparatus model 6ST
Watson Marlow pump
Hewlett Packard diode array spectrophotometer model
HP8451A with 7 cell transport acquisition CONDITIONS
Figure imgf000028_0001
274nm
Dihydrocodeine tartrate 284n-n 5) RESULTS
The dissolution profiles for drug-wax combinations are shown in the following order.
Oxprenolol hydrochloride Stearyl alcohol (Figu-e 9) (Example 2) Tristearin (Figure Q ) Cetostearyl alcohol (Figure 11 Witepsol E85 (Figure 12) Dynasan 118 (Figure 13)
Dihydrocodeine tartrate Stearyl alcohol (Figure 14) (Example 3) Cetostearyl alcohol (Figure 15) Witepsol E85 (Figure 16) Dynasan 118 (Figure 17)
SURFACE CHARACTERISTICS OF THE PELLETS
Examination method - microscopic Magnification : 10x Illumination : Natural
Pellets coated with Eudraσit NE30D only
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.
Pellets coated with wax and Eudraσit NE30D
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.
6) SUMMARY OF RESULTS
On coating pellets of drug with an aqueous dispersion of Eudragit they frequently softened and 5 fragmented. The presence of a waxy coat prevented this and made coating with Eudragit easier.
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.
From the dissolution studies, it can be seen that coatings of wax and Eudragit significantly affect 15 the rate of release of the drug. All pellets remained intact during dissolution testing, except those with no wax/Eudragit coating. On crushing the pellets after a 12 hour dissolution test, more drug was 0 released, confirming that the wax/Eudragit coatings used are effective in slowing and maintaining release of the drug over longer periods than 12 hours, although in some cases there is evidence of convergence to an asymptote at less than 100% release. 5 The dissolution profiles revealed that the presence of a waxy coat alone does not significantly retard drug release; thus any retardation i;. drug release must be due to the Eudragit coating. In pellets without a waxy coat, the Eudragit had little
30 effect on the dissolution profiles, whereas on wax coated pellets with the same degree of Eudragit coating the rate of drug release was reduced.
Microscopic examination of Eudragit coats on waxed and unwaxed pellets showed that on some of the unwaxed pellets the quality of the coating was poor. No recrystallised drug was seen to protrude through the coat; however it is possible that drug recrystallisation has occured within the coat disrupting its structure; hence its poor appearance (in some cases) and rapid release characteristics.
It is clear that coating of pellets containing oxprenolol hydrochloride and dihydrochloride tartrate with Eudragit NE30D alone does not have the desired effect on the dissolution profile (retardation of release) probably due to poor formation of the coating structure during preparation.
The addition of a layer of waxy material before coating with Eudragit prevents this; in this way drug release can be satisfactorily retarded.

Claims

1. 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.
2. A formulation as claimed in claim 1, wherein the pharmaceutical wax is a long chain alcohol, acid or ester, a paraffin wax or a silicone wax.
3. A formulation as claimed in claim 1, wherein the pharmaceutical wax is a cetyl ester wax or hard paraffin wax.
4. A formulation as claimed in claim 1 , wherein the pharmaceutical wax is cetostearyl alcohol.
5. A formulation as claimed in any one of claims 1 to 4, wherein all or some of the 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.
6. A formulation as claimed in claim 5, wherein the coating is a polymer coating and comprises 100 part- of a water insoluble but water swellable acrylic polymer and from 20 to 70 parts of a water soluble hydroxylated cellulose derivative, the weight of this coating being from 2 to 25% of the weight of the underlying granule.
7. A formulation as claimed in claim 5 or claim 6, which provides sustained-release over a period of up to 48 hours.
8. A formulation as claimed in claim 5 or claim 6, wherein the diameter of the granules coated with the polymer or other non-wax material is between
0.5 and 2.5 mm.
9. A formulation as claimed in claim 6, wherein the diameter of the polymer coated granules is between 0.7 and 1.2 mm, the polymer coating contains from 20 to 40 parts of the water soluble hydroxylated cellulose derivative, and the weight of said coating is between 2 and 10% of the weight of the underlying granule.
10. A formulation as claimed in claim 6, wherein the polymer coating contains 30 parts of the hydroxylated cellulose derivative and which is hydroxypropylmethyl cellulose having a degree of substitution of 28 to 30% of methoxy groups and 7 to 12% of hydroxy groups.
11. A formulation as claimed in any one of the preceding claims, wherein the granules are contained within a capsule.
12. A formulation as claimed in any one of claims 1 to 10, wherein the granules are in tablet form.
13. A formulation as claimed in any of the preceding claims, wherein the drug is isosorbide-5- mononitrate, chlorpheniramine maleate, dextropropoxyphene HCl, dihydrocodeine tartrate, oxprenolcl HCl, pheniramine maleate, promethazine HCl, salbutamol sulphate or morphine sulphate.
14. A formulation as claimed in any one of claims 1 to 12, wherein the drug is ιsosorbide-5- mononitrate.
15. A method for preparing a sustained-release formulation of a water soluble or highly water soluble drug and which comprises:- i) forming granules comprising said water soluble or highly water soluble drug;
li) providing each of the said granules with a coating of a pharmaceutical wax or wax-like material; and optionally
iii) forming an aqueous suspension or solution comprising a polymer or other non-wax material, and
iv) coating at least a proportion of the granules with the said suspension or solution.
16. A method as claimed in claim 15, wherein 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.
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US5958459A (en) * 1991-12-24 1999-09-28 Purdue Pharma L.P. Opioid formulations having extended controlled released
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