JP2001515862A - Controlled release microsphere delivery system - Google Patents

Abstract

(57) A composition that may be used to provide a release rate of a drug that is approximately linear over time and to not produce a significant burst effect, the composition comprising a drug and a fatty acid. A pharmaceutical composition comprising a polymeric microsphere.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to certain new drug delivery compositions comprising biodegradable microspheres and / or microcapsules, which are particularly useful in parenteral drug delivery.

[0002]

[Prior art]

Olanzapine is 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] -benzodiazepine. It is a serotonin (5-HT ₂ ) and dopamine (D ₁ / D ₂ ) receptor with anticholinergic activity. The preparation of olanzapine is described in U.S. Pat. No. 5,229,382, which is incorporated herein by reference. The comparative pharmacology of this mixture is described by A. Moore et al., Curr. Opin. Invest. Drugs
2, 281 (1993). This drug is currently on the market as a daily oral tablet formulation.

[0003] Encapsulation of drugs into microspheres of polymers is a well-established technique,
There are various reviews and books (eg, DG, Microencapsulation and Related Pharmaceutical Processes, Decker, New York, 1987, and Langer, Biodegradable Polymers as Drug Delivery Systems, Decker, New York, 1919).
90). A variety of drugs, including peptides and proteins, as well as low molecular weight conventional drugs, have been incorporated into polymers such as polylactic coglycolide. The purpose of encapsulation is generally to provide a sustained or controlled release of the therapeutic reagent or antigen.

[0004] Microencapsulation processes by emulsification and solvent removal are well known in the art (
U.S. Pat. No. 3,523,906, U.S. Pat. No. 3,523,907, U.S. Pat. No. 3,960,757). U.S. Pat. No. 3,691,090 describes that an organic solvent is evaporated from a dispersion of microparticles held in an aqueous medium.

[0005] US Pat. Nos. 4,389,330 and 4,530,840 describe the preparation of microparticles containing an active reagent. First, the active reagent and the wall constituent reagent are dissolved in a general solvent. Thus, the solution is dispersed in a suitable unmixed solvent such as water. Then, the solution is evaporated to form microparticles containing the active reagent. The final residual solvent can be removed by an extraction process. The particles can range in size from less than 1 μm to 100 μm or more. In the formulation of controlled release microparticle systems, their prior art references do not mention the use of fatty acids.

[0006] The use of polylactic coglycolide materials as controlled delivery of neuroleptics has been demonstrated by haloperidol (WO 94/10982), respyridone (WO 95/138).
14) and fluphenazine (lamtoula et al., J. Microencaps. 2,
415 (1992)). Encapsulation of chloropromazine in polyactizide was performed by Suzuki and Price. J. Phar
m. Sci. 74, 21 (1985). Sustained-release microspheres containing antipsychotics were reported by Shigeni et al. In Chem. Abs. 121 (6) Abs
Tract 65597. However, none of these references disclose preparations containing fatty acids.

[0007] Carboxylate surfaces as emulsifiers in oil in water emulsions used to prepare microspheres with spherical nuclei formed from biodegradable polymers such as polylactic acid and poly (lactic coglycolide) The use of activators is described in the prior art, such as U.S. Pat. No. 4,384,975 and Fong et al. Control
led Release 1, 119, (1986). In these documents, the chemicals are referred to as polymer solutions (containing organic solvents) and aqueous solutions (containing organic solvents).
(Containing sodium oleate or potassium oleate as an emulsifier). However, there is no mention or suggestion of the use of free fatty acids as components of the microspheres.

When a drug such as olanzapine is useful, such as in schizophrenia, patient compliance is life-critical. It is often observed that patients refuse oral drug administration for reasons related to the signs of their condition. For improved patient compliance, for example, an intramuscular formulation of such a drug would be beneficial in improving long-term activity. In this regard, particularly for intramuscular or subcutaneous administration, which provides a stable cytoplasmic concentration of the drug, if such preparations can stabilize the drug that can actually modulate the disease and provide a sufficiently high concentration. It is expected that controlled release preparations of drugs such as olanzapine will be effective.

[0009] Encapsulation of large amounts of a drug, such as olanzapine, in a microsphere preparation may cause a high initial release of the drug (ie, a burst effect). (In fact, applicant has confirmed in experiments that this is the case (see below).) Something like a burst effect has been associated with the toxicity of drugs and sedatives (for drugs like olanzapine). This results in unacceptable side effects, including problems.

Surprisingly, we can prepare novel microparticles containing drugs such as polyglycolide co-glycolide (eg, basic drugs such as the neuroleptic olanzapine), polymers and fatty acids. Discovered that it could provide a formulation with little or no burst effect, as well as zero order release of the drug over time.

[0011] We use simple techniques, such as the oil-in-water emulsification method, to incorporate drugs such as olanzapine into polymeric (eg, polylactic coglycolide) microparticles, without the presence of fatty acids. Below, we have found that unacceptable burst effects occur. Conversely, we believe that a particulate composition comprising fatty acids, basic drugs (and more particularly neuroleptic drugs) in biodegradable polymer microparticles not only enhances the drug loading of the microspheres, but also minimizes them. Have been found to result in an initial burst of and a substantially (ie, substantially) linear drug release. Such compositions are neither described nor proposed in the prior art literature.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION

According to the present invention, there is provided a pharmaceutical composition comprising polymer microparticles containing a drug mixed with a fatty acid (hereinafter, referred to as “the composition of the present invention”).

[0013] The compositions of the present invention may include biodegradable and / or biocompatible microparticles, particularly including the basic drug, and more particularly including thioenol benzodiazepine (eg, olanzapine) and fatty acids.

Preferably, the drug is weakly basic. By the term "weakly basic" we mean a mixture having a pKa of 10.5 or less.

The mixture of the present invention may be prepared by dispersing a drug and a fatty acid in a polymer solution using a standard aqueous surfactant solution such as an emulsifier.

In particular, the compositions of the present invention may be produced by emulsification of a solution of a biodegradable polymer and a fatty acid, preferably to provide a wall building material or a matrix material. In such a method, the polymer and fatty acid are first dissolved in a suitable organic solvent and then dispersed in an aqueous environment as an oil-in-water emulsion or oil-in-oil emulsion in a water-insoluble environment. Disperse as an object. The solid particles can then be produced by a suitable treatment such as solvent evaporation or spray drying to remove the organic solvent. Suitable drugs for use in the compositions of the present invention include, but are not limited to, neuroleptics such as thioenol benzodiazepines (eg, olanzapine), benzodiazepines such as chromazepam, clobazam, diazepam,
Includes acetophenazine maleate, bromoperidone, rispyridone, chloroprotizene, haloperidol, phenothiazines such as fluphenazine, fluspirylene, and sex hormones such as danazol.

The term “neuroleptic” will be well understood by those skilled in the art in the following literature (eg, Martindale, “The Extra Pharm”
acopoeia ", 31st edition, Royal Pharmaceutical S
ocietyy (1996), p. 669 or less, and the Dorland Illustrated Medical Dictionary, 28th edition, W.C. B. Sanders (1994), p. 110). The term most preferably refers to a mixture selected from the group consisting of haloperidol, clozapine, respyridone, amisalpride, Seroquel® (quetiapine), searchdol, ziprazidone, zotepin, and olanzapine. The most preferred neuroleptic is olanzapine. The term "neuroleptic" includes both basic and acidic drugs; however, basic, especially weakly basic, neuroleptics are preferred.

[0018] A particularly useful polymeric material that may be used in the compositions of the present invention comprises polylactic coglycolide (PLG). PLG is available in a variety of molecular weights and molecular ratios of polyglycotide to polyglycolide from known manufacturers (eg,
Boehringer Ingelheim). PLG is preferred because it is degraded into materials that are incorporated into its established regulatory mode and metabolic pool.

The ratio of lactide to glycolide is from 85:15 or so, preferably from 7:15.
It may be 5:25 or so, and more preferably 50:50. PL
The preferred molecular weight for the G polymer material is Mark Houwink Equa
4 to 50 kD, which will be determined by Tion (MHE), and 20 to 15 as determined by gel permeation chromatography using polystyrene standards.
The range is 0 kD. When the characteristics of the polymer are shown by the conditions of the intrinsic viscosity, a preferable range is 0.2 to 1.2 dl / g.

Suitable fatty acids that may be used in the compositions of the present invention include mixtures containing saturated or unsaturated, linear or branched, acyclic hydrocarbon chains having one or more carboxyl groups. In the present invention, the C ₈ chain length may be a fatty acid is used containing shall to have a up to C _24; chain length of from C ₁₄ however until C ₂₀ is more preferable.

A more preferred fatty acid is oleic acid. Oleic acid available on the market may consist primarily of octadeca-9-enoic acid and may contain some stearin and palmitic acid. Ricinoleic acid is another preferred material. The ricinoleic acid available on the market may consist primarily of 12-hydroxy-9-octadecenoic acid, and may also contain other fatty acids obtained from the hydrolysis of castor oil from which ricinoleic acid was obtained.

A suitable concentration range for fatty acids in the composition of the invention is 1 to 50% w / w (ie wt%, which is expressed as a percentage of the mass of the microparticles), preferably 5%. To 30% w / w, most preferably 10 to 20% w / w. A suitable concentration range for the polymeric material in the compositions of the present invention is 5 to 98% w / w (ie, wt%, which is expressed as a percentage of the mass of the microparticle), preferably 1%.
0 to 96% w / w, most preferably 20 to 90% w / w.

The compositions of the present invention not only provide high loading of the drug (over 10% w / w, which is expressed as a percentage in the final formulation), but also provide a nearly linear drug release, For example, it may be able to be provided in vitro for 30 days or more, and may not cause significant burst effects.

By the term “substantially linear release” we mean that the release follows essentially zero order kinetics and that a plot of release rate versus time can best be described by a linear relationship. I have. The deviation allowed from that line is
0 to 5 over the major part of the release of the drug from the composition according to the dosing regimen indicated below.
It is in the range of 0%, preferably 0 to 25% and more preferably 0 to 10%. In other words, by the term "substantially linear release" we mean that the release rate of a drug is essentially constant over a major part of the time during which the drug is released according to the dosing regimen set out below. Means. The range of deviations allowed from "constant" is 0% over the major part of the release of the drug from the composition according to the dosage regime shown below.
To 50%, preferably 0 to 25%, more preferably 1 to 10%. By the word "major part" of the drug release, we follow the following dosing regimen:
For example, it refers to the time between any initial burst that may occur on the first day and a "tailing response" that may occur at the end of the release. The major part of the release typically comprises at least 80%, preferably at least 90%, of the total time of release of the drug.

The term “without significant burst effect” refers to a day (eg, as measured in an in vivo dissolution test using a phosphate buffered saline solution as its release medium).
That is, the loaded drug released on the first day following administration) is less than 30%, preferably less than 25%, more preferably less than 23% and particularly preferably less than 2%.
0% or less (for example, see below).

The compositions of the present invention may provide a long, almost linear release of the drug,
May not have a significant burst effect. In addition, the compositions of the present invention may be readily utilized to provide a substantially linear release according to techniques such as those described below to avoid significant burst effects.

The composition of the present invention may be in a size range suitable for injection, such as between 1 and 500 μm, preferably or between 20 and 150 μm, as measured by a suitable technique such as laser diffraction.

[0028] The route of administration and the rate of release often dictate the size of the microspheres. Similarly, the choice of polymer (eg, in the case of PLG, the condition of the ratio of lactide to glycolide)
, And the molecular weight of the polymer molecules can be utilized to achieve different release rates of the encapsulated material. Furthermore, the choice of fatty acid content and fatty acids can provide further control over the release rate of the encapsulated material.

[0029] The microparticles can be administered using methods known in the art. Most preferably, the microparticle is administered parenterally.

As used herein, the term “microparticle” includes microspheres, microcapsules and the like. We use the term "microsphere" herein to indicate a particle that distributes the drug by a polymeric matrix (eg, as a unit therein). We will use the term "microcapsules" herein to refer to microparticles whose drug acts like a coating or shell and particles contained (eg, as crystals) within the polymer core. use.

The properties of the microspheres and microcapsules can be controlled by the amount of polymer, fatty acid and drug encapsulated in the polymer particles.

The appropriate dosage regimen for a particular drug can be readily determined by a physician or skilled person based on the condition of the patient and the characteristics of the drug. For example, a preferred olanzapine dosage is 1 to 25 mg / kg. More preferably, the dose is between 5 and 10 mg / kg.

The compositions of the present invention can be administered to mammals via a delivery device in a suitable dosage form according to techniques well known to those skilled in the art. However, we prefer that the compositions of the present invention be administered parenterally. By the term "parenteral administration", we allow injection into warm-blooded animals by the subcutaneous, intramuscular, intravenous, epidural, or subarachnoid route or such methods known to those skilled in the art. Means to deliver. Further preferred routes of administration are subcutaneous and intramuscular.

The compositions of the present invention are polymer biodegradable and biocompatible designed to provide an effective amount of an active ingredient (ie, a drug; such as a neuroleptic) over an extended period of time. May be included. A preferred embodiment is a single administration of drug-loaded microparticles to release the drug over an extended period of time so as to avoid the need for repeated injections.

The present invention provides for controlled delivery of drugs, such as neuroleptics, for a period ranging from 5 to 100 days depending on the microparticle system selected. A preferred embodiment is to provide a release for between 10 and 50 days, and more preferably between 20 and 40 days. The duration can be controlled by the choice of polymer, microsphere particle size, fatty acid selection and appropriate choice of drug loading. A more preferred embodiment is release over a period of about 14 to about 30 days. By the word "approximately" we mean plus or minus 5 (eg, 2) days for the shortest period of the release period range and plus or minus 1 for the longest period of the release period range.
It means 0 (for example, 5) days.

The wall configuration or substrate polymer may be selected from a range of materials known in the art. The range of materials includes polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolide, polycaprolactone, polyalkanoic acids (especially mixtures of polyhydroxybutyrate and polyhydroxyvalerate), polyorthoesters , Including polyanhydride. A preferred polymer is polylactic acid coglycolide (P
LG) and the preferred ratio of lactide to glycolide is about 50:50. The molecular weight of the selected polymer will be chosen after considering the fatty acids to provide the required release rate. A suitable molecular weight for the polymer is 2
To 200 kD. Its preferred material (polylactide coglycolide)
Has a molecular weight (intrinsic viscosity) in the range of 9-50 kD or so. A particularly preferred molecular weight range is 25 kD or so.

The polymers can be used alone or in combination. A preferred material is the copolymer polylactic acid coglycolide (PLG).

The microparticles may be produced by a suitable oil in water method following a solvent removal treatment or other treatment known to those skilled in the art. Such solvents include those that are immiscible in an aqueous environment and include ethyl acetate, benzyl alcohol, dichloromethane and halogenated hydrocarbons. More preferred solvents are dichloromethane and ethyl acetate. Methods including spray drying, coacervation (colloid demixing phenomenon), solvent evaporation, heating and / or cooling coagulation, supercritical solutions, and other methods known to those skilled in the art may be used.

A preferred method for preparing the fine particles is by an emulsification solvent evaporation method. The chemicals, fatty acids and polymers (eg, polylactic coglycolide (P
LG)) is co-dissolved in a suitable solvent such as dichloromethane. This oil layer is mixed and emulsified with an aqueous solution containing an emulsifier such as polyvinyl alcohol. Stirring may assist this emulsification process. The emulsion may be stirred at room temperature for up to 24 hours for solvent evaporation. The microparticles may be collected by a suitable method such as centrifugation, washed with a suitable solvent such as water, and then dried (eg, by lyophilization). The dried particles may be sieved to recover a suitably sized fraction.

The emulsion may (and generally will) be stabilized by a suitable emulsifying reagent. Materials that may be relevant to the end of this specification include polyvinyl alcohol, polyvinylpyrrolidone, bile salts and non-ionic surfactants. A preferred emulsifying material is polyvinyl alcohol. Suitable concentrations are from 0.25 to 7% w / v. The preferred concentration is 1-3% w / v. The size of the resulting particles may be controlled by processing conditions, including agitation, organic / aqueous layer volume ratio, size and shape of the processing vessel.

A size in the range of 1-500 μm is suitable for parenteral administration. A size of 20 to 150 μm, for example 60 to 120 μm, is preferred.

The solvent can be removed by evaporation or spray drying, or by solvent extraction involving the use of a supercritical solution.

[0043] The particles may be stored dry and mixed with a suitable pharmaceutically acceptable diluent to aid administration. Such diluents include aqueous sodium carboxymethyl cellulose solutions and may or may not include stabilizers (such as surfactants, such as polysorbate), sesame oil, and miglyol A12.

Fatty acids suitable for use in the compositions of the present invention include oleic, linoleic, linoleic, ricinoleic, capric, elaidic, lauric, stearic, palmitic, arachidonic, pentane Includes sandinonic acid and highly unsaturated fatty acids such as eicosapentanoic acid and docosahexanoic acid. Oleic acid is a more preferred material. Hydroxylated fatty acids may also be used.
Litinoleic acid (hydroxylated fatty acid) is also a preferred material.

The microparticles can be produced in a sterile manner through aseptic processing and may be processed after conditioning with gamma radiation of 2 Mrad or more per dose.

In the compositions of the present invention, the drug loading will depend on the physicochemical properties of the mixture, but in lipophilic materials from 1 to 90% (ie, as a percentage of the mass of the microparticles). Wt%). By the term "lipophilic mixture" we mean a mixture in which the partition coefficient between 1-octanol and an aqueous buffer solution, measured at pH 7.0, is 10 or more. More preferably, the compositions of the present invention comprise from 1 to 50% of the active reagent, most preferably 1 to 50%.
It may contain 0-35% active reagent.

For the avoidance of doubt, the terms “drug” and “therapeutic reagent” shall herein include drugs / reagents suitable for use in treating and preventing disease.

The compositions of the present invention may be utilized to treat / prevent a disease / condition in a mammalian patient depending on the therapeutic reagent used. In contrast to the above list of drugs, which is not meant to be limiting, the diseases / conditions monitored are those whose therapeutic reagents are known to be questionable but effective, and those described by Martindale, "The Extra Pha.
rmacopoeia ", 31st edition, Royal Pharmaceutical
Includes those that are questionable in Society (1996) but are specifically labeled for that drug. If the composition according to the invention comprises a neuroleptic, the invention relates to the treatment of a warm-blooded animal suffering from or susceptible to a psychotic disorder by parenteral administration of a composition as according to the invention. Provide a way.

The term “dissolution test” as used herein means a method known to those skilled in the art.

The present invention is illustrated by the following examples, which are not meant to be limiting in any way:

FIG. 1 shows PLG (50/5) loaded with 28.6% olanzapine; 30.8% olanzapine / 7.7% oleic acid; and olanzapine / 15.4% oleic acid.
0; 9 kD) shows cumulative release of olanzapine from microspheres (particle size is less than 250 μm).

FIG. 2 shows PLG (50/5) loaded with 28.6% olanzapine; 30.8% olanzapine / 7.7% oleic acid; and olanzapine / 15.4% oleic acid.
0; 25 kD) shows cumulative release of olanzapine from microspheres (particle size is less than 250 μm).

FIG. 3 shows PLG (50/5) loaded with 30% olanzapine / 15% oleic acid.
0; 9 kD) shows cumulative release of olanzapine from microspheres (particle size is less than 250 μm).

FIG. 4 shows PLG (50%) loaded with fatty acids ranging from 30% olanzapine / 15%.
/ 50; 25 kD) shows cumulative release of olanzapine from microspheres (particle size is less than 150 μm).

FIG. 5 shows PLG (50/5) loaded with 30% olanzapine / 15% oleic acid.
0; 9 kD) shows in vitro release of olanzapine from microspheres (particle size is less than 150 μm).

FIG. 6 shows PL following loading with 30% olanzapine / 15% oleic acid.
5 over time from G microspheres (particle size is 150 μm or less)
1 shows the cytoplasmic concentration of olanzapine in a group of beagle dogs.

[0057]

EXAMPLE 1 does not contain additional fatty acid, 28.6% of olanzapine PLG microspheres (particle size is 250μm or less) (demonstrating that such in the child provide release properties frustrating a simple preparations Comparative example to perform)

100 mg of olanzapine and 250 mg of PLG (50/50, 9 kD or 25 kD) were co-dissolved in 2-3 ml of dichloromethane to form an oil layer. The oil layer was dropped into 100 to 150 ml of a cooled aqueous layer containing 1% polyvinyl alcohol (PVA) and emulsified at 1000 rpm. The resulting o / w emulsion was continuously stirred at room temperature for 4 hours continuously. The microspheres were collected by centrifugation, washed with water and lyophilized. The dried particles were sieved through a 250 μm sieve to remove any aggregates and then stored in a desiccator at room temperature. Duplicate samples of drug-loaded PLG microspheres containing approximately 5 mg of olanzapine were accurately weighed and suspended in two separate 500 ml pH 7.4 PBS solutions. The solution was kept warm at 37 degrees and stirred slowly twice a day for 1 hour.

At the appropriate time after the start of the test, 5 ml of the supernatant was removed from each solution and passed through a 0.2 μm membrane filter into screw vials. Thereafter, 5 ml of fresh PBS solution was added to each solution. The samples were evaluated for drug content by the UV method at 228 nm wavelength.

FIGS. 1 and 2 show the results. Cumulative release of olanzapine indicates rapid drug release from formulations produced at 50:50, 9 kD and 25 kD molecular weight of PLG without added fatty acids. Such particles would not be suitable for administration to a patient due to the high initial burst of drug.

[0061]

EXAMPLE 2 30.8% olanzapine: 7.7% w / w PLG microspheres body loaded with oleic acid (particle size is 250μm or less) olanzapine 200mg, oleic acid and 400mg of 50 mg PLG (
(50/50; 9 kD or 25 kD) was co-dissolved in 4 ml of dichloromethane to form an oil layer. 200 m containing 1% polyvinyl alcohol (PVA)
The mixture was added dropwise to the cooled aqueous layer (1) and emulsified at 1000 rpm. The resulting o / w emulsion was continuously stirred at room temperature for 4 hours continuously. The microspheres were collected by centrifugation, washed with water and lyophilized. 250 μm of the dried particles
To remove any aggregates and then stored in a desiccator at room temperature. The drug release form of the microspheres was determined as described in Example 1. Figures 1 and 2 show that the addition of 7.7% oleic acid reduces the release of olanzapine.

[0062]

Example 3 PLG microspheres loaded with 30.8% olanzapine / 15.4% w / w oleic acid (particle size is less than 250 μm) 200 mg olanzapine, 100 mg oleic acid and 350 mg PLG
(50/50; 9 kD or 25 kD) was co-dissolved in 4 ml of dichloromethane to form an oil layer. The oily layer is made up of 200% with 1% polyvinyl alcohol (PVA).
The solution was dropped into a cooled aqueous layer of ml, and emulsified at 1000 rpm. The resulting o
The / w emulsion was continuously stirred at room temperature for 4 hours continuously. The microspheres were collected by centrifugation, washed with water and lyophilized. 250 μl of the dried particles
m to remove any aggregates and then stored in a desiccator at room temperature. The drug release form of the microspheres was determined as described in Example 1.
Figures 1 and 2 show that the addition of 15.4% w / w oleic acid reduces the release rate of olanzapine. If the molecular weight of the polymer is 25 kD, there is almost no burst effect and the release profile is essentially linear over 10 days.

[0063]

Example 4 PLG microspheres loaded with 30.8% olanzapine / 15% oleic acid (particle size is less than 250 μm) 218 mg olanzapine, 109 mg oleic acid and 400 mg PLG
(50/50; 9 kD or 25 kD) was co-dissolved in 4 ml of dichloromethane to form an oil layer. The oily layer is made up of 200% with 1% polyvinyl alcohol (PVA).
The solution was dropped into a cooled aqueous layer of ml, and emulsified at 1000 rpm. The resulting o
The / w emulsion was continuously stirred at room temperature for 4 hours continuously. The microspheres were collected by centrifugation, washed with water and lyophilized. 150 μm of the dried particles
m to remove any aggregates and then stored in a desiccator at room temperature. The drug release form was determined as described in Example 1. In FIG. 3, the results show that a linear release of olanzapine can be obtained using PLG with 15% oleic acid and a molecular weight of 25 kD.

[0064]

EXAMPLE 5 30% of olanzapine and PLG microspheres fatty acids was loaded in the range of 15% (particle element size is 150μm or less) oleic acid 109mg had been described in Example 4, the fatty acid of a range (Arachidonic acid, docosahexanoic acid, eicosapentanoic acid, linoleic acid, linoleic acid and ricinoleic acid). The adjustment and the drug release measurement were as in Example 4. The molecular weight of the PLG polymer was 25 kD in all cases. The results, shown in FIG. 4, indicate that different release rates can be obtained by selecting different fatty acids. The essentially linear properties obtained in arachidonic acid, ricinoleic acid and linoleic acid appear to have utility.

[0065]

Example 6 Evaluation of Olanzapine Microspheres In Vivo Using a Dog Model The prescription unit of olanzapine (4 g) for animal experiments was prepared as described in Example 4. The polymer was 50:50 PLG with a molecular weight of 25 kD. The particles were loaded with 30% w / w olanzapine using 15% w / w oleic acid. The dissolution form was measured as described in Example 1. FIG. 5 shows the results of the dissolution. Almost linear characteristics of olanzapine were obtained. In the experiment,
The amount of intact olanzapine remaining in the microspheres was measured.

Samples of microspheres were removed from the lysis media on days 7 and 14. After lyophilization of the sample, it was analyzed by HPLC using an effective method to determine the amount of intact olanzapine. Table 1 shows the amount of olanzapine released into the lysis medium on days 7 and 14, respectively, and the amount remaining in the microspheres compared to the theoretical amount if the amount released was the correct result. And the amount of olanzapine to be used. All of the unreleased olanzapine appears to be completely captured from the microspheres.

[0067]

[Table 1] * Calculated from the amount of olanzapine released into the lysis medium and the olanzapine content of the microspheres at the beginning of the lysis experiment.

The olanzapine microspheres were administered intramuscularly to a group of five beagle dogs. The microspheres were suspended in a dosing medium containing 2% CMC and 0.15% Tween 80 using a 21 gauge needle. The dose of drug was 5 mg / kg. The cytoplasmic concentration of the drug was determined by a validated HPLC method. The results in FIG. 6 show that stable concentrations of the drug were obtained over the long term in the required range of 10-20 mg / ml.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/22 A61P 25/22 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, G E, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN , MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (71) Applicant West Pharmaceutical Services Drug Delivery and Clinical Research Center Limited WEST PHARMACEUTICAL SERVICES DRUG DELIV ERY & CLINICAL RESE ARCH CENTRE NL Nottingham, University Ballard, Nottein Mu Science and Technology Park, Albert Einstein Center (72) Inventor Ilm Lisbeth UK, N.G. 71, Nottingham, The Park, 19 Cavendish Crescent North (72) Inventor Cheng Yuhui, N.G. Nottingham, Beeston, 74 E Dennis Avenue (72) Inventor Watts Peter James United Kingdom, NG26 D.R., Nottingham, West Bridge Ford, 47 Highfield Road, Flat 2 (72) Invention Person Davis Stanley Stewart United Kingdom, NG71 BIA, Nottingham, The Park, 19 Cavendish Crescent North F-term (reference) 4C076 AA64 AA95 CC01 DD41 DD43H EE06 EE48H FF21 FF32 4C08 6 AA01 AA02 CB26 MA02 MA05 MA38 NA10 NA12 NA13 ZA18

Claims (21)

[Claims] 1. A pharmaceutical composition comprising microparticles of a polymer comprising a drug and a fatty acid. 2. The composition of claim 1, which is suitable for providing a substantially linear release rate of said drug. 3. The method according to claim 1, wherein the drug is suitable for providing an initial release of the drug, as determined using a dissolution test using a phosphate buffered saline solution as less than 25% of the release medium. Composition. 4. The composition according to any one of the preceding claims, wherein the drug is weakly basic. 5. The composition according to claim 1, wherein the drug is a neuroleptic. 6. The method according to claim 1, wherein the drug is olanzapine.
The composition described in any one of the above. 7. The composition according to claim 1, wherein the chemical is a copolymer of polylactic acid and polyglycolic acid. 8. The composition according to claim 1, wherein said fatty acid is oleic acid or ricinoleic acid. 9. The composition according to any one of the preceding claims, wherein said microparticles comprise from 1 to 90% w / w of an active reagent. 10. The composition according to any one of the preceding claims, wherein the size of the microparticles is from 1 to 500 microns. 11. The composition according to claim 10, wherein the size of the microparticles is in the range from 20 to 150 microns. 12. The composition according to any one of the preceding claims, wherein the microparticles comprise from 1 to 50 wt% of the active reagent. 13. The composition of claim 12, wherein said microparticles comprise from 10 to 35 wt% of an active reagent. 14. A pharmaceutical preparation comprising a composition according to any one of the preceding claims and a pharmaceutical carrier. 15. The method of claim 1, further comprising mixing the drug with a fatty acid and encapsulating or dispersing the composite in a polymeric material.
A method for preparing a composition according to any one of the above. 16. A method for treating a warm-blooded animal suffering from or susceptible to a psychiatric disorder, comprising the oral administration of a composition according to any one of claims 1 to 13 or a preparation according to claim 14 to the animal. the method of. 17. Use of a composition according to any one of claims 1 to 13 in the manufacture of a medicament for use in the treatment of a warm-blooded animal suffering or susceptible to a psychotic disorder. 18. A patient in need of such treatment or prevention of a composition according to any one of claims 1 to 13 or a preparation according to claim 14 comprising an active ingredient effective against said disease. A method for the treatment or prevention of a disease, which comprises the administration of a drug. 19. The method according to claim 18, wherein said disease is a psychotic disorder. 20. An agent for the treatment or prevention of a disease comprising administration of the composition to a patient in need of such treatment or prevention, comprising a therapeutic reagent effective against the disease. Use of a composition according to any one of claims 1 to 13 in the manufacture. 21. The use according to claim 20, wherein said disease is a psychotic disorder.