MXPA00003040A - 2-methyl-thieno-benzodiazepine formulation - Google Patents

Abstract

The invention provides a pharmaceutically acceptable oleaginous or cholesterol microsphere formulation of olanzapine or olanzapine pamoate or solvates thereof. The invention further provides novel olanzapine pamoate salts or solvates thereof.

Description

FORMULATION OF 2 -METIL-TIENO-BENZOD AZEPINE Field of Invention This invention provides a pharmaceutically appropriate formulation of 2-methyl-4 - (4-methyl-1-piperazinyl) -lOH-thieno [2, 3-b] [1,5] benzodiazepine, (hereinafter referred to as " olanzapine ") or a pamoate salt or solvate thereof.

Background of the Invention Olanzapine has been shown as a great promise in the treatment of psychotic patients and is currently marketed for that purpose.

Such psychotic patients are often disobedient, making it difficult to assess whether or not they have received the appropriate dose of the medication. Applicants have discovered that it may be especially desirable to formulate olanzapine in a depot formulation or as a rapid intramuscular formulation to ensure consistent and appropriate dosage of the drug substance and to adapt compliance.

Ref: 32869 Such formulation must be carefully designated and selected due to the tendency of olanzapine to be metastable, to experience a pharmaceutically undesirable discoloration, and to the surprising potency of olanzapine that requires care to ensure homogeneity and stability of the final formulation.

Typically, the artisan should prepare an ester form of the active drug substance to provide sustained release.

Unfortunately, the olanzapine molecule is not sensitive to the formation of the ester product.

In addition, applicants have discovered that olanzapine undergoes undesirable discoloration when contacted with certain excipients including powder mixtures. The discoloration is exacerbated by the environmental conditions of the air, at high temperatures, and by humid environments. Although the phenomenon of discoloration may not produce an increase in the number of total related substances, the color change is generally not considered to be pharmaceutically acceptable for commercial purposes.

In addition, it is known that the pH of muscle tissue can vary with exercise, tension and injuries that can affect the solubility of the drug, and thus the absorption ratio of injectable drugs. Therefore, it is desired to find an injectable sustained release formulation in which the release ratio of the active ingredient is minimally dependent on the pH.

Description of the invention.

Applicants have discovered that a formulation comprising olanzapine or a pamoate salt or solvate thereof as an active ingredient, and one or more carriers, can meet the widely demanded need for such a pharmaceutically appropriate formulation, stable with a controllable release ratio that it may be useful as a depot formulation or for a rapid action for intramuscular or subcutaneous use.

The present invention provides a formulation comprising olanzapine or a pamoate salt or solvate thereof, and an oleaginous or cholesterol microespherical carrier.

The present invention also provides novel pamoate salts of olanzapine. Such salts are especially useful for the preparation of a sustained release formulation in which the release ratio is minimally dependent on the pH of the environment.

Olanzapine can be used. However, applicants have discovered that olanzapine pamoate salts may be preferred for a durable release effect of the above compositions. The different forms of olanzapine solvate or its pamoate salts may be useful, including, for example, the olanzapine D, E and F dihydrates, olanzapine pamoate, and the monohydrate, dimethanolate, THF (tetrahydrofuran) and acetone solvates of the olanzapine. olanzapine pamoate. The bis (olanzapine) pamoate and its solvates may be useful in the current invention. A preferred salt is olanzapine pamoate monohydrate. Bis (olanzapine) pamoate monohydrate is also a preferred salt.

The formulation may contain the most stable anhydrous form, referred to herein as Form II; however, other forms of olanzapine are contemplated.

A typical example of an X-ray diffraction pattern for Form II is as follows where d represents the interplanar space and the intensity represents the typical relative intensities as shown in Table 1: Table 1 Spaces d Intensity 10.2689 100.00 8.577 7.96 7.4721 1.41 7.125 6.50 6.1459 3.12 6.071 5.12 5.4849 0.52 5.2181 6.86 5.1251 2.47 4.9874 7.41 4.7665 4.03 4.7158 6.80 4.4787 14.72 4.3307 1.48 4.2294 23.19 4. 141 11.28 3.9873 9.01 3.7206 14.04 3.5645 2.27 3.5366 4.85 3.3828 3.47 3.2516 1.25 3. 134 0.81 3.0848 0.45 3.0638 1.34 3.0111 3.51 2.8739 0.79 2.8102 1.47 2.7217 0.20 2.6432 1.26 2.6007 0.77 The X-ray diffraction patterns shown above were obtained using a Siemens D500 X-ray powder diffractometer having a wavelength Ka radiation source of wavelength, 1 = 1500'Á.

An especially preferred olanzapine pamoate solvate is pamoate monohydrate having a typical X-ray powder diffraction pattern as represented by the following interplanar spaces and the relative intensities as shown in Table 2.

Table 2 Olanzapine Pamoate Monohydrate Clearances d Intensity 10.76 98 9.20 62 8.38 85 8.18 24 7.62 20 6.67 18 6.56 18 6.51 20 6.44 20 6.11 26 5.88 22 5.64 15 5.38 100 4.90 11 4.72 12 4.64 17 4.48 18 4.35 23 4.29 31 4.24 32 • 4.09 71 4.02 84 3.98 73 3.81 23 3.62 14 3.52 30 3.39 11 3.25 12 2.90 15 2.85 13 Another especially preferred olanzapine pamoate solvate is pamoate dimethanolate having an X-ray powder diffraction pattern as represented by the following interplanar spaces and relative intensities as shown in Table 3.

Table 3 Olanzapine Pamoate Dimetanolate Spaces d Intensity 11.17 73 9.37 17 8.73 40 8.29 23 7.77 14 7.22 24 6.84 31 6.66 54 6.42 11 6.40 11 6.17 26 5.87 12 5.56 100 4.84 11 4.66 17 4.57 26 4.48 22 4.35 19 4.28 19 4.12 94 4.03 91 3.89 52 3.62 44 3.54 11 3.29 16 3.13 16 Yet another preferred olanzapine pamoate solvate is the THF solvate of pamoate having an X-ray powder diffraction pattern as represented by the following interplanar spaces and relative intensities shown in Table 4.

Table 4 Solvate THF Olanzapine Spaces d Intensity 14.59 100 7.78 16 7.24 56 7.00 19 6.37 12 6.04 11 6.01 11 4.85 19 4.69 42 4.39 25 4.28 19 3.95 13 3.84 20 Yet another particularly preferred olanzapine pamoate solvate is the pamoate bis (olanzapine) acetone solvate having a typical X-ray powder diffraction pattern as represented by the following interplanar spaces and relative intensities shown in Table 5.

Table 5 Acetone Solvate of Olanzapine Pamoate Spaces d Intensity 16.87 32 9.58 35 80 8.40 16 8.19 35 7.85 16 7.34 29 7.22 25 7.04 30 6.87 18 6.77 11 6.73 11 6.65 21 6.36 12 6.26 26 5.76 31 5.58 79 5.53 100 5.45 61 5.32 42 5.19 39 5.02 55 4.91 69 4.87 51 4.85 57 4.69 44 4.61 68 4.44 23 4.34 14 4.18 17 4.07 36 3.99 28 3.93 65 3.81 23 3.78 24 3.77 20 3.65 23 3.59 28 3.45 13 3.32 19 3.25 26 An especially preferred olanzapine pamoate solvate is bis (olanzapine) pamoate monohydrate having a typical X-ray powder diffraction pattern as represented by the following interplanar spaces and relative intensities as shown in Table 6.

Table 6 Bis (olanzapine) monohydrate Clearances d Intensity 15.77 26 10.44 23 9.64 24 9.31 13 8.27 23 8.17 14 8.13 14 7.84 27 7.81 30 7.41 60 7.12 40 7.00 13 6.96 13 6.55 45 6.18 53 5.87 38 5.80 19 5.59 89 5.25 26 5.00 34 4.96 31 4.88 61 4.85 73 4.71 34 4.52 19 4.33 11 4.19 100 4.12 48 4.05 39 3.97 30 3.89 31 3.80 29 3.72 20 3.70 21 3.58 33 3.45 27 3.04 13 2.84 16 X-ray powder diffraction patterns for pamoate salts and solvates were collected on a Siemens D5000 diffractometer, using Cu Ka radiation at a wavelength of 1.5406 A. Instrumental conditions: step size 0.01 °, sweep ratio 1.0 seconds / step; 4 ° -35 ° 2 ratio ?; 0.6 mm divergence opening; 1.0 mm dispersed radiation aperture; 0.2 mm reception opening; 560 kV; 40 mA; Kevex solid state detector. Samples were packed in hollow sample containers.

The formulation of the invention may contain substantially pure Form II as the active ingredient. As used herein, "substantially pure" refers to Form II associated with less than about 15% undesired polymorphic form of olanzapine (referred to herein as "Unwanted Form"), preferably less than about 5% Form No Desired, and more preferably less than about 2% Undesired. In addition, Form II "substantially pure" must contain less than about 5% unwanted chemical impurities or residual solvent or water. In particular, Form II "substantially pure" preferably contains less than about 0.05% acetonitrile content, more preferably, less than about 0.005% acetonitrile content.

Form II is the most stable anhydrous form of olanzapine known and is therefore important for the commercial development of pharmaceutically appropriate formulations.

The O-dihydrate refers to a crystalline dihydrate D of polymorph olanzapine (referred to herein as "Dihydrate D") having a typical X-ray powder diffraction pattern as represented by the following interplanar spaces d and relative intensities shown in FIG. Table 7: Table 7 Olanzapine Dihydrate D Spaces d Intensity 9.4511 100.00 7.7098 14.23 7.4482 22.43 6.9807 5.73 6.5252 5.45 5.7076 4.24 5.5539 1.60 . 223 62.98 4.9803 22.21 4.8908 15.03 4. 784 27.81 4.6947 5.15 4.4271 13.00 4.3956 16.63 4.3492 34.43 4.2834 51.38 4.1156 18.32 3.7837 5.30 3.7118 1.56 3.5757 0.71 3. 482 9.39 3.3758 24.87 3.3274 13.49 3.2413 5.97 3.1879 1.04 3. 135 3.18 3.0979 1.43 3. 016 1.95 2.9637 0.48 2. 907 2.42 2.8256 7.46 2.7914 3.61 2.7317 1.47 2.6732 5.19 2.5863 10.62 Another especially preferred dihydrate is polymorphous crystalline dihydrate B of olanzapine (referred to herein as "Dihydrate B") having an X-ray powder diffraction pattern as represented by the following interplanar spaces and relative intensities as shown in Table 8: Table 8 Olanzapine Dihydrate B Spaces d Intensity 9.9045 100.00 6.9985 0.39 6.763 0.17 6.4079 0.13 6.1548 0.85 6.0611 0.99 5.8933 0.35 5.6987 0.12 5.4395 1.30 5.1983 0.67 5.0843 0.24 4.9478 0.34 4.7941 6.53 4.696 1.26 4.5272 2.65 4.4351 2.18 4.3474 1.85 4.2657 0.49 4.1954 0.69 4.0555 0.42 3.9903 0.89 3.9244 1.52 3.3931 0.27 3.3289 0.20 3.2316 0.31 3.1982 0.19 3.1393 0.35 3.0824 0.18 2.9899 0.26 2.9484 0.38 2.9081 0.29 2.8551 0.37 2.8324 0.49 2.751 0.37 2.7323 0.64 2.6787 0.23 2.6424 0.38 2.5937 0.21 Another preferred olanzapine dihydrate is the crystalline polymorph O-dihydrate Dihydrate (referred to herein as "Dihydrate E") having an X-ray powder diffraction pattern as represented by the following interplanar spacings and relative intensities as shown in Table 9: Table 9 Olanzapine Dihydrate E Spaces d Intensity 9. 9178 100.00 9.6046 16.75 7.0163 2.44 6.1987 8.78 6.0971 10.62 . 9179 1.73 4.8087 50.14 4.7150 10.24 4.5335 14.20 4.4531 7.80 4.3648 3.04 4.2726 0.98 3.1450 2.66 3.1225 1.63 3.0880 2.11 2.9614 2.49 2.9014 1.03 2.8695 2.06 2.8359 1.63 2.7647 1.95 2.7582 1.68 2.7496 1.84 2.7421 1.03 2.7347 1.36 2.6427 2.01 X-ray powder diffraction patterns shown here in Tables 7, 8 and 9 were obtained with a cob-re k of wavelength = 1541 Á. The interplanar spaces in the column marked with "d" are reported in Angstroms. The detector was a solid-state detector of lithium silica Kevex.

Dihydrate D of olanzapine is prepared by extensive agitation of olanzapine technique, as described in Preparation 9, under aqueous conditions. The term "aqueous conditions" refers to an aqueous solvent that can be either water or a solvent mixture comprising water and an aqueous solvent that is sufficiently miscible in water to allow the stoichiometric amount required of the water to be present in the mixture of water. solvent. If the solvent mixture is used, then the organic solvent must be removed, first removing the water, and / or replacing with water. The term "extensive agitation" may be from about four (4) hours to about six (6) days; however, the artisan will appreciate that time may vary with reaction conditions such as temperature, pressure, and solvent. It is preferred that the aqueous conditions include an aqueous solvent.

The completion of the reaction can be monitored using X-ray powder diffraction or other methods such as those familiar to the skilled artist. Several such techniques are described below.

Compound characterization methods include, for example, X-ray powder pattern analysis, thermogravimetric analysis (TGA), moisture characteristics, atomization characteristics, differential scanning calorimetry (DSC), titremetric analysis for water, and H1-NMR analysis for solvent content. SEMs, porosity, residual solvents (HPLC), syringe ability, luminous microscopic particle size, area surface, IR (for solvent / crystal form) of higher density, friability to characterize the compound can also be used.

The olanzapine dihydrates described herein in Preparations 9, 10 and 11 are true dihydrates having two water molecules per drug molecule, wherein the water molecules are incorporated into the crystalline lattice of the dihydrate compound.

Carriers that promote slow absorption of olanzapine include both aqueous and non-aqueous compositions.

Aqueous suspensions of olanzapine, pamoate salts of olanzapine or solvates thereof include the PLURONICs, such as PLURONIC F68, which at the appropriate concentrations gel at body temperature. Concentrations of PLURONIC in the range of 40-45% in the presence of olanzapine gels at body temperature and is a preferred composition for this use.

Alternatively, aqueous suspensions of polysaccharide gums, including sodium carboxymethyl cellulose or sodium alginate, may provide a prolonged release of olanzapine, olanzapine pamoate or solvates thereof. Other natural or synthetic biopolymers can be used, such as chitosans, gelatins, collagens, haluronic acids, and the like. In addition, up to about 30% by weight of the release modifying agents can be added.

Aqueous compositions include, but are not limited to, hydrophobic PLURONICs, propylene glycols, polyethylene glycols and oleaginous formulations. Hydrophobic PLURONICs include those with a hydrophilic / lipophilic balance of less than 8 and can be incorporated individually with olanzapine, olanzapine pamoate salts or solvates thereof or in conjunction with more than about 30% by weight of other release modifying agents that slow absorption in the body.

The oleaginous compositions include olanzapine, olanzapine pamoate salts or solvates thereof suspended in or solubilized in oils and oils thickened with anti-hydration or gelling agents. These anti-hydration or gelling agents give the body of the oil a greater viscosity (and therefore greater structural stability) and therefore reduce the penetration of the oil by body fluids, prolonging the absorption of medication.

The oil is preferably chosen from oils that are readily obtainable in a reasonably pure form and which are physiologically and pharmaceutically acceptable. Of course, the oil must be sufficiently refined to be stable to storage, without producing a precipitation at rest, without having any chemical reaction observed, and without having any physiological reaction observed when it is administered to the body. Preferred oils are vegetable oils such as soybean oil, peanut oil, sesame oil, cottonseed oil, corn oil, olive oil, castor oil, palm oil, almond oil, fractionated refined oils, such as MIGLYOL 810, MIGLYOL 812, and the like and derived oils, such as, MIGLYOL 840, and the like. A more preferred oil is MIGLYOL 812, a fractionated coconut oil. Other oils can be used that provide the meeting requirements specified above.

Exemplary antihydration and gelling agents include various salts of organic acids, for example fatty acids having from about 8 (preferably at least 10) to about 22 (preferably more than about 20) carbon atoms, for example, salts of aluminum, zinc, magnesium or calcium of lauric acid, palmitic acid, stearic acid and the like. Such salts can be mono-, di- or tri-substituted, depending on the valence of the metal and the degree of oxidation of the metal by the acid. Particularly useful are the aluminum salts of such fatty acids. Anti-hydration agents of aluminum monostearate and distearate are preferred. Others that may be useful include aluminum tristearate, calcium mono- and distearate, magnesium mono- and di-stearate and the corresponding palmitates, laurates and the like. The concentration of these hydrating agents is usually based on the weight of the oil plus the drug agent, and is usually between 1% and 10%, and more typically between 2% and 5% by weight. Other concentrations may be appropriate on a case-by-case basis.

Waxes, natural and synthetic, lecithins, tocopherols and their esters, such as tocopherol acetate or tocopherol succinate, castor oil derived from polyoxyethylene (for example, CREMOPHOR EL), hydrogenated castor oil derived from polyoxyethylene, (CREMOPHOR RH40, CREMOPHOR RH60), fatty acid esters (for example ethyl- and methyl oleate), cholesterol and its derivatives can also be included in the oils to impart attenuating effects of viscosity or absorption. The waxes are preferably chosen from vegetable, animal or synthetic sources. Preferred sources include plant or synthetic sources. For example, useful waxes include Carnauba wax and beeswax. Beeswax is available in various degrees of purification, including white wax and yellow beeswax. Other synthetic waxes or wax derivatives may be used, such as, CRODACOL CS-50, CROTHIX, POLA AX, SYBCRO AX, polyoxyethylene sorbitol beeswax derivatives (e.g., G-172®) and the like.

Other release-modifying agents can be added in the oils to either accelerate or delay the release of the drug. These include but are not limited to oleic acid, the oleic acid esters, such as ethyl oleate, benzyl alcohol, benzyl benzoate and the like. Additives that modify the release of lecithin-based compositions include, but are not limited to cholesterol, ethylcellulose, tocopherols, polyvinylpyrrolidone, and polyethylene glycols, these additives may be added at various concentrations of more than about 30% by weight to effect the drug release.

The biodegradable material, hexai sobutyrate to sucrose diacetate (SDHB), in solution with a solvent or pharmaceutically acceptable solvents such as ethanol and polyethylene glycol, has been used to provide a prolonged release of olanzapine. Other SDHB compositions with release modifying agents in concentrations of more than about 20% by weight, such as propylene glycol, PLURONIC, cellulose, lecithin, oils and the like can be used to modify or prolong the release of olanzapine.

A preferred oil formulation comprises olanzapine, or pamoate salts or solvates thereof, a carrier oil and a gelling agent or anti-hydration agent. However most preferred is an oil formulation comprising olanzapine pamoate monohydrate, MIGLYOL 812 and white wax.

As used herein, the term "microparticle" has the common meaning known to the skilled artisan. In this manner, the term includes, but is not limited in any way to microspheres wherein the active ingredient can be uniformly distributed through the carrier, or microcapsules wherein the active ingredient is distributed around by a well-defined outer layer, and the like . The microparticles can be prepared using techniques, such as complex coacervation, polymer / polymer incompatibility, interfacial polymerization, in situ polymerization, solvent aporadiation / extraction, thermal and ionic gelation, spray-chilled, fluidized bed, rotating disk, rotational suspension separations , spray drying, and other methods known to the artisan.

For example, cholesterol microspheres can be formed using a solvent evaporation process that effectively entraps olanzapine, or a salt of olanzapine pamoate or solvate itself and provides a sustained release of olanzapine into the body. The trapping procedure consists of emulsifying an organic cholesterol solution, the dispersed phase, and the active of interest in the processing medium, an aqueous surfactant solution. The aqueous surfactant solution allows the formation of a stable emulsion and prevents agglomeration.

The emulsification can be performed by general processes known to those skilled in the art, including, but not limited to, magnetic bar stirring, mixing, overfilling, in-line homogenization, static mixing, and the like.

Examples of cationic, anionic, and nonionic compounds that can be used as surfactants include, but are not limited to, polyvinyl alcohol (PVA), carboxymethyl cellulose, gelatin, polyvinyl pyrrolidone, TWEEN 80, TWEEN 20, sodium lauryl sulfate. , and similar. The concentration of the surfactant may be sufficient to stabilize the emulsion. The concentration of the surfactant effects the final size of the cholesterol microspheres. Generally, the surfactant in the aqueous medium is from 0.1% to about % by weight depending on the surfactant, the solvent used to dissolve the cholesterol, and the processing medium used.

Alternatively, the processing medium may be an oil not miscible with cholesterol. Examples of suitable oils include, but are not limited to, mineral oil and silica oil. Suitable surfactant agents for the oily processing medium can be chosen to stabilize the emulsion and optimize the final size of the resulting cholesterol microspheres. In addition, surfactants can be added for the dispersed phase, or colestial phase, to beneficially effect emulsion stability, microsphere size and performance.

The cholesterol derivatives used to effect a durable release include cholesterol acetate, cholesterol semisuccinate, cholesterol oleate, cholesterol palmitate, cholesterol stearate, and the like. Compatible cholesterol additives can be used to effect additional releases, such as oleic acid, ethyl oleate, methyl oleate, tristearin, and the like.

The concentration of emulsifying agent, amount of stirring, stirring ratio, and the temperature of the stirred emulsion effect the ratio of solvent removal, size and quality of the resulting cholesterol microspheres. In general, this needs to be controlled to make injectable microspheres. The generally acceptable size range for the microparticles is l-5,000μm. The preferred microparticle size range useful for parenteral injection is 20-500μm. A more preferred range is from 30 to 200μm. However, it is more preferred from 40 to 100 μm.

Briefly, an aqueous surfactant agent solution of polyvinyl alcohol (PVA) is made by dissolving the PVA in deionized water. Polyvinyl alcohol concentrations greater than 6% are known to be effective, but may be limited if the viscosity of the processing medium is very high. For this invention, a preferred concentration of polyvinyl alcohol is 1%, (5 g of PVA added to 500 ml of deionized water). The surfactant solution is stirred with a magnetic stir bar and warmed at 50-60 ° C for several hours until all of the PVA is dissolved. The solution is allowed to cool to room temperature. The PVA surfactant solution is emptied into a square plastic container and agitated with an over stirring at 450 RPM. Olanzapine and cholesterol dissolve in methylene chloride. The dispersed phase is emptied directly, and immediately, into a PVA solution with stirring and allowing to stir for 18 hours at room temperature, to allow the methylene chloride to evaporate and form the cholesterol microspheres.

The cholesterol microspheres can be collected by isolating the microspheres in standard mesh sieves, washed with water or other suitable medium, and dried with air. Other methods of drying and collection and pharmaceutically acceptable equipment can be used and are known to those skilled in the art.

The particle size of olanzapine, olanzapine pamoate salts or solvates thereof used in the formulations of this invention can be controlled and performed by particle size reduction methods known to those skilled in the art, such as air jet grinding. . The milled medicament can vary in particle size from coarse to fine, depending on the type of formulation used and the desired drug release properties. The coarse particles have an average particle size from about 20 to about 60 μm; the average particles are from about 5 to about 20 μm; and the fine particles are less than 5 μm.

As used herein, the term "mammal" refers to the mammalian class of higher vertebrates. The term "mammal" includes, but is not limited to, the human. The term "treatment" as used herein includes prophylaxis of the named condition or relief or elimination of the condition once it has been established.

Olanzapine is effective in a wide range of doses, the current dose administered depends on the condition being treated. For example, in the treatment of adult humans, doses of from about 0.25 to 200 mg, preferably from 1 to 30 mg, and more preferably from 1 to 25 mg per day can be used. In this way, the reservoir formulation can be adjusted to provide the desired dose per day for a period from several days to more than about one month.

If a multiple dose formulation is contemplated, additional excipients, such as a preservative, may be required, for example, preservatives such as, but not limited to, tocopherol or propyl gallate may be employed. Other preservatives include phenol, cresol, sodium benzoate and the like.

More preferably, the olanzapine formulation is contained in packaging materials that protect the formulation from moisture and light. For example, suitable packaging material includes amber colored high density polyethylene containers, amber glass bottles, polypropylene syringes, and other containers, including but not limited to bagged bubble packaging, made of a material that inhibits the passage of light. More preferably, the package may include a desiccant pack. The container can be sealed with an aluminum foil pack to provide the desired protection and maintain the stability of the product.

The materials of the present invention can be purchased or prepared by a variety of methods well known to those of ordinary skill in the art. Olanzapine can be prepared as described by Chakrabarti in U.S. Pat. No. 5, 229,382 (382), incorporated in its entirety here for reference. Generally olanzapine pamoate salts and solvates can be prepared by mixing the olanzapine and the pamoic acid in an appropriate solvent followed by washing and drying the resulting product. Equimolar amounts of pamico acid and olanzapine are required for palamic salts of olanzapine (1: 1). The bis (olanzapine) pamoate salts (2: 1) require two molar equivalents of olanzapine per mole of pamico acid.

Applicants have surprisingly discovered that the solubility of olanzapine pamoate and solvates are somewhat independent of pH, particularly in the range of 4 to 8. This makes such salts especially suitable for intramuscular injections since muscle pH varies with exercise, tension, metabolic state, and wound healing, at ranges usually between 7.4 and 4.. In addition, the bis (olanzapine) salts have the additional advantage of improving the activity of the drug per unit mass, allowing greater fillings of the resulting microparticle and reducing the injection volume per unit dose.

Preferably, the formulation has a sustained sustained release of a pharmaceutically effective amount of olanzapine, or a pamoate salt or solvate thereof for a period of greater than 7 days, more preferably at least 14 days, more preferably more than 30 days with a Release explosion of less than 15% active ingredient. The term "explosion" will be understood by those skilled in the art to mean the immediate release of the active ingredient. In addition, a preferred formulation is injectable through a 21 gauge or smaller needle with an injection volume of 2 ml or less. Other desirable characteristics include the use of excipients that are toxicologically and pharmaceutically acceptable. The formulations are desirable in a unit dosage form suitable, preferably, for subcutaneous or intramuscular administration.

The formulations claimed herein may be used alone or in combination with another. Depending on the carrier selected, the formulations claimed herein may be especially useful for intramuscular administration of small action or as a depot formulation. Olanzapine oleaginous carrier formulation is useful either in combination with cholesterol microspheres (more than 50% by mass of unit) or by itself without the use of microspheres. The cholesterol microspheres can also be mixed with an oleaginous carrier and water in an amount greater than and include 50% by mass of unit injection, depending on the type of excipients used.

The following examples are provided for purposes of illustration and are not constructed as limiting the scope of the claimed invention.

Preparation 1 Technical Grade Olanzapine Intermediary 1 The following was added in a suitable three-necked flask: Dimethylsulfoxide (analytical) 6 volumes Intermediate 1 75 g N-methylpiperazine (reactive) 6 equivalents Intermediary 1 was prepared using methods known to the skilled artisan. For example, the preparation of Intermediary 1 is taught in the patent x 382.

A bubbling line of sub-surface nitrogen-1 was added to remove the ammonia formed during the reaction. The reaction was heated to 120 ° C and maintained at this temperature for the duration of the reaction. The reactions were followed by HPLC until about 5% of intermediate 1 was removed without reaction. After the reaction was complete, the mixture was allowed to cool slowly to 20 ° C (around 2 hours). The reaction mixture was then transferred to an appropriate three-necked round bottom flask and water bath. To this stirred solution was added 10 volumes of reactive grade methanol and the reaction was stirred at 20 ° C for 30 minutes. Three volumes of water were added slowly over about 30 minutes, the thick reaction mixture was cooled from zero to 5 ° C and stirred for 30 minutes. The product was filtered and washed with cooled methanol. The wet cake was dried in vacuo at 45 ° C overnight. The product was identified as olanzapine technique.

Yield: 76.7%; Power: 98.1% Preparation 2 Form II 270 g of a sample of 2-methyl-4- (4-methyl-1-piperazinyl) -1OH-thieno [2, 3-b] [1,5] benzodiazepine was suspended in anhydrous ethyl acetate (2.7 L) . The mixture was heated to 70 ° C and maintained at 76 ° C for 30 minutes. the mixture was allowed to cool to 25 ° C. The resulting product was isolated using vacuum filtration. The product was identified as Form II using X-ray powder analysis.

Yield: 197 g The process described above for the preparation of Form II provides a pharmaceutically appropriate product having a potency of > 97%, total related substances < 0.5% and an isolated performance of > 73%.

Preparation 3.

Preparation of 2-methyl-4- (4-methyl-1-piperazinyl) -lOH-thieno [2, 3-b] [1,5] benzodiazepine pamoate (olanzapine pamoate) A. Olanzapine (3.12 g, 0.01 mol) was dissolved in tetrahydrofuran (50 ml) with heating. The pamico acid (3.88 g, 0.01 mol) was dissolved in tetrahydrofuran (100 ml) with heating. The two solutions were mixed and filtered through a pad of celite while still warm. The yellow solution was transferred to a Buchi flask and evaporated under reduced pressure (bath temperature 50 ° C). After about 50 ml of solvent had been removed, ethanol (50 ml) and continuous evaporation were introduced. An additional 50 ml of ethanol was introduced after 50 ml of solvent was collected. The evaporation continued until the crystallization began. The yellow crystals were collected by filtration and dried under high vacuum at 120 ° C. P.f. 203-205 ° C. It was good for 1H NMR, X13C TMN and MS. Purity of HPLC 99.61%.

It was fine for ÍH NMR, 113C TMN and MS. Purity HPLC 99.61%. Spectrum peaks ÍH, 8.4, s, 2p, s, 8.2, d, 2p, d, 7.9, s, lp, s, 7.8, d, 2p, d, 7.2, t, 2p, t, 7.1, t, 2p , t, 6.9, m, 2p, 6.7, m, lp, t ?, 6.4, s, lp, s, 4.8, s, 2p, s, 3.6, br, 4p, br, 3.3, br, 4p, br, 2.8, s, 3p, s, 2.3, s, 3p, s Peaks 13C, 171.4, 156.6, 154.6, 154.5, 143.7, 138. 2, 135.1, 129.5, 128.9, 128.0, 126.9, 126.6, 125. 8, 124.0, 123.1, 122.9, 121.8, 121.6, 119.3, 118. 5, 117.8, 115.9, 51.9, 43.6, 42.0, 19.3, 14.4.

Preparation 4.

Preparation of 2-methyl-4- (4-methyl-1-piperazinyl) -lOH-thieno [2, 3-b] [1,5] benzodiazepine dimetanolate pamoate (olanzapine pamoate dimethanolate).

Into a 250 ml precipitation beaker equipped with a magnetic stirrer was added dimethisulfoxide (DMSO) (10 ml, 0.636 M), pamico acid (2.49 g, 6.41 mmol), and olanzapine (2.0 g, 6.40 mmol). The thick mixture was stirred at 20-25 ° C until dissolved. The solution was added for 10 minutes to a 250 ml three neck flask equipped with a mechanical stirrer containing methanol (100 ml) at 20-25 ° C. Starting with small additions of methanol, the solution became turbid as crystals began to form. The solids increased as the addition continued. After the addition was complete, the temperature was adjusted to 5 ° C for about 15 minutes and stirred for 120 minutes, the thickened mixture was filtered. The flask and the wet cake were washed with methanol (25 ml). The product was dried in vacuo overnight at 50 ° C to give 4.61 g of olanzapine pamoate dimethanolate as identified by X-ray powder diffraction (DPRX), TGA (8.2%), gas chromatography (GC) (8.6% methanol), and nuclear magnetic resonance (NMR) analysis (1: 1 salt).

Preparation 5.

Preparation of the THF solvate of pamoate of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine (THL solvate of olanzapine pamoate).

In a 250 ml three-necked flask equipped with a magnetic stirrer was added tetrahydrofuran (THF) (60 ml), pam. (2.49 g, 6.41 mmol), and olanzapine (2.0 g, 6.40 mmol). The thick mixture was stirred at 20-25 ° C until dissolved (about 20 minutes). to the THF solution was added methanol (30 ml) for 10 minutes. As the addition for the mixture was completed soon, half of the thickened mixture was filtered. The wet cake (1) was then dried in vacuo overnight at 50 ° C to give 2.07 g. The remaining thick mixture was stirred for 2 hours at room temperature and filtered. The wet cake (2) was then dried in vacuo overnight at 50 ° C to give 2.16 g. In both cases, the isolated material was identified as THF solvate of olanzapine pamoate by DPRX, TGA (12.7-13.5%), and NMR analysis (12.2-12.9% THF, 1: 1 salt).

Preparation 6 Preparation of pamoate monohydrate of 2-me-il-4- (4-yl-l-piperazinyl) -1OH-ieno [2,3-t b] [1,5] benzodiazepine (olanzapine pamoate monohydrate).

In an appropriate precipitation euberate equipped with a magnetic stirrer, dimethyl sulfoxide (22 ml), pamico acid (2.49 g, 6. 1 mmol), and olanzapine (2.0 g, 6.40 mmol) were added. The thick mixture was stirred at 20-25 ° C until it dissolved (about 20 minutes). The solution was added for 20 minutes to a 250 ml three neck flask equipped with a mechanical stirrer and containing water (96 ml) at 40 ° C. After the addition was complete, the thick mixture was stirred for about 20 minutes at 40 ° C, cooling to 20-25 ° C for about 30 minutes, filtering and washing with water (25 ml). The product was dried in vacuo at 50 ° C to give 4.55 g of olanzapine pamoate monohydrate by DPRX, TGA (3.0%), and titrimetric analysis (KF = 3.2%).

Preparation 7 A. Preparation of bis (2-methyl-4- (4-methyl-1-piperazinyl) -lOH-thieno [2, 3-b] [1, 5] benzodiazepine) acetone solvate (acetone pamoate solvate) of bis (olanzapine).

In a three-neck flask of 100 ml equipped with an agitator, acetone (10 ml), pamico acid (1.25 g, 3.22 mmol) and olanzapine (2.0 g, 6.4 mmol) were added. The thick mixture was stirred at 20-25 ° C for about 60 minutes and filtered. The wet cake was washed with acetone (5 ml.

The product was dried in vacuo at 40 ° C to give bis (olanzapine) acetone pamoate solvate (3.24) by DPRX, TGA (7.0%), and NMR analysis (3.7% acetone, 2: 1 salt).

B. Preparation of acetone solvate of pamoate bis (2-methyl-4- (4-methyl-1-piperazinyl) -1OH-thieno [2,3- b] [1,5] benzodiazepine) (acetone solvate pamoate bis (olanzapine) Into a 100 ml three-necked flask equipped with a stirrer was added dimethyl sulfoxide (10.8 ml) and pamico acid (3.75 g, 9.65). the thickened mixture was stirred at -20 -25 ° C until dissolved. The solution was added for 15-20 minutes to a 250 ml three neck flask equipped with a mechanical stirrer and containing acetone (150 ml) and olanzapine (6.0 g, 19.2 mmol) at 50 ° C. After the addition was complete, the thick mixture was stirred for about 20 minutes at 50 ° C. The thick mixture was cooled to 20-25 ° C for about 60 minutes, stirred for 60 minutes and filtered. The wet cake was washed with acetone (15 ml). Half of the wet cake was re-mixed in acetone (54 ml) for 2 hours at 20-25 ° C, filtered and washed with acetone (10 ml). The product was dried in vacuo at 35-40 ° C to give bis (olanzapine) acetone pamoate solvate (4.54 g) by PDRX, TGA (5.8%), GC (5.57% acetone), and NMR analysis (2%). : 1 of salt).

Preparation 8.

Preparation of bis (-2-methyl-4- (4-methyl-l-piperazinyl) -10H-ieno [2, 3-b] [1,5] benzodiazepine) (bis (olanzapine) pamoate monohydrate.

Into a 100 ml three-necked flask equipped with a stirrer, dimethyl sulfoxide (10.8 ml) and pamico acid (3.75 g, 9.65 mmol) were added. The thick mixture was stirred at 20-25 ° C until dissolved. The solution was added for 15-20 minutes to a 250 ml three-necked flask equipped with a mechanical stirrer and containing acetone (150 ml) and olanzapine (6.0 g, 19.2 mmol) at 50 ° C. After the addition was complete, the thick mixture was stirred for about 20 minutes at 50 ° C. The thick mixture was cooled to 20-25 ° C for about 60 minutes, stirred for 60 minutes and filtered. The wet cake was washed with acetone (15 ml). Half of the wet cake was dried in vacuo at 35-40 ° C to give bis (olanzapine) pamoate monohydrate (5.01 g) by DPRX, TGA (3.3%), GC, titrimetric (KF = 2.2%) and NMR analysis (2: 1 salt).

Preparation 9.

Preparation of (2-methyl-4- (-methyl-1-piperazinyl) -lOH-thieno [2, 3-b] [1, 5] benzodiazepine) dihydrate D. 100 g of a technical grade olanzapine sample (see Preparation 1) was suspended in water (500 mL). The mixture was stirred at about 25 ° C for 5 days. The product was isolated using vacuum filtration. The product was identified as Olanzapine Dihydrate D using X-ray powder analysis. Yield: lOOg. The lowest mass TGA was 10.2%.

Preparation 10.

Preparation of (2-methyl-4- (4-methyl-1-piperazinyl) -1OH-ieno [2,3-b] [1,5] benzodiazepine) dihydrate E. 0. 5 g of a technical grade olanzapine sample was suspended in ethyl acetate (10 mL) and toluene (0.6 mL). The mixture was heated to 80 ° C until all the solids dissolved. The solution was cooled to 60 ° C and water (1 mL) was slowly added. As the solution was cooled to room temperature, a thick crystalline mixture formed. The product was isolated using vacuum filtration and dried under ambient conditions. The product was identified as Dihydrate E using X-ray powder analysis and 13C solid state NMR. The smallest mass TGA was 10.5%. Yield: 0.3 g.

Preparation 11 Preparation of (2-methyl-4- (4-methyl-1-piperazinyl) -lOH-thieno [2, 3-b] [1, 5] benzodiazepine) dihydrate B. g of a technical grade olanzapine sample was suspended in water (88 mL). The mixture was stirred at about 25 ° C for 6 hours. The product was isolated using vacuum filtration. The product was identified as Olanzapine Dihydrate B using X-ray powder analysis. Yield 10.86 g.

The following abbreviations are used in the examples that are in the following tables: 0 Olanzapine particle size not determined O-F Fine milled olanzapine; particle size less than 5 μm O-C Coarse ground olanzapine; particle size from 20-60 μm OPDM-C coarse ground olanzapine pamoate dimethanolate, particle size from 20-60 μm OPDM-F Olanzapine pamoate dimethanolate fine grind, particle size less than 5 μm OPMH Olanzapine pamoate monohydrate OPMH-F Fine milled olanzapine pamoate monohydrate; particle size less than 5 μm BOPM or BOP Bis (olanzapine) pamoate monohydrate BOPM-F or BOP = F bis (olanzapine) pamoate monohydrate from fine grinding; particle size less than 5 μm ac Aqueous PEG200 Polyethylene glycol having an average cell-mass weight of 200 EtOH ethanol CHITOSAN® low MW, High MW Quitin deacetylated, low and high molecular weight NaCMC Carboxymethyl cellulose sodium, salt of sodium Cra With respect to BRIJ®-52 Polyoxoethylene (2) cetyl ether surfactant Carnauba Wax G-1726® Poliostylene (20) serbitol derived from beeswax to PLURONIC Nonionic surfactants which are blocks of copolymers of propylene oxide and ethylene oxide. The propylene oxide is sandwiched between two blocks of ethylene oxide. The poly (oxyethylene) groups at both ends of the polyoxypropylene chain. HO (CH2CH20) a (CHCH3CH20) bCH 2CH20) CH The alphabetical designation explains the physical form of the product:? L 'for liquids,? P' for pastes,? F 'for solid forms. The first digit (two digits in a three-digit number) in the numerical designation, multiplied by 300, indicates the approximate molecular weight of the hydrophobe). The last digit, when multiplied by 10, indicates the approximate ethylene oxide content in the molecule.

NF = National Form = meets the standards for polaxomers which is the generic designation for pluronic LF and D = Low foam version Includes: PLURONIC F68 PLURONIC F 68NF PLURONICS L121 PLURONICS L092 MIGLYOL 810 = Triglycerides of split vegetable fatty acids C8 and CIO (caprylic / capric acids) MIGLOYOL 812 It differs from 810 only in the C8 / C10 ratio. It has a higher CIO ratio and the viscosity and the cloud point is higher. MIGLOYOL 840 Di-ester of propylene glycol of saturated vegetable fatty acids with chain lengths C and CIO (capric / capric acids). CREMAPHOR EL A derivative of castor oil and ethylene polyethoxylated castor oil oxide. A mixture of a hydrophobic portion containing ricinoleic acid esters, glycerol and polyglycol ethers, and castor oil and a hydrophobic portion containing polyethylene glycol and ethoxylated glycerol.

CHREMAPHORE RH40 40 moles of ethylene oxide per mole of hydrogenated castor oil. CHREMAPHORE RH60 60 moles of ethylene oxide per mole of hydrogenated castor oil. POVIDONE USP (K-30) Polyvinyl pyrrolidone from United States Pharmacopeia XXIII: k-value: 30 (intrinsic viscosity) Synonyms of α-tocopherol Vitamin E, alpha tocopherol, 2,5,7,8-tetramethyl-2- (4 ') , 8 ', 12' - trimethyl tridecl) -6- chromanol NMP 1-methyl-2-pyrrolidinone CROTHIX PEG 150 pentoaritrityl tetrastearate SYNCROWAX Synthetic beeswax POLAWAX Emulsified wax Tween 20 Polyoxyethylene 20 sorbitan monolaurate, sorbitol laurate ester . The number 20 is established for 20 moles of ethylene oxide copolymerized with one mole of sorbitol. Tween 80 Polyoxyethylene 80 mono sorbate sorbitan, an oleate ester of sorbitol. The number 80 is set for 80 moles of ethylene oxide copolymerized with one mole of sorbitol.

Example 1.

PLURONICS®: PLURONIC® F68NF (50 g) was mixed in 111 ml of water grade HLCP. The mixture was intermittently stirred with a spatula and cooled in the freezer. A sonicator was used to help break the non-dissolvable material. The mixture was cooled and stirred until a clear solution resulted. Olanzapine (300 mg) was mixed with 10 ml of the PLURONIC® solution with a spatula until it became homogeneous. The mixture was stored under refrigeration until it was used.

The following Examples were prepared using substantially the same procedure described in Example 1.

Example 13 Sucrose Diacetate Hexaisobutyrate (SDHB): A solution of 10% ethanol and 90% SDHB were mixed together with a spatula in a mixing bucket until they were homogeneous. The ground olanzapine (150 mg) is weighed in the mixing bucket. The SDHB solution (5 ml) was added and shaken with a spatula until the olanzpain was uniformly mixed in the vehicle.

The following Examples were prepared using substantially the same procedure described in Example 13.

Example 19 Chitosan®: Water (70 g) was weighed in a precipitation bucket, lactic acid (1 g) was added and then 2 g of Chitosan®, and finally 300 mg of olanzapine. The mixture was stirred with a spatula until it was uniform.

The following Examples were prepared using substantially the same procedure described in Example 19.

Example 22 CHITOSAN: Weigh water (25 g) in a precipitation bucket. Lactic acid (0.5 g) was added, and then 765 mg of olnazapine, and finally 1 g of CHITOSAN, the mixture was stirred with a spatula until it became uniform.

The following Examples were prepared using substantially the same procedure described in Example 22.

Example 25 Miscellaneous: NaCMC (2 g) was measured in a precipitation cuvette and 100 ml of water was added. The mixture was stirred at room temperature with a magnetic stir bar on a stirring tray until all the solids dissolved. Olanzapine was weighed in a beaker and 4.85 ml of NaCMC vehicle was added. The mixture was stirred with a spatula until the mixture became homogeneous. The formulation was resuspended by movement or agitation immediately before use.

The following Examples were prepared using substantially the same procedure described in Example 25.

Example 28 Oil: Ground olanzapine (120 mg) was weighed into a pellet and 3.88 MIGLYOL® 812 oil was added. The mixture was stirred with a spatula until it became homogeneous. The solids in the formulation were easily established in such a way that the formulation was resuspended by movement or agitation immediately before use.

The following Examples were prepared using substantially the same procedure described in Example 28.

Example 1.

Oleic acid: Oléic acid (0.54 ml) and 300 mg of olanzapine were warmed together. MIGLYOL® 840 oil (9.2 ml) was then added and all the solids dissolved slightly warming.

The following Examples were prepared using substantially the same procedure described in Example 41. 57 Gel oil: To the oil gel, 25 g of aluminum monostearate was added to 475 g of sesame oil in a flask. The oil was mixed with a static mixer with a stainless steel propeller, while it was warmed in an oil bath at 155 ° C for 20 minutes, a flow of nitrogen gas was allowed on the system during the process. The oil was then allowed to cool to room temperature. The milled olanzapine (120 mg) was weighed in a beaker and 3.88 ml of gelled sesame oil was added. The mixture was stirred with a spatula until it became homogeneous.

The following Examples were prepared using substantially the same procedure described in Example 57.

Example 61 Wax / Oil: White wax (400 mg) was measured in a beaker and 3.6 g of MIGLYOL® 812 oil was added. The mixture was warmed in a water bath at about 80 ° C until the wax melted. It was then stirred with a spatula until it became homogeneous. Ground olanzapine (1 g) was added from the pellet and stirred with a spatula until the mixture became homogeneous. The mixture was allowed to cool to room temperature while mixing.

The following Examples were prepared using substantially the same procedure described in Example 61. In some cases the mixture was made homogenous with a hand-held homogenizer to reduce the large particle sizes and aggregates of the active ingredient.

Example 97 Lecithin: Olanzapine (500 mg) plus 12.0 g of lecithin were stirred thoroughly with a spatula for approximately 15 minutes to ensure homogeneity.

Example 98 Lecithin + a-tocopherol: Lecithin (8.9972 g) plus 1.0204 g a-tocopherol was stirred thoroughly and kept overnight in the refrigerator. The mixture was stirred thoroughly, and then 300.7 mg of olanzapine was added and mixed well.

Example 99 Lecithin / NM: Olanzapine (500 mg) was dissolved in 3 ml of N-methyl pyrrolidone (NMP). Lecithin (9 ml) was added and stirred well with a spatula for approximately 15 minutes to obtain a homogeneous mixture.

Example 100 Cholesterol / POVIDONE USP (K-30) / ethyl cellulose / NMP: Olanzapine was completely shaken (500 mg), ethyl cellulose (0.062 g) and NMP (5 ml) and was gently warmed for 2-3 minutes until a clear solution was obtained. POVIDONE USP (K-30) (0.309 g) and cholesterol were then added (2.475 g) to obtain a formulation similar to thick gum, dry in consistency.

Example 101 Cholesterol / POVIDONE USP (K-30) / ethyl cellulose / NMP: Cholesterol (2.475 g), 0.3098 g of POVIDONE USP (K-30), 0.0622 g of ethyl cellulose and 9.1686 were weighed in a 25 ml beaker. g of NMP. The materials contained in the precipitation cuvette were thoroughly mixed and warmed slightly to dissolve any insoluble material. Care was taken to use minimal exposure to heat for solubility purposes. The clear solution was cooled and to this was added 500 mg of olanzapine which was mixed thoroughly, giving a clear pale yellow solution.

Example 102 Lecithin / Cholesterol / POVIDONE USP (K-30) / ethyl cellulose / NMP: 0.2511 g POVIDONE USP (K-30) was weighed in a precipitation bucket. To this was added 300.5 mg of coarse olanzapine, 28.5 mg of ethyl cellulose and 2,008 g of cholesterol. This dry mixture was completely stirred. To this dry mixture was added 0.7463 g of α-tocopherol and this mixture was completely stirred. To this solution was added 3.3806 g of lecithin, mixing thoroughly. Then another 3.0825 g of lecithin was added and again mixed thoroughly. 103 Lecithin / Cholesterol / POVIDONE USP (K-30) / ethyl cellulose / NMP: Thick olanzapine (300.7 mg), 2.5821 g of NMP and 25.4 mg of ethyl cellulose were thoroughly shaken. To this was added 248.0 mg of POVIDONE USP (K-30), 2,0008 g of cholesterol and 2.6020 g of lecithin. This formulation was well shaken. The mixture was separated in two layers and warmed in a 37 ° C bath for 5 minutes. A formulation such as soft lumps coagulated in the thick solution. Lecithin (2.5074 g) was added and mixed thoroughly. Eventually the formulation appeared to lose gel-like coagulation and an olanzapine suspension formed.

The following Examples were prepared using substantially the same procedures described in Examples 97-103, above.

Example 118 Olanzapine-Cholesterol microparticles. g (1%) of polyvinyl alcohol was added (PVA) to 500 ml of deionized water. The solution was stirred with a magnetic stir bar for several hours until all the PVA dissolved. The mixture was allowed to cool to room temperature. The solution was emptied into a square plastic container and stirred with a stirrer over full at 450 RPM. 1.2 g of olanzapine and 8.8 g of cholesterol were dissolved in 100 ml of methylene chloride. The PVA solution was added and the mixture was stirred for 18 hours.

Microparticle Collection: Method 1: A PVA / olanzapine solution was emptied through 100 and 230 mesh screens (USA standard) respectively. Large and thin sections were discarded. The sieve particles 230 were washed with water in a Buchner funnel with a Whatman # 4 filter paper and filtered under vacuum. The particles were transferred to a weighing tray and allowed to air dry. The particle size collected was: > 63 μm - < 150 μm.

Method 2: A PVA / olanzapine solution was vacuum filtered using a Buchner funnel through Whatman # 4 filter paper and washed with water. The particles were transferred to a weighing tray and allowed to air dry. The particles were dried by sieving through a 30 mesh screen (US standard) to remove any large particles.

Method 3: A PVA / olanzapine solution was emptied through a 230 mesh screen (USA standard). The sieve particles were washed with water in a Buchner funnel with Whatman # 4 filter paper and filtered under vacuum. The particles were transferred to a weighing tray and allowed to air dry. The particle size collected was: > 63 μm.

Method 4: A PVA / olanzapine solution was emptied through a 230 mesh screen (USA standard). The sieve particles were washed with water in a Buchner funnel with Whatman # 4 filter paper and filtered under vacuum. The particles were transferred to a weighing tray and allowed to air dry. The dried particles were screened through a 100 mesh screen (USA standard). The particle size collected was: > 63 μm - < 150 μm.

Method 5: A PVA / olanzapine solution was emptied through a 100 mesh screen (USA standard). The sieve particles were washed with water in a Buchner funnel with Whatman # 4 filter paper and filtered under vacuum. The particles were transferred to a weighing tray and allowed to air dry. The particle size collected was: > 150 μm. the solution of PVA / sieved olanzapine was centrifuged and decanted. The pellets were vacuum filtered with a Buchner funnel through Whatman # 4 filter paper, transferred to a weighing tray and air dried. The particle size collected was < 150 μm.

Method 6: A PVA / olanzapine solution was vacuum filtered using a Buchner funnel through Whatman # 4 filter paper and washed with water. The particles were transferred to a weighing tray and allowed to air dry.

The product was tested for its potency by high performance liquid chromatography. 00 00 00 00 00 V_0 U3 O u > co co Example 165 Dried by spray Olanzapine (0.5 g ground) and 4.5 g of cholesterol were dissolved in 50 ml of methylene chloride. This solution was spray-dried with a scale label Yamato spray dryer with a 60 cm long drying column. The drying conditions were placed as follows: indoor temperature = 50 ° C, outside temperature = 33 ° C, air flow volume 55 m3, atomizing spray volume 0.55 kgf / cpr The microparticles were collected in a small flask on the outside and they were sieved to a particle size of 63-150 μm and tested for potency by high performance liquid chromatography.

The following examples were prepared using substantially the same procedure as described in Example 164.

CD MGTODOS SUMMARY- The formulations were mixed and filled in 5 ml syringes. Ends of an available plastic pipette were cut and filled into the syringe. The dialysis tubes were cut into lengths of 5-6 cm and kept from the humidity in a bucket of water precipitation, one end of the tube was completely secured with a holding tube. The tube was taked on a scale and from a one ml syringe the formulation was dispensed into the tube. The open end was adjusted and the final weight recorded. The filled dialysis tube was placed in a 900 ml solution vessel filled with 250 ml of Dulbecco's phosphate buffered saline pH 7.4 at 37 ° C. The vessels were placed in a Vankel dissolution apparatus with a paddle rotating at 50 RPM. The samples were manually removed by stopping the rotation of the paddles and removing 2 ml of aliquot samples with pipettes. Samples were removed at 2, 4, 8, 12, 24, 48, and consecutively at 24 hour intervals up to 48 for 4 weeks duration. At sample time 2, 4, 8, and 12 the medium was replaced with 2 ml of fresh buffer. At each 24-hour time point, the entire volume of the medium was replaced with fresh medium pre-warmed to 37 ° C. The samples were placed directly in small HPLC bottles and tested for their potency by high pressure liquid chromatography.

The formulations were tested using the release assay described above and found to have an acceptable sustained sustained release ratio of active at from 48 hours to more than 4 weeks.

Essay with Rabbit.

New Zealand White rabbits were selected for evaluation of depot formulation since the size of their leg muscles facilitates the administration and evaluation of injection site dose.

Three rabbits of the same sex were used for each formulation that were selected based on their availability. The rabbits were at least 5 months old and weighed between 2.5 to 5 kg. The rabbits were given a simple injection with a 20 or 21 gauge needle in the femoral biceps. The dose volume varied with the concentration of the formulation but did not exceed 2 mL per injection. The rabbits were given 10 mg olanzapine / kg body weight.

A 2 mL blood sample was collected from the middle artery of the ear or the jugular vein in heparinized collection tubes once before the administration of the dose and at 4 hours after the administration of the dose and again daily after 1, 2, 7, 10, and 14 days. The plasma was collected and the plasma concentration of olanzapine was determined by HPLC.

The formulations of the present invention were tested in the rabbit assay and were found to show effective olanzapine concentrations of more than 14 days.

Essay with Dog.

The beagle dog was selected as much is known about the pharmacokinetics of olanzapine in dogs. Since this is not a difference in the pharmacokinetics of olanzapine between the sexes, the selection of the dog was not based on sex. Three dogs (males or females) were used for each formulation. The dogs were adults (> 6 months old) and weighed between 8 to 21 kg. The dogs were given an injection with a 20 or 21 gauge needle in the buttock or femoral muscle. The dose volume varied with the concentration of the formulation but did not exceed 2 mL per injection. The dogs were given 10 mg of olanzapine / kg body weight.

At each time point, a 2 mL blood sample was collected from the jugular vein in heparinized collection tubes. The blood samples were collected once before the administration of the dose and at various time points after the administration of the dose completely in the 28-day period. Typical time points are at 0.5, 1, 2, 4, 8 and 24 hours after dose administration and once daily after 2, 4, 7, 14, 21, and 28 days. The plasma was collected and the plasma concentration of olanzapine was determined by HPLC.

The formulations of the present invention were tested in the dog test and were found to show effective concentrations of olanzapine over 28 days.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (33)

Claims

1. A formulation characterized in that it comprises olanzapine or a pamoate salt or solvate thereof as an active ingredient and one or more carriers selected from the group consisting of an oleaginous carrier or cholesterol bead carrier.

2. The formulation as claimed in claim 1, characterized in that the formulation has a prolonged sustained release of more than 7 days and a burst release of less than 15% of the active ingredient.

3. The formulation as claimed in claim 1, characterized in that the carrier is oleaginous.

4. The formulation of claim 1, characterized in that the carrier is selected from the group consisting of PLURONIC, cellulose, gums, polysaccharide gums, vegetable oils, fractionated refined oils, hexaisobutyrate sucrose diacetate, chitosan, lecithin, and POVIDONE.

5. The formulation as claimed in claim 4, characterized in that the carrier is selected from the group consisting of PLURONICOS, cellulosic gums, polysaccharide gums, vegetable oils, and refined fractionated oils.

6. The formulation as claimed in claim 2, characterized in that the formulation further comprises one or more pharmaceutically acceptable excipients.

7. The formulation as claimed in claim 6, characterized in that the pharmaceutically acceptable excipient is selected from the group consisting of a gelling agent and an anti-hydration agent.

8. The formulation as claimed in claim 7, characterized in that it comprises olanzapine pamoate monohydrate, MIGLYOL812 and white wax.

9. The formulation as claimed in claim 1, characterized in that olanzapine is the substantially pure polymorphic Form II having an X-ray powder diffraction pattern as represented by the following interplanar spaces: d (A) 10.2689 8.577 7.4721 7.125 6.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 3. 9873 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007

10. The formulation as claimed in claim 1, characterized in that the carrier is a microparticle of cholesterol.

11. The formulation as claimed in claim 10, characterized in that the microparticle is a microsphere.

12. The formulation as claimed in claim 19, characterized in that the cholesterol is selected from the group consisting of cholesterol, cholesterol palmitate, cholesterol oleate, cholesterol stearate, and cholesterol semisuccinate.

13. The formulation as claimed in claim 19, characterized in that the microspheres have a particle size from 20 to 500 μm.

14. The formulation as claimed in claim 13, characterized in that the particle size is from 30 to 200 μm.

15. The formulation as claimed in claim 14, characterized in that the particle size is from 40 to 100 μm.

16. The formulation as claimed in claim 10, characterized in that the microspheres are administered in an oleaginous carrier.

17. The formulation as claimed in claim 16, characterized in that the oleaginous carrier is selected from the group consisting of PLURONIC, cellulose gums, polysaccharide gums, vegetable oils, and refined fractionated oils.

18. The formulation as claimed in claim 1 for use as a depot dosage form.

19. The formulation as claimed in claim 1 for use as a fast acting intramuscular dosage form.

20. The formulation as claimed in claim 1, characterized in that the active ingredient is selected from the group consisting of olanzapine, olanzapine D-dihydrate, olanzapine pamoate, olanzapine pamoate dimetanolate, olanzapine pamoate monohydrate, THF solvate of olanzapine pamoate, acetone solvate bis (olanzapine) pamoate, and pamoate bis (olanzapine) monohydrate.

21. The formulation as claimed in claim 20, characterized in that the active ingredient is milled.

22. The formulation as claimed in claim 21, characterized in that the particle size is from 20 to 60 μm.

23. The formulation as claimed in claim 22, characterized in that the particle size is from 5 to 20 μm.

24. The formulation as claimed in claim 23, characterized in that the ground particles are less than or equal to 5 μm.

25. The formulation as claimed in claim 20, characterized in that the active ingredient is olanzapine pamoate monohydrate having an X-ray powder diffraction pattern as represented by the following interplanar space: Spaces d Intensity 10. 76 98 9.20 62 8.38 85 8.18 24 7.62 20 6.67 18 6.56 18 6.51 20 6.44 20 6.11 26 5.88 22 5.64 15 5.38 100 4.90 11 4.72 12 4.64 17 4.48 18 4.35 23 4.29 31 4.24 32 4.09 71 4.02 84 3.98 73 3.81 23 3. 62 14 3.52 30 3.39 11 3.25 12 2.90 15 2.85 13

26. The formulation as claimed in claim 20, characterized in that the active ingredient is bis (olanzapine) monohydrate having an X-ray powder diffraction pattern as represented by the following interplanar space: Spaces d Intensity 15.77 26 10.44 23 9.64 24 9.31 13 8.27 23 8.17 14 8.13 14 7.84 27 7.81 30 7. 41 60 7.12 40 7.00 13 6.96 13 6.55 45 6.18 53 5.87 38 5.80 19 5.59 89 5.25 26 5.00 34 4.96 31 4.88 61 4.85 73 4.71 34 4.52 19 4.33 11 4.19 100 4.12 48 4.05 39 3.97 30 3.89 31 3.80 29 3.72 20 3.70 21 3. 58 33 3.45 27 3.04 13 2.84 16

27. A compound, characterized in that it is a pamoate salt of olanzapine or solvate thereof.

28. The compound as claimed in claim 27, characterized in that the pamoate salt is olanzapine pamoate dimethanolate having an X-ray powder diffraction pattern as represented by the following interplanar space: Spaces d Intensity 11.17 73 9.37 17 8.73 40 8.29 23 7.77 14 7.22 24 6.84 31 6.66 54 6. 42 11 6.40 11 6.17 26 5.87 12 5.56 100 4.84 11 4.66 17 4.57 26 4.48 22 4.35 19 4.28 19 4.12 94 4.03 91 3.89 52 3.62 4 4 3.54 11 3.29 16 3.13 16

29. The compound as claimed in claim 27, characterized in that the pamoate salt is olanzapine pamoate monohydrate having an X-ray powder diffraction pattern as represented by the following interplanar space: Spaces d Intensity 10.76 98 9.20 62 8.38 85 8.18 24 7.62 20 6.67 18 6.56 18 6.51 20 6.44 20 6.11 26 5.88 22 5.64 15 5.38 100 4.90 11 4.72 12 4.64 17 4.48 18 4.35 23 4.29 31 4.24 32 4.09 71 4. 02 84 3.98 73 3.81 23 3.62 14 3.52 30 3.39 11 3.25 12 2.90 15 2.85 13

30. The compound as claimed in claim 27, characterized in that the pamoate salt is an acetone solvate of bis (olanzapine) pamoate having an X-ray powder diffraction pattern as represented by the following interplanar space: Spaces d Intensity 16.87 32 9.58 35 80 8.40 16 8.19 35 7.85 16 7. 34 29 7.22 25 7.04 30 6.87 18 6.77 11 6.73 11 6.65 21 6.36 12 6.26 26 5.76 31 5.58 79 5.53 100 5.45 61 5.32 42 5.19 39 5.02 55 4.91 69 4.87 51 4.85 57 4.69 44 4.61 68 4.44 23 4.34 14 4.18 17 4.07 36 3. 99 28 3.93 65 3.81 23 3.78 24 3.77 20 3.65 23 3.59 28 3.45 13 3.32 19 3.25 26

31. The compound as claimed in claim 27, characterized in that the pamoate salt is a bis (olanzapine) pamoate monohydrate solvate having an X-ray powder diffraction pattern as represented by the following interplanar space: Spaces d Intensity 15.77 26 10.44 23 9.64 24 9.31 13 8.27 23 8. 17 14 8.13 14 7.84 27 7.81 30 7.41 60 7.12 40 7.00 13 6.96 13 6.55 45 6.18 53 5.87 38 5.80 19 5.59 89 5.25 26 5.00 34 4.96 31 4.88 61 4.85 73 4.71 34 4.52 19 4.33 11 4.19 100 4.12 48 4.05 39 3.97 30 3. 89 31 3.80 29 3.72 20 3.70 21 3.58 33 3.45 27 3.04 13 2.84 16

32. The compound as claimed in claim 27, characterized in that the pamoate salt is a THF solvate of olanzapine pamoate having an X-ray powder diffraction pattern as represented by the following interplanar space: Spaces d Intensity 14.59 100 7.78 16 7.24 56 7.00 19 6.37 12 6.04 11 6.01 11 4. 85 19 4.69 42 4.39 25 4.28 19 3.95 13 3.84 20

33. A method for the treatment of an animal, including a human, that suffers from or is susceptible to psychosis, acute mania or medium anxiety states, characterized in that it comprises administering a pharmaceutically effective amount of a compound of claim 27, 28, 29 , 30, 31 or 32. FORMULATION OF 2-METHYL-TIENO-BENZODIAZEPINE Summary of the Invention. The invention provides a pharmaceutically acceptable cholesterol or oleic acid microsphere formulation of olanzapine or olanzapine pamoate or solvates thereof. The invention further provides novel olanzapine pamoate salts or solvates thereof.