HK1026632B - Stable complexes of poorly soluble compounds - Google Patents

Description

Stable complex of poorly soluble compound

The present invention provides pharmaceutical compositions comprising water-insoluble complexes consisting of an amorphous therapeutically active compound (i.e., drug) dispersed in an ionic polymer. The complexes according to the invention lead to a significant increase in the bioavailability of poorly soluble therapeutically active compounds.

The bioavailability of a therapeutically active compound is generally affected by (i) the solubility/dissolution rate of the compound and (ii) the partition coefficient/permeability of the compound through the patient's gastrointestinal membrane. The main reason for the poor bioavailability of therapeutically active compounds is the low solubility/dissolution rate of the above compounds. Poor bioavailability is also associated with undesirable patient variability and unpredictable dose/therapeutic effects due to unstable absorption of the therapeutically active compound (e.g., drug) by the patient.

Several techniques are used to improve the bioavailability of poorly soluble therapeutically active compounds. These techniques are summarized below.

1. Reduction of particle size: poorly soluble therapeutically active compounds are often mechanically milled to reduce the particle size of the compound and increase the surface area. See Lachman et al, theory and practice of industrial pharmacy, Chapter 2, page 45 (1986). The average particle size obtained by means of a jet mill is generally in the range from 1 to 10 μm. Similarly, wet milling of a therapeutically active compound in the presence of a protective gel or polymer generally results in compound particle sizes in the range of about 300-800 nm. According to the present technique, the therapeutically active compound and the polymer are dispersed in water and milled by means of milling media such as microbeads (0.2-0.5 mm). See us patent 5,494,683. However, a reduction in the size of the microparticles can only improve the dissolution rate of the therapeutically active compound, but not the total amount of compound at the dissolution equilibrium.

2. Solid dispersion

2.1 melting method: in accordance with the present technique, a therapeutically active compound is dispersed in a non-ionic polymer to form a solid dispersion. Typically, a nonionic polymer (e.g., Pluronic)^*And polyethylene glycol) at a temperature above its melting point, the therapeutically active compound being dissolved into the molten polymer under stirring. See us patent 5,281,420. The resulting melt was then cooled to room temperature. As a result of this process, the therapeutically active compound melts into the polymer and precipitates out in amorphous form on cooling. Compounds in the amorphous state generally have a faster dissolution rate than the initial crystalline state of the compound. Thus, the bioavailability can be improved by a process in which the compound is in an amorphous state. However, due to the relatively high solubility and low melting point of nonionic polymers in water, therapeutically active compounds in the amorphous state do not retain their stability and eventually convert back to the crystalline state upon exposure to high humidity and high temperatures, which are often encountered during long-term storage. See Yoshinka et al, j.pharm.sci.83: 1700-1750(1994). This technique is therefore unsuitable for most formulation forms of therapeutically active compounds and certainly not for those which are poorly soluble.

2.2 coprecipitation:

in another prior approach to improve the bioavailability of poorly soluble therapeutically active compounds, the compound and a non-ionic hydrophilic polymer, such as polyvinylpyrrolidone, are dissolved in an organic solvent. The solvent is removed by evaporation, during which the therapeutically active compound is precipitated in the hydrophilic polymer matrix. See h.g. britain, physical characteristics of drug solids, pharmaceutical and pharmaceutical science, volume 70 (marcedekker, new york, 1995). Due to the hygroscopic nature and solubility in water of the polymers, such polymers do not protect the therapeutically active compound from heat and moisture in the amorphous state. Thus, the therapeutically active compound in the hydrophilic polymer matrix cannot remain in the amorphous state and eventually transforms into the crystalline state upon storage. Thus, this approach is also not practical for improving the bioavailability of poorly soluble therapeutically active compounds.

3. Self Emulsifying Drug Delivery System (SEDDS):

in this system, the therapeutically active compound is dissolved in a suitable mixture of oil and emulsifier. The resulting lipid formulation forms a very fine emulsion or microemulsion upon exposure to gastrointestinal fluids. The bioavailability of poorly soluble therapeutically active compounds dissolved in such oils is significantly increased due to the large surface area of the oil globules. See p.p.constants, pharm.res.12 (11): 1561-1572(1995). The main requirements for the use of this system are that the therapeutically active compound must be soluble in the oil and must remain in a stable form in solution once dissolved in the oil. SEDDS is therefore not a useful co-alternative for most therapeutically active compounds because of the limited solubility and poor stability of these compounds in oil-based solutions.

We have surprisingly found that when poorly soluble therapeutically active compounds (generally in crystalline form) are molecularly dispersed in a water insoluble ionic polymer having a molecular weight greater than about 80,000 daltons and a glass transition temperature equal to or greater than about 50 ℃, the physical stability of the compound (now in amorphous form) remains for a long time even under high humidity and temperature storage conditions. Due to the high molecular weight and high glass transition temperature of the ionomer, and due to its relative insolubility in water, the ionomer immobilizes the therapeutically active compound in its amorphous state, thus providing superior stability of the compound than provided by prior methods. In addition, the bioavailability of the therapeutically active compound is significantly increased due to the increased solubility of the compound in the compound/polymer complex. This method is therefore particularly useful for increasing the bioavailability of poorly soluble therapeutically active compounds.

The present invention provides a pharmaceutical composition comprising a stable, water-insoluble complex consisting of a water-insoluble ionomeric carrier macromolecule having a molecular weight greater than about 80,000 daltons and a glass transition temperature equal to or greater than about 50 ℃, and an amorphous therapeutically active compound, wherein the therapeutically active compound is blended or dispersed in the ionomer in a stable amorphous state to produce a compound/polymer complex. Another aspect of the invention is a water-insoluble compound/polymer complex. The complexes of the invention are formed by microprecipitation of the therapeutically active compound in an ionophore.

The compound/polymer complex of the invention may be in solid form (e.g., paste, granules, powder) which can be filled into capsules or compressed into tablets. The powdered complex may also be sufficiently powdered or micronized to form a stable liquid suspension or semi-solid dispersion. The complexes of the invention may be sterilized prior to parenteral administration in vivo, for example, by gamma or electron beam irradiation.

The present invention relates to a stable water-insoluble complex consisting of a water-insoluble ionic polymer carrier having a molecular weight greater than 80,000 daltons and a glass transition temperature equal to or greater than 50 ℃, and a therapeutically active compound in a stable amorphous state. The invention also relates to methods of making such complexes and pharmaceutical formulations containing such complexes. Advantages of the complexes of the invention include substantially increased bioavailability of the relatively insoluble therapeutically active compound and prolonged delivery time of such compounds (i.e., sustained release of such complexes into the bloodstream).

Herein, the following terms have the following meanings.

By "compound/polymer complex" or "water insoluble complex" is meant a physically stable product formed by co-precipitating ("microprecipitating") a therapeutically active compound and a water insoluble ionic polymer according to the methods described herein.

"Dispersion" means the random distribution of the therapeutically active compound in the ionic polymer.

"dissolution rate" refers to the rate at which a particular compound dissolves in physiological fluids in vitro.

"Ionic polymers" or "ionophore polymers" include anionic (negatively charged) and cationic (positively charged) polymers.

"microprecipitation" refers to any method of dispersing a compound, particularly a therapeutically active compound molecule, in a polymer.

By "molecularly dispersed" is meant that the therapeutically active compound is present in the polymer in a finely divided final state. See, e.g., m.g. vachon et al, journal of microencapsulation, 14 (3): 281-301 (1997); m.a. and Vandelli et al, journal of microencapsulation, 10 (1): 55-65(1993).

"patient" refers to a human patient.

By "poorly soluble therapeutically active compound" is meant a therapeutically active compound having a water solubility of less than 1mg/mL, typically less than 100. mu.g/mL.

In one aspect, the invention relates to a pharmaceutical composition comprising a stable water-insoluble complex consisting of a carrier macromolecule of an ionomer and a therapeutically active compound that is stable in the amorphous state. The use of such compound/polymer complexes is particularly preferred when the solubility of the compound is poor, making it difficult to achieve the desired oral bioavailability of the compound.

According to the invention, when a poorly soluble crystalline therapeutically active compound is microprecipitated with a water-insoluble ionic polymer having a molecular weight greater than 80,000 daltons and a glass transition temperature equal to or greater than 50 ℃, the compound is molecularly dispersed in the ionic polymer in an amorphous state, resulting in a stable water-insoluble complex. Microprecipitation may be achieved, for example, by any of the following methods, each of which is further described below.

a) Spray drying or freeze drying

b) Solvent controlled precipitation

c) pH controlled precipitation

d) Hot melt extrusion process

e) Supercritical fluid technology

Once the therapeutically active compound is so dispersed in the ionomer, it retains its amorphous structure even during long-term storage, i.e. it is "stable". In addition, the ionic polymers protect the compounds from harmful external environmental factors such as moisture and heat, thus maintaining enhanced solubility and thus enhanced bioavailability.

The therapeutically active compound according to the invention, which is contained in the amorphous state of the complex, is significantly more bioavailable than the compound in the crystalline state and is stable in long term storage. In addition, the complex provides sustained release characteristics to the therapeutically active compound dispersed in the compound/polymer complex due to the controlled dissolution rate of the complex in gastrointestinal fluids.

The invention can be used for any therapeutically active compound, in particular a therapeutically active compound with a solubility in water of less than 1mg/mL, in particular less than 100. mu.g/mL. Such poorly soluble therapeutically active compounds include, for example, retinoids and protease inhibitors. In particular, the invention is particularly applicable to the following therapeutic compounds:

in the crystalline state, the above-mentioned compound I has particularly poor water solubility (< 10. mu.g/mL) and bioavailability.

The present invention is also applicable to the compound tolcapone (sold by Roche Laboratories, Inc. under the brand name Tasmar)^*) Compound 1, 3-cis-retinoic acid (commercially available from Roche Laboratories, Inc. under the trade name ACCUTANE)^*) Compound saquinavir (sold by Roche Laboratories, Inc. under the trade name FORTOVASE)^TM) And the following compounds:

suitable ionic polymers for use in accordance with the present invention are cationic or anionic polymers having a molecular weight greater than 80,000 daltons, a glass transition temperature equal to or greater than 50 ℃, and are relatively water insoluble and preferably have pH dependent solubility. Examples of such polymers include polyacrylates (e.g., Eudragit @)^*Rohm America), chitosan, Carbopol^*(BF Goodrich), polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylate, hydroxypropylmethylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose acetosuccinate, carboxymethylcellulose and low-substituted hydroxypropylcellulose. According to the invention, the water-insoluble complex may also consist of a mixture of two or more of the above-mentioned ionic polymers (see, for example, examples 9 and 10).

Particularly preferred anionic polymers include Eugragit^*L100-55 (methacrylic acid and ethyl acrylate copolymer) and Eugragit^*L100 or Eugragit^*S100 (methacrylic acid and methyl methacrylate copolymer), all of which are available from Rohm America. Eugragit^*L100-55 is soluble at pH greater than 5.5 and practically insoluble at pH less than 5.5. Eugragit^*The molecular weight of L100-55 is about 250,000D, and the glass transition temperature is 110 ℃. Eugragit^*L100 is soluble at pH above 6 and almost insoluble at pH below 6. Eugragit^*L100 ofThe molecular weight was about 135,000D and the glass transition temperature was about 150 ℃. Eugragit^*S100 is soluble at pH above 7 and practically insoluble at pH below 7. Eugragit^*The molecular weight of S100 is about 135,000D and the glass transition temperature is about 160 ℃.

Particularly preferred cationic polymers include Eugragit^*E (Rohm America), a copolymer of dimethylaminoethyl methacrylate and neutral methacrylate. Such polymers are soluble at pH less than 4 and are almost insoluble at pH greater than 4. Eugragit^*E has a molecular weight of about 150,000D and a glass transition temperature of about 50 ℃.

The pharmaceutical composition of the present invention comprising the water-insoluble complex of the present invention can be manufactured in a manner known in the art, for example, by a conventional mixing, milling, encapsulating, dissolving, concentrating, granulating or lyophilizing process. In addition to the water-insoluble complexes, these pharmaceutical compositions may also include therapeutically inert inorganic or organic carriers ("pharmaceutically acceptable carriers") and/or excipients other than ionic polymers. Pharmaceutically acceptable carriers for tablets, dragees and hard gelatine capsules include lactose, maize starch or derivatives thereof, talc, stearic acid or salts thereof. Suitable carriers for soft gelatin capsules include vegetable oils, waxes, fats and semi-solid or liquid polyols.

The pharmaceutical compositions according to the invention may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. These compositions may also contain additional therapeutically active compounds or more than one therapeutically active compound/polymer complex.

Preparation method

In one embodiment of the present invention, the water-insoluble complex of the present invention is prepared by one of the following methods.

a) Spray drying or freeze drying: the therapeutically active compound and the ionic polymer are dissolved in a common low boiling solvent, such as ethanol, methanol, acetone, etc. The solvent is evaporated by spray drying or freeze drying, leaving the therapeutically active compound micro-precipitated in the ionic polymer matrix in an amorphous state. This technique is not preferred for therapeutically active compounds that do not have sufficient solubility (> 5%) in the preferred solvents.

b) Solvent-controlled precipitation: the therapeutically active compound and the ionic polymer are dissolved in a common solvent, such as dimethylacetamide, dimethylformamide and the like. The therapeutically active compound/polymer solution is added to cold water (2-5 ℃) and adjusted to the appropriate pH. The pH required depends on the polymer used and is readily determined by one skilled in the art. This results in microprecipitation of the therapeutically active compound in the polymer matrix. The microprecipitate is washed several times with an aqueous medium until the residual solvent falls to the limit allowed for the solvent. The "allowable limits" for each solvent are determined according to the International Union of mediation (ICH) guidelines.

c) precipitation method with pH control: in the present process, the microprecipitation of the therapeutically active compound in the ionomer is controlled by drastically changing the pH of the solution. The therapeutically active compound and the ionic polymer are dissolved at high pH (e.g. pH-9) and precipitated by lowering the pH of the solution (e.g. to-1), or vice versa. This method is particularly suitable for therapeutically active compounds having pH dependent solubility.

d) A hot-melt extrusion process: the microprecipitation of the therapeutically active compound in the ionomer having thermoplastic properties can be achieved by a hot melt extrusion process. The therapeutically active compound and the polymer in crystalline form are mixed in a suitable compounder and continuously fed into a temperature controlled extruder resulting in the dispersion of the therapeutically active compound molecules in the molten ionomer. The resulting extrudate was cooled to room temperature and ground to a fine powder.

e) Supercritical fluid technology: the therapeutically active compound and the ionic polymer are dissolved in a supercritical fluid such as liquid nitrogen or liquid carbon dioxide. The supercritical fluid is removed by evaporation, leaving the therapeutically active compound micro-precipitated in the polymer matrix. In another method, the therapeutically active compound and the ionic polymer are dissolved in a suitable solvent. The micro-precipitated powder is formed by spraying the solution into a superfluid as an anti-solvent.

In another embodiment of the invention, the pharmaceutical formulation may be prepared according to any of the above steps, plus the last step, i.e., the compound/polymer complex of the invention is formulated by methods known in the art.

In a preferred embodiment of the invention, the therapeutically active compound and the ionic polymer are dissolved in an organic solvent. Thereafter, the compound and ionic polymer are co-precipitated at substantially the same time, preferably in aqueous solution and preferably at a pH at which neither the compound nor the polymer is soluble.

The organic solvent used to dissolve the therapeutically active compound and the ionic polymer should have good solubility for both the poorly soluble compound and the polymer used. These solvents include ethanol, methanol, acetone dimethyl sulfoxide, dimethylacetamide, dimethylformamide, N-methylpyrrolidone, Transcutol^*(diethylene glycol monoethyl ether, gattefose, inc.), furanmethylene glycol (glycofurol), propylene carbonate, tetrahydrofuran, polyethylene glycol, and propylene glycol.

The pH selected for co-precipitation of the therapeutically active compound and the ionic polymer depends on the solubility of each particular polymer and compound to be precipitated. The preferred pH required for the combination of co-precipitation of each polymer and the therapeutically active compound can be readily determined by one skilled in the art. In one application, one is selected from Eudragit^*L100-55，Eudragit^*L100 and Eudragit^*In a preferred embodiment of the anionic polymer of S100, the solution precipitates at a pH below 4. In another one use Eudragit^*In a preferred embodiment of the cationic polymer of E100, the solution precipitates at a pH above 4.

The amount of therapeutically active compound and polymer necessary to obtain the stable water-insoluble complex of the present invention may vary depending on the particular compound and polymer used, as well as the particular solvent and precipitation parameters. For example, the compound may comprise about 0.1-80% by weight of the composite. Similarly, the polymer typically constitutes no less than 20% by weight of the composite. Preferably, the compound is present in the composite in an amount of about 30 to about 70 weight percent, more preferably about 40 to about 60 weight percent. Most preferably, the compound is present at about 50%. For complexes to which compound I is added, the compound is present in the complex at about 30-70%, more preferably at about 50%.

Once the compound/polymer precipitates from solution, the resulting complex can be recovered from the solution by procedures known to those skilled in the art, such as by filtration, centrifugation, washing, and the like. The recovered material is then dried (air dried, oven dried or vacuum dried) by methods known in the art and the resulting solid is ground, powdered or micronized into a fine powder. The fine complex powder may then be dispersed in a carrier to form a pharmaceutical formulation.

The pharmaceutical formulations according to the invention may be administered to a patient by any suitable route in order to obtain the desired therapeutic effect. Preferred routes of administration include parenteral and oral.

The pharmaceutical formulation according to the invention comprises a therapeutically effective amount of a therapeutically active compound. A therapeutically effective amount is that amount necessary to achieve the desired therapeutic effect at such dosages and for such periods of time. Moreover, such amounts must be such that the overall therapeutic benefit outweighs the toxic or undesirable side effects. The therapeutically effective amount of the compound will often vary depending on the condition, age and weight of the patient being treated. Thus, the dosage regimen will generally be adapted to the individual requirements in each particular case and is within the skill of the art.

For example, for compound I above, a suitable daily dose for administration to an adult human weighing about 70 kg is about 10-10,000mg, preferably 200-1000mg, although the upper limit may be exceeded if so indicated.

The daily dose of the therapeutically active compound can be administered in a single dose, in divided doses, or for parenteral administration, by subcutaneous injection.

The following examples refer to the accompanying drawings, in which

FIG. 1 is a powder x-ray diffraction pattern of the compound/polymer complex of example 4 compared to the drug alone and to a physical mixture of drug and polymer.

Figure 2 is a powder x-ray diffraction pattern of the compound/polymer composite of example 4 exposed to an accelerated stress state as compared to an unpressurized (virgin) mixture/polymer composite.

Figure 3 is a plasma concentration profile of the compound/polymer complex of example 4 in dogs.

FIG. 4 is a powder x-ray diffraction pattern of Compound II and Compound/Polymer Complex (example 11) after microprecipitation in accordance with the present invention.

FIG. 5 is a powder x-ray diffraction pattern of Compound III and Compound/Polymer Complex (example 13) after microprecipitation in accordance with the present invention.

FIG. 6 is a powder x-ray diffraction pattern of Compound IV and Compound/Polymer Complex (example 15) after microprecipitation in accordance with the present invention.

FIG. 7 is a powder x-ray diffraction pattern of Compound V and Compound/Polymer Complex (example 16) after microprecipitation in accordance with the present invention.

Examples

The following examples illustrate the preparation of the water-insoluble compound/polymer complexes of the invention and the pharmaceutical formulations containing the same.

For the examples reported herein, the compounds tested were compounds I, II, III, IV and V, the structures of which are given above. These compounds are almost insoluble in gastrointestinal fluids. Prior to the present invention, the crystalline insoluble form of Compound I was the only stable form of the compound that could be obtained.

General procedure

Procedure suitable for example 1 (micronized compound)

Compound I was micronized using a fluid energy mill, resulting in a mean particle size of 10 microns. This step did not change the crystalline state of compound I.

Procedure applicable to example 2 (micronized compound)

Suspending 10% of compound I in EF solution containing 5% Klucel^*(hydroxypropyl cellulose, AqualonCorp.) as a protective colloid to prevent wet grinding in a coagulated aqueous medium. Milling was done in a batch process for 24 hours in Dynomill using 0.25mm glass beads as milling media. The average particle size of the resulting suspension was 700nm and the residue obtained after drying the suspension indicated that the compound was present in crystalline form.

Procedure suitable for example 3 (Pluronic F68 dispersion)

A 10% compound II dispersion of 90% Pluronic F68 (polymer) was prepared using a hot melt technique. The compound was mixed into molten Pluronic F68 at 60 ℃ and then the dispersion was heated to 180 ℃ to dissolve compound I. The solution was cooled to room temperature to form a solid material. The powder x-ray diffraction ("XRD") pattern of the melt dispersion was similar to that of Pluronic F68. This XRD showed that compound I was present in the solid dispersion in an amorphous state. The solid dispersion obtained by this technique is further dispersed in an aqueous medium before use in a pharmaceutical animal.

Procedure applicable to examples 4-12 and 15-16 (molecular Dispersion according to the invention)

According to the process of the invention, compounds I, II, IV or V and the particular polymers indicated in each case (for example Eudragit)^*L100-55、Eudragit^*L100 or Eudragit^*S100) dissolvingIn dimethyl lactamide.

The resulting solution was slowly added to a cold (2-5 ℃) aqueous solution at pH2, causing the compound and copolymer to co-precipitate as an insoluble matrix in which the compound molecules were dispersed in the polymer. The precipitate was washed several times with cold (2 ℃ C. -5 ℃ C.) aqueous solution at pH2 in each case until the residual dimethyl lactamide was below 0.2%. The precipitate was dried in a forced air oven at 40 ℃ for 24 hours to a moisture of less than 2% and a Fitz Mill was used^*(Fitzpatrick) and a front knife were ground at low speed and a No. 0 sieve was used to size the desired particles. The desired average particle size is 90% in the range of 5-400. mu.m.

Procedure suitable for examples 13 to 14 (Compound III)

According to the above-described method, Compound III and the particular Polymer identified in each case (e.g., Eudragit @)^*L100-55、Eudragit^*L100, hydroxypropyl methylcellulose phthalate (HP-50) or Eudragit^*S100) was dissolved in ethanol.

The resulting solution was either vacuum oven dried at 40 ℃ for 24 hours until less than 2% of the weight was lost upon drying, or replaced by spray drying. As a result of this process, the compound and copolymer co-precipitate as an insoluble matrix in which the compound molecules are dispersed in the polymer. The resulting dried film was ground with a pestle/mortar and sieved through a 60 mesh screen.

Data of

Table 1 below summarizes the results of examples 1-16. Table 1 details the individual therapeutically active compounds, as well as the compounds/polymer complexes prepared where applicable, the methods of preparing the compounds/polymer complexes, and the physical properties of the products obtained in each example.

Table 1: examples 1 to 14 summarises

Example #	Composition (% w/w)	Preparation method	Characteristics of the obtained product
				1	Compound I100% (micronized)	Fluid energy mill	XRD-crystal with particle size of 50-10 μm
2	Compound I67% Kluel EF* 33％	Wet milling with 0.25mm glass beads	XRD-crystal with particle size of 50-0.7 μm
				3	Compound I10% Pluronic F6890%	Hot melt extrusion at about 180 ℃	XRD-amorphous
4	Compound I30% Eudragit L100-5570%	Solvent controlled precipitation	XRD-amorphous (FIGS. 1 and 2)
				5	Compound I50% Eudragit L100-5550%	Solvent controlled precipitation	XRD-amorphous
6	Compound I70% Eudragit L100-5530%	Solvent controlled precipitation	XRD-amorphous
				7	Compound I30% Eudragit L10070%	Solvent controlled precipitation	XRD-amorphous
8	Compound I50% Eudragit L10050%	Solvent controlled precipitation	XRD-amorphous
				9	Compound I15% Eudragit L100-5542.5% Eudragit S10042.5%	Solvent controlled precipitation	XRD-amorphous
10	Compound I30% Eudragit L100-5535% Eudragit S10035%	Solvent controlled precipitation	XRD-amorphous
				11	Compound II 30% Eudragit L10070%	Solvent controlled precipitation	XRD-amorphous (FIG. 4)
12	Compound II 30% HP-50* 70％	Solvent controlled precipitation	XRD-amorphous
				13	Compound III 30% Eudragit L10070%	Spray drying	XRD-amorphous (FIG. 5)
14	Compound III 50% Eudragit L10050%	Spray mistDrying	XRD-amorphous
				15	Compound IV 20% Eudragit L10080%	Solvent controlled precipitation	XRD-amorphous (FIG. 6)
16	Compound V30% Eudragit L10070%	Solvent controlled precipitation	XRD-amorphous (FIG. 7)

^*Hydroxypropyl methylcellulose phthalate

The composite powder x-ray diffraction ("XRD") pattern obtained in example 4 is shown in fig. 1 and table 1. That is, when compound I is included in an ionic polymer according to the present invention, it exhibits an amorphous state.

Table 1 and fig. 4-7 also show that the process of the present invention is useful in providing compounds II, III, IV and V in amorphous form.

The compounds I are incorporated into ionic polymers which protect the compounds from the external environment, for example moisture and heat. This result is illustrated in fig. 2, where compound I embedded in a polymer maintains amorphous characteristics even under accelerated storage conditions as shown by powder X-ray diffraction. The ability of the composite to remain amorphous even under accelerated conditions is attributed to the high molecular weight (> 80,000), high glass transition temperature (> 50 ℃) and water insolubility of the polymer.

In addition, as shown in table 2 below, the bioavailability of compound I in dogs according to the present invention is unexpectedly higher when the compound I is molecularly dispersed in an ionomer than when the compound is applied to animals in a conventional manner (micronised or wet milled). The bioavailability obtained from solid dispersed compound I prepared by the hot melt process with pluronic f68 (a nonionic water soluble polymer containing polyoxyethylene and polyoxypropylene chains, BASF) is also shown in table 2. Although the bioavailability of the compound dispersed in solid is better than when the compound is micronised or present in a wet-milled suspension, the biostability of the solid dispersion is unsatisfactory for pharmaceutical products, since it is clear that the compound reverts to its crystalline state by storage under ambient conditions for a period of one month. The above results indicate that the technique for preparing solid dispersion pharmaceutical products in non-ionic water soluble polymers is not applicable.

Table 2: for four animals (two males and two females), the oral administration is carried out in a single dose (10mg/kg)^*Bioavailability of late Compound I in dogs

Preparation	AUC0-∞Dose (nghml)/(mg/kg)	% biological effectiveness**
			Micronized drug suspension (example 1)	29.5±8.3	3.85
Wet milled drug suspension (example 2)	86.1±13.7	11.2
			Pluronic F68 solid suspension***(example 3)	532±152	69.5
Compound/Polymer composite (example 4)	529±189	69.1
			Compound/Polymer composite (example 5)	560±72	73.1
Compound/Polymer composite (example 6)	588±399	76.8
			Compound/Polymer composite (example 7)	604±124	78.9
Compound/Polymer composite (example 8)	768±387	100.3
			Compound/Polymer Complex (example 9)	415±152	54.2
Compound/Polymer composite (example 10)	264±152	34.5

^*The results are the mean (with standard deviation) for four animals (males and females).

^**Compared with single dose intravenous administration.

^***The transition to the crystalline state was achieved after exposure at 40 ℃ at 75% pH, 1wk, open air.

Figure 3 shows plasma-time curves for different batches of the compound/polymer complex produced in example 4. The results of these experiments (summarized in fig. 3) indicate batch-to-batch repeatability and consistency. Batch-to-batch repeatability and consistency is an important aspect of any formulation intended for administration to a human patient.

FIGS. 4-7 show that compounds II, III, IV and V can also be converted to the amorphous state using this method.

In summary, from the data shown in tables 1 and 2 above and FIGS. 1, 2 and 4 to 7, the X-ray diffraction patterns of the compound/polymer composite powders obtained in examples 4 to 16 show that the molecularly dispersed poorly soluble compound according to the present invention is converted into an amorphous state and that the amorphous compound maintains excellent stability in long-term storage.

Claims (35)

1. A pharmaceutical composition comprising a water-insoluble complex of a therapeutically active, stable amorphous compound selected from the group consisting of:

the ionic polymer has a molecular weight greater than 80,000 daltons and a glass transition temperature equal to or greater than 50 ℃, selected from the group consisting of polyacrylates, chitosan, carboxylic vinyl polymers, polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropyl methylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose acetosuccinate, carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, or a mixture of two or more of the above ionomers, powder x-ray diffraction measurements show, wherein the therapeutically active compound is molecularly dispersed in the water-insoluble ionic polymer in a predominantly amorphous state, the amount thereof in the water-insoluble complex is not less than 10% by weight, and the amount of the water-insoluble ionic polymer in the water-insoluble complex is not less than 20% by weight.

2. The pharmaceutical composition of claim 1, wherein the ionic polymer is a copolymer of dimethylaminoethyl methacrylate and neutral methacrylate.

3. The pharmaceutical composition of claim 2, wherein the ionic polymer is Eudragit^*E。

4. The pharmaceutical composition of claim 1, wherein the ionic polymer is a copolymer of methacrylic acid and ethyl acrylate or a copolymer of methacrylic acid and methyl methacrylate.

5. The pharmaceutical composition of claim 4, wherein the ionic polymer is selected from the group consisting of Eudragit L100-55^*、Eudragit-L100^*And Eudragit S-100^*。

6. The pharmaceutical composition of claim 1, wherein the ionic polymer is selected from the group consisting of polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylate, hydroxypropyl methylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose acetosuccinate, carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.

7. The pharmaceutical composition of claim 1, wherein the ionic polymer has a solubility that is pH dependent.

8. The pharmaceutical composition of claim 7, wherein the ionic polymer is insoluble above pH 4.

9. The pharmaceutical composition of claim 1, wherein the ionic polymer and the therapeutically active compound in the crystalline state are relatively insoluble above pH 4.

10. The pharmaceutical composition of claim 7, wherein the ionic polymer is insoluble at less than pH 4.

11. The pharmaceutical composition of claim 1, wherein the ionic polymer and the therapeutically active compound in the crystalline state are relatively insoluble at less than pH 4.

12. Pharmaceutical composition according to claim 1, characterized in that the therapeutically active compound is compound I.

13. A pharmaceutical composition according to claim 1, wherein the therapeutically active compound is present in the water-insoluble complex in an amount of from 30% to 70% by weight of said complex.

14. A process for preparing a pharmaceutical composition comprising a water-insoluble complex of a stable amorphous therapeutically active compound selected from the group consisting of:

said ionic polymer having a molecular weight greater than 80,000 daltons and a glass transition temperature equal to or greater than 50 ℃ and being selected from the group consisting of polyacrylates, chitosan, carboxyvinyl polymers, polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropyl methylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose acetosuccinate, carboxymethyl cellulose and low substituted hydroxypropyl cellulose, or mixtures of two or more of the foregoing ionic polymers, as shown by powder x-ray diffraction, wherein the therapeutically active compound is present in the complex predominantly in the amorphous state in an amount of no less than 10% by weight of the complex and the ionic polymer in the complex in an amount of no less than 20% by weight, the method comprising:

(a) dissolving a therapeutically active compound and an ionic polymer in an organic solvent;

(b) contacting the solution of step (a) with an aqueous solution at a pH at which the ionic polymer is poorly soluble, thereby micro-precipitating the therapeutically active compound and the ionic polymer as a compound/polymer complex;

(c) preparing a pharmaceutical formulation comprising the compound/polymer complex of step (b) above.

15. The method of claim 14, wherein in step (a), the therapeutically active compound and the ionic polymer are dissolved in a solvent selected from the group consisting of ethanol, methanol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, N-methylpyrrolidone, diethylene glycol monoethyl ether, methylenefuranone glycol, propylene carbonate, tetrahydrofuran, polyethylene glycol, and propylene glycol.

16. The method of claim 14, wherein in step (b), the microprecipitation is carried out by removing the solvent by spray drying or freeze drying.

17. The method of claim 14, wherein in step (a), the insoluble therapeutically active compound and the ionic compound polymer are dissolved by adjusting the pH.

18. The method of claim 14, wherein residual solvent is removed after step (b).

19. The method of claim 18, wherein the residual solvent is removed by washing the compound/polymer composite.

20. The method of claim 18, wherein the residual solvent is removed by evaporation or drying.

21. The method of claim 20, wherein the residual solvent is removed by spray drying.

22. A process for preparing a pharmaceutical formulation comprising a water-insoluble complex of a stable amorphous therapeutically active compound selected from the group consisting of:

said ionic polymer having a molecular weight greater than 80,000 daltons and a glass transition temperature equal to or greater than 50 ℃ and being selected from the group consisting of polyacrylates, chitosan, carboxyvinyl polymers, polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropyl methylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose acetosuccinate, carboxymethyl cellulose and low substituted hydroxypropyl cellulose, or mixtures of two or more of the foregoing ionic polymers, the powder x-ray diffraction assay showing that the therapeutically active compound is present predominantly in the amorphous state in the complex in an amount of no less than 10% by weight and the ionic polymer in the complex in an amount of no less than 20% by weight, the method comprising:

(a) dissolving the therapeutically active compound and the ionic polymer in the crystalline state in an organic solvent;

(b) contacting the product of step (a) with an aqueous solution at a pH at which the ionic polymer and therapeutically active compound will precipitate as a compound/polymer matrix;

(c) cleaning the compound/polymer matrix;

(d) drying the compound/polymer matrix;

(e) preparing a pharmaceutical formulation incorporated in the compound/polymer matrix washed and dried in step (b) above.

23. The method of claim 22, wherein the ionic polymer is selected from the group consisting of eudragit e100^*、Eudragit L100^*、Eudragit L100-55^*And Eudragit S100^*。

24. A process for preparing a water-insoluble complex comprising a stable amorphous compound selected from the group consisting of:

said ionic polymer having a molecular weight greater than 80,000 daltons and a glass transition temperature equal to or greater than 50 ℃ and being selected from the group consisting of polyacrylates, chitosan, carboxyvinyl polymers, polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropyl methylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose acetosuccinate, carboxymethyl cellulose and low substituted hydroxypropyl cellulose, or mixtures of two or more of the foregoing ionic polymers, the powder x-ray diffraction assay showing that the compound is present in the composite predominantly in the amorphous state in an amount of no less than 10% by weight of the composite and the ionic polymer in the composite in an amount of no less than 20% by weight, the method comprising:

(a) melting together the therapeutically active compound and the ionomer; and are

(b) Cooling the mixture produced in step (a).

25. A process for preparing a pharmaceutical formulation comprising a water-insoluble complex of a stable amorphous therapeutically active compound selected from the group consisting of:

said ionic polymer having a molecular weight greater than 80,000 daltons and a glass transition temperature equal to or greater than 50 ℃ and being selected from the group consisting of polyacrylates, chitosan, carboxyvinyl polymers, polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropyl methylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose acetosuccinate, carboxymethyl cellulose and low substituted hydroxypropyl cellulose, or mixtures of two or more of the foregoing ionic polymers, the powder x-ray diffraction assay showing that the therapeutically active compound is present predominantly in the amorphous state in the complex in an amount of no less than 10% by weight and the ionic polymer in the complex in an amount of no less than 20% by weight, the method comprising:

(a) dissolving a therapeutically active compound and an ionic polymer in a supercritical fluid;

(b) removing the supercritical fluid to allow microprecipitation of the therapeutically active compound in the ionic polymer matrix; and are

(c) Preparing a pharmaceutical formulation comprising the product of step (b) above.

26. The method of claim 25, wherein the supercritical fluid used in step (a) is selected from the group consisting of liquid nitrogen and liquid carbon dioxide.

27. The method of claim 25, wherein the removal of the supercritical fluid is accomplished by evaporation in step (b).

28. A stable, water-insoluble complex prepared by:

(a) the compound I

And a water-insoluble ionic polymer having a molecular weight greater than 80,000 daltons and a glass transition temperature equal to or greater than 50 ℃ dissolved in a suitable solvent, the ionic compound being selected from the group consisting of polyacrylates, chitosan, carboxylic vinyl polymers, polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropyl methylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, or two or more of the foregoing ionic polymers

A mixture of a plurality; and are

(b) Coprecipitating compound I and an ionic polymer as a compound/polymer composite, powder x-ray diffraction measurements show that the compound I molecules are dispersed in the compound/polymer composite in an amount of not less than 10% by weight of the composite and the ionic polymer is present in the composite in an amount of not less than 20% by weight.

29. The composite of claim 28, wherein the precipitation of step (b) is carried out by contacting the solution of step (a) with an aqueous solution at a pH at which the ionic polymer is poorly soluble.

30. A water-insoluble complex comprising a stable amorphous compound selected from the group consisting of:

the ionic compound has a molecular weight greater than 80,000 daltons and a glass transition temperature equal to or greater than 50 ℃ and is selected from the group consisting of polyacrylates, chitosan, vinyl carboxylates, polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropyl methylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose acetosuccinate, carboxymethyl cellulose and low substituted hydroxypropyl cellulose, or mixtures of two or more of the foregoing ionic polymers, and powder x-ray diffraction measurements show that the therapeutically active compound is present in the complex predominantly in the amorphous state in an amount not less than 10% by weight of the complex and the ionic polymer is present in the complex in an amount not less than 20% by weight.

31. The composite of claim 30, wherein the amorphous compound is poorly soluble in the crystalline state.

32. The composite of claim 30, wherein the amorphous compound is compound I.

33. A method of stabilizing a compound in an amorphous state as determined by powder x-ray diffraction, the amorphous compound being selected from the group consisting of:

comprising dispersing the compound in a water-insoluble ionic polymer having a molecular weight of greater than 80,000 daltons and a glass transition temperature of 50 ℃ or greater selected from the group consisting of polyacrylates, chitosan, carboxylic vinyl polymers, polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropyl methylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose sulfosuccinate, carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, or mixtures of two or more of the foregoing ionic polymers to provide a water-insoluble composite, wherein the amount of amorphous compound in the composite is not less than 10% by weight and the amount of ionic polymer in the composite is not less than 20% by weight.

34. A process for converting a poorly soluble crystalline compound to a stable amorphous form of said compound as determined by powder x-ray diffraction, said compound being selected from the group consisting of:

comprising dispersing the compound in a water-insoluble ionic polymer having a molecular weight of greater than 80,000 daltons and a glass transition temperature of 50 ℃ or greater selected from the group consisting of polyacrylates, chitosan, carboxylic vinyl polymers, polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropyl methylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose sulfosuccinate, carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, or mixtures of two or more of the foregoing ionic polymers to provide a water-insoluble composite, wherein the amount of amorphous compound in the composite is not less than 10% by weight and the amount of ionic polymer in the composite is not less than 20% by weight.

35. A water-insoluble complex comprising a therapeutically active compound dispersed as a stable amorphous molecule in a water-insoluble ionic polymer, said therapeutically active compound being selected from the group consisting of:

the ionic polymer has a molecular weight greater than 80,000 daltons and a glass transition temperature equal to or greater than 50 ℃, selected from the group consisting of polyacrylates, chitosan, carboxylic vinyl polymers, polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropyl methylcellulose phthalate, cellulose acetate triphthalate, hydroxypropyl methylcellulose acetosuccinate, carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, or a mixture of two or more of the above ionomers, powder x-ray diffraction measurements show that the therapeutically active compound is dispersed in the water-insoluble ionomer predominantly as amorphous molecules, the amount thereof in the water-insoluble complex is not less than 10% by weight, and the amount of the water-insoluble ionic polymer in the water-insoluble complex is not less than 20% by weight.