JP2004503511A - New solid dispersant composition - Google Patents

Abstract

The present invention relates to novel immediate release solid dispersion pharmaceutical compositions with improved solubility and dissolution characteristics, and enhanced bioavailability, their preparation and the use of these compositions.

Description

[0001]
(Field of the Invention)
The present invention relates to novel immediate release solid dispersion pharmaceutical compositions with improved solubility and dissolution properties, and increased bioavailability, their preparation and the use of these compositions. In particular, the invention provides a solid dispersion consisting essentially of a poloxamer surfactant, a medium molecular weight polyethylene glycol, and a co-melt of a therapeutically active compound that melts without decomposing below the flash point of the polyethylene glycol. And pharmaceutical compositions.
[0002]
(Background of the Invention)
A solid dispersion formulation is a drug-containing drug bulk material that contains a drug dissolved or dispersed in a polymer. Solid dispersions are useful for increasing the solubility of the drug and / or for controlling the rate of release of the drug from the dosage form, or for improving the bioavailability of the drug. Typically, the solid dispersion is a slow release or controlled release formulation.
[0003]
Conventional methods of making solid dispersants use a temperature above the melting point of the polymer used to form a dense colloidal dispersion of drug particles, from a melting process with some dissolution of the drug in the polymer, And eutectic processes using temperatures above the melting point of the drug. The molten mixture is then immediately cooled to give an agglomerate, which is then often comminuted to produce a powder, which is often encapsulated or tableted. Although simple, this method is inconvenient, for example, when the drug and polymer are immiscible in the molten state. In addition, the process is limited in that the drug tends to degrade due to the high temperatures required to melt the components.
[0004]
If there is a problem with respect to thermal instability and / or miscibility between the drug and the carrier, a hybrid method called a fusion-solvent method for making a solid dispersion is used. The drug is first dissolved in a small amount of an organic solvent and then added to the molten carrier. The solvent is then evaporated to give the product, which is then ground to make a powder. However, this solvent method is, for example, an explosion accident during manufacturing, the difficulty of removing all traces of solvent from the solid dispersant product for pharmaceutical use, and the release of solvent into the atmosphere, which is a source of contamination. There is also an inconvenience.
[0005]
Other issues that have limited the industrial application of technology for solid dispersants include preparation methods, reproducibility of physicochemical properties, formulation of pharmaceutically acceptable dosage forms, and scales for producing GMP clinical supplies. And physicochemical stability of drugs and excipients.
To overcome the above disadvantages, experts have proposed a number of options, such as avoiding the eutectic temperature and replacing poorly soluble drugs with polyvinylpyrrolidone (PVP) or high molecular weight polyethylene glycols (eg PEG 6000). And a plasticizer / solubiliser (eg, low molecular weight PEG 200, 300, 400 or 600 and optionally a surfactant such as Tween 80) in a fluid bed granulator. ), Extruding the resulting granules from a twin screw extruder with at least one heating zone, and then grinding the extrudate (WO 93/24 published June 24, 1993). 11749 pamphlet). U.S.A. issued October 10, 1995. S. In US Pat. No. 5,456,923, a twin screw extruder is used with various derivatives of a pH-dependent polymer, for example HPMC. Published international application WO 93/23022, published November 25, 1993, discloses a method for mixing the drug tebuferon (15-75%) with a poloxamer surfactant (25-75%) having a melting point of 40 ° C. or higher. Disclose a lysate. PEG (0-60%) is disclosed as an optional additional component of a solid dispersant.
[0006]
According to the present invention, there is no need to use an organic solvent, the drug does not thermally decompose at a temperature above the melting point of the drug, and the formation of an immediate release solid pharmaceutical dispersant that does not require grinding or altering of the solid dispersant, Increases bioavailability of water-insoluble drugs.
[0007]
(Summary of the Invention)
The invention is essentially
(A) from about 0.1% to about 20% of the active drug;
(B) about 2% to about 20% of a poloxamer surfactant having an HLB value between about 20 and about 30;
(C) an immediate release solid dispersant which is an atypical drug-containing coagulated eutectic mixture comprising from about 60% to about 97.9% medium molecular weight polyethylene glycol, wherein the drug degrades at a temperature below the flash point of the polyethylene glycol Pharmaceutical compositions, including those that melt without doing so, their preparation, and their use in dosage formulations.
[0008]
More specifically, the present invention essentially comprises
(A) about 10% to about 20% of (S)-(-)-N-([alpha] -ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide;
(B) about 5% to about 10% of a poloxamer surfactant, preferably poloxamer 188;
(C) an immediate release solid dispersant which is a coagulated eutectic mixture containing an atypical drug comprised of about 70% to about 85% medium molecular weight polyethylene glycol.
[0009]
(Detailed description of the invention)
A eutectic mixture of a poorly soluble drug and a poloxamer surfactant having an HLB value between about 20 and about 30, especially poloxamer 188, and a medium molecular weight PEG, where the drug is the flash point of polyethylene glycol (about 230 ° C.) It melts without decomposition at temperatures below, but has been found to greatly increase solubility, speed of dissolution, and bioavailability. Unexpectedly, the inventive combination demonstrates a 9-10 fold increase in solubility compared to the same drug substance alone for 1 hour dissolution in USP device 2 non-sink conditions (where non-sink is (Means the solubility limit of the drug in the medium, typical sink conditions indicated by the USP are drug concentrations 3-5 times lower than the solubility limit). The present invention provides a solid dispersant formulation that is an immediate release solid dispersion formulation, whereas a typical solid dispersant enhances solubility and therefore bioavailability but is a delayed release formulation. Can be.
[0010]
Without being combined with any particular active mechanism, the following illustrates the principle of unexpectedly increasing the dissolution rate that allows providing an immediate release solid dispersion composition according to the present invention. The interaction between the polymer and the hydrophobic drug is important for adequately and stably dissolving otherwise poorly soluble drug substances. The application of a solid dispersion to an immediate release mechanism to enhance bioavailability relates only to poorly water-soluble or poorly wettable compounds. These poor solubility properties usually occur when the compounds are inherently very hydrophobic, so the present theory applies to these compounds.
[0011]
Polymeric polyethylene glycol consists of hydrophilic oxyethylene chains. The nonionic surfactant, poloxamer, consists of a polyoxyethylene-polyoxypropylene copolymer. The polyoxypropylene segments are hydrophobic, while the polyoxyethylene segments are hydrophilic. The use of both polymers together allows for interaction of the polymer with the hydrophobic drug, increasing dissolution rates and bioavailability. When in an amorphous form, i.e., in an amorphous form after cooling the melt at a temperature above the melting point of the drug substance to form a stable solid dispersion, the poloxamer forms a liquid between the polyethylene glycol and the drug. Acts as a link. The direct result of the interaction is a stable erosion of the solid dispersant, which allows the drug to dissolve, without the drug aggregating from the amorphous state to form crystals. If the polymer evolves too quickly, crystals of the drug are formed, completely left behind in the water-soluble polymer. The link between the drug, surfactant, and polymer is important to completely and stably supersaturate the water-insoluble drug in the aqueous medium at the appropriate pH.
[0012]
It is known that certain quinoline derivatives are neurokinin-3 receptor antagonists and are therefore effective in treating certain diseases, particularly chronic obstructive pulmonary disease (COPD) and urinary incontinence. Of particular relevance to the present invention are those described in Farina et al. (S)-(-)-N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide disclosed in WO95 / 32948 pamphlet published on December 7, 1995. It is. Related compounds are described in Farina et al. WO 96/02509 published on February 1, 1996; Giardina et al., And WO 97/19926 published on June 5, 1997; Giardina et al. WO98 / 52942, published on November 26, 1998; Grugni et al .; WO98 / 05640 published on February 12, 1998; and Bichon et al. And the like, which are disclosed in the pamphlet EP 0 673 928 published Sep. 27, 1995, which is incorporated herein by reference in its entirety.
[0013]
In addition to the quinoline derivatives disclosed therein, the present invention is useful for any compound with poor water solubility and poor wettability that melts without decomposition at temperatures below the flash point of polyethylene glycol.
The present invention relates to chemically stable pharmaceutical compositions intended for oral administration to mammals, especially humans. The composition is essentially a medium molecular weight PEG, a drug that melts without decomposition at temperatures below the flash point of PEG, and poloxamer surfactants having HLB values between about 20 and about 30, especially BASF Poloxamer 188 (having the trademark Pluronic® F68), commercially available from E.I.
[0014]
The term "solid dispersant", whenever it appears herein, is a substance that is solid at room temperature and mixes a molten drug with a surfactant and PEG to obtain a homogeneous molten mixture. Means the material produced by cooling the resulting mixture to form a solid in which the components are substantially evenly dispersed.
[0015]
More particularly, the instant release solid dispersions of the present invention comprise essentially from about 0.1% to 20% drug; from about 2% to about 20% interface having an HLB value between about 20 and about 30. An active agent; and about 60% to about 97.9% PEG. Preferred embodiments of the present invention are essentially about 10% to about 20% drug; about 5% to about 10% surfactant having an HLB value between about 20 and about 30, preferably poloxamer 188. And about 70% to about 85% medium molecular weight polyethylene glycol. The drug is one that melts without decomposition at temperatures below the flash point of PEG. For the free base form of the preferred active compound useful in the present invention, (S)-(-)-N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide, the melting point is 165 ° C. .
[0016]
The free base form of (S)-(−)-N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide has very low in vitro solubility and solubility characteristics (including enzymes). No simulated gastric fluid, 31 microgram / mL in pH 1.2). This translates into low bioavailability. The solid dispersant consisting of medium molecular weight (1500-6000) PEG and (S)-(-)-N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide does not contain enzymes In simulated gastric fluid ("SGF"), solubility and dissolution rate increased at 37 ° C. Although an increase in solubility can be expected with the addition of PEG and a surfactant, an unexpected 9- to 10-fold increase in solubility was observed with the three combinations for the formulations of the present invention. Therefore, in addition to having high solubility and bioavailability, the formulation is surprisingly even released rapidly.
[0017]
PEG with an average molecular weight ("MW") of less than 800 is characterized by being liquid at room temperature and highly hygroscopic, making it unsuitable for dispersants. Solid PEG below MW 2000 is a waxy solid with a low melting point and some hygroscopic properties, and therefore, has poor processability and stability. Medium molecular weight PEGs of 2400-8000 are relatively stable with considerable processing power, but those of MW above 4600 are viscous liquids that, when melted, have poor fluidity and do not mix well . Higher MW PEGs (such as 20,000) are also unsuitable for use in solid dispersants because their slow dissolution time is not suitable for an immediate release mechanism. Large amounts of peroxide can be trapped in the folded MW crystal structure of the high MW, which raises problems with chemical stability.
[0018]
Suitable polyethylene glycols include medium molecular weight PEG having an average molecular weight in the range of 1500-6000, preferably 3000-6000. A particularly preferred PEG useful in the solid dispersants of the present invention is PEG 3350 (also known as Carbowax ^™ Sentry ^™ Polyethylene Glycol 3350 Powder NF, FCC) available from Union Carbide Corporation, Danbury, CT. The flash point of PEG 3350 is 246 ° C. (Pensky-Martens closed cup ASTM D 93) or 279 ° C. (Clearland open cup ASTM D 92). The flash point of a PEG is based on the range of molecular weight associated with a particular PEG (eg, PEG is specified in the range of PEG polymers with a molecular weight of 3000-3700), and therefore the flash point varies with the properties of the material used. PEG 6000 has a flash point of about 246 ° C.
[0019]
An example of a preferred poloxamer surfactant useful in the solid dispersions of the present invention includes poloxamer 188 (Pluronic® F68), commercially available from BASF Corporation, New Jersey. Poloxamer 188 is about 80% by weight poly (oxyethylene), has an average molecular weight between about 7680 and about 9510, and a melting point of about 52 ° C.
[0020]
Suitably, the solid dispersants of the present invention may contain up to about 10% of an inert filler that does not significantly affect the properties of the final product. Examples of such fillers include hydroxypropylmethylcellulose phthalate 22084 (HP50), hydroxypropylmethylcellulose phthalate 2202071 (HP55), hydroxypropylmethylcellulose acetate succinate (AQOAT), carboxymethyl-ethylcellulose (CMEC), cellulose acetate phthalate (CAP), methacrylic copolymer LD (L30 D55), methacrylic copolymer S (S-100), aminoalkyl methacrylate copolymer E (gastric coating base), poly (vinyl acetal) diethylaminoacetate (AEA), polyvinylpyrrolidone (K -25, 30, 90; PVP), ethyl cellulose (EC), methacrylic copolymer RS (RS 30D) Polyvinyl alcohol (PVA), methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose 2208 (Metolose 90SH), hydroxypropylmethylcellulose 2906 (Metolose 65SH), hydroxypropylmethylcellulose 2910 (Metolose 60SH), sodium carboxymethylcellulose (sodium) Cellulose glycolate), dextrin, pullulan, acacia, tragacanth, sodium alginate, propylene glycol alginate, agar powder, gelatin, starch, modified starch, phospholipids (lecithin), glucomannan and the like.
[0021]
The instant release solid dispersion of the present invention is preferably made by melting the drug, polyethylene glycol and poloxamer surfactant together while mixing to form a homogeneous molten mixture. The tertiary melt mixture is then immediately cooled and solidified. Suitably, other ingredients may be added to the tertiary mixture before coagulation.
[0022]
Preferred dosage formulation compositions of the invention are made from the solid dispersions described above. Preferred solid dispersions of the present invention may be filled into capsules or moulds prior to coagulation. Changing the solid dispersant from the original chilled solid form by physical means (i.e., adding more energy) results in uncontrolled release of the drug substance and agglomeration of the drug substance in a milled, high surface area formulation. Results in dramatically different solubilization. Because of this property, the present invention differs from known solid dispersion dosage formulations in which a solid dispersion consisting of the drug and PEG is ground and filled into capsules or tableted.
[0023]
The drug to PEG ratio affects dissolution, since the higher the drug loading, the lower the dissolution rate. The ratio of poloxamer to PEG is very important for the stability of the solid dispersant dissolution rate. A preferred component ratio for the present invention was found to be 4 parts drug: 1 part poloxamer surfactant: 15 parts medium molecular weight polyethylene glycol.
[0024]
Example
The preparation <br/> melting or fusion process for producing a solid dispersion to form a solid dispersion. Melts were made in Digi-block heaters using aluminum heating blocks using 13 x 100 mm borosilicate glass tubes or 22-44 mL borosilicate scintillation vials. Most dispersants of low drug composition will completely melt at approximately 152 ° C, but the melting temperature was above the melting point temperature of the free base drug component, 165 ° C. The temperature of the block was controlled by a thermocouple and a control program scaled block. The temperature was checked with a scaled thermocouple and a scaled thermometer. Most carriers tested have a melting point of about 50 ° C., which causes a low matrix melting point at high polymer compositions.
[0025]
After 5 to 20 minutes of thawing time, the thawing matrix was pipetted into a gelatin capsule of size 0 or smaller or a hydroxypropylmethylcellulose (HPMC) capsule. The temperature of the matrix was above 150 ° C. during filling and deformation of the gelatin capsule was unusual because the dispersant cooled rapidly at room temperature at the interface with the capsule. The dispersant was cooled and solidified overnight in a desiccator at room temperature or 5 ° C. overnight. A portion of the dispersant was poured into a Teflon weighing dish to facilitate removal of the solid dispersant for another test.
[0026]
Physical matrix mixtures and molten carriers were made and tested to compare baseline solubility and background absorption to that of the solid dispersant. The resulting solid dispersant was a yellow-orange hard solid with some cavities formed by the cooling process. The solubility and dispersion rate of the dispersant was analyzed by USP Apparatus 2 dissolution. Lysis was performed under the following conditions: SGF dissolution medium, enzyme-free 0.1 M HCl pH 1.2; 350-370 mL medium under non-sink conditions; paddle speed of 50 rpm; Analysis of (S)-(−)-N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide was performed using a UV spectrophotometer at 359 nm and compared to a reference solution. .
A maximum temperature of 165 ° C. was required to completely transform the drug into the amorphous form.
[0027]
All publications, including, but not limited to, patents and patent applications cited herein, are each individually and individually set forth as if fully set forth herein by reference. Is incorporated herein by reference as if set forth as such.
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, any examples are to be construed as merely illustrative and in no way limiting of the scope of the invention. Aspects of the invention which require exclusive rights or privileges are set forth in the following claims.

Claims (17)

An immediate release pharmaceutical composition consisting essentially of a poloxamer surfactant, a medium molecular weight polyethylene glycol, and an active compound that melts without decomposition at temperatures below the flash point of the polyethylene glycol. An immediate release pharmaceutical composition consisting essentially of a poloxamer surfactant, a medium molecular weight polyethylene glycol, and a co-melt of the active compound that melts without decomposition at temperatures below the flash point of the polyethylene glycol. An immediate release solid dispersant co-melt composition consisting essentially of a poloxamer surfactant, a medium molecular weight polyethylene glycol, and an active compound that melts without decomposition at temperatures below the flash point of the polyethylene glycol. In essence, (a) from about 0.1% to about 20% of the active drug;
(B) about 2% to about 20% of a poloxamer surfactant having an HLB value between about 20 and about 30;
(C) a solidified eutectic mixture of about 60% to about 97.9% medium molecular weight polyethylene glycol, wherein the drug melts without decomposing at a temperature below the flash point of polyethylene glycol, with immediate release. Solid dispersant composition. 5. The composition according to claim 1, wherein the active compound is (S)-(-)-N-([alpha] -ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide. . (A) melting while mixing the drug, polyethylene glycol and poloxamer surfactant together to form a tertiary homogeneous molten mixture;
(B) cooling the molten mixture until it solidifies; and
5. A method for preparing a composition according to claim 1, 2, 3 or 4 comprising (c) forming a preferred dosage formulation from a solidified molten mixture. The composition according to any one of claims 1, 2, 3 or 4, wherein the surfactant is a poloxamer surfactant. The composition of claim 7, wherein the poloxamer surfactant is poloxamer 188. The composition of any of claims 1, 2, 3, or 4, wherein the polyethylene glycol has an average MW between about 1500 and 6000. 10. The composition of claim 9, wherein the polyethylene glycol has an average MW between about 3000 and 6000. The composition according to claim 9, wherein the polyethylene glycol is selected from PEG3350 or PEG6000. 5. A method for delivering an active substance to a mammal in need thereof, comprising orally administering a therapeutically effective amount of the composition of claim 1, 2, 3 or 4. 13. The method of claim 12, wherein the composition is administered to a mammal exhibiting symptoms of COPD or urinary incontinence. In essence, (a) from about 10% to about 20% of (S)-(-)-N-([alpha] -ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide;
(B) about 5% to about 10% of a poloxamer surfactant; and
(C) a solidified eutectic mixture of about 70% to about 85% medium molecular weight polyethylene glycol, wherein the drug melts without decomposing at a temperature below the flash point of the polyethylene glycol; Dispersant composition. 5. The composition of any of claims 1, 2, 3 or 4, wherein the ratio of drug: poloxamer surfactant: polyethylene glycol is 4 parts drug: 1 part poloxamer surfactant: 15 parts polyethylene glycol. In essence, (a) about 0.1 to about 20% of the active drug;
(B) about 2% to about 20% of a poloxamer surfactant having an HLB value between about 20 and about 30;
(C) a solidified eutectic mixture comprising an atypical drug consisting of about 60% to about 97.9% medium molecular weight polyethylene glycol, wherein the drug melts without decomposition at temperatures below the flash point of polyethylene glycol. However, an immediate release solid dispersant composition. In essence, (a) from about 10% to about 20% of (S)-(-)-N-([alpha] -ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide;
(B) about 5% to about 10% of a poloxamer surfactant, preferably poloxamer 188;
17. The composition of claim 16, wherein the composition is a solidified eutectic mixture comprising (c) an amorphous drug comprised of about 70% to about 85% medium molecular weight polyethylene glycol.