JP2002520377A - Microdispersed drug delivery system - Google Patents

Abstract

  (57) [Summary] Methods and compositions for microdispersed formulations for enhanced bioavailability of therapeutic agents are disclosed. The microdispersions of the present invention are formed upon contact with aqueous fluids, including physiological fluids.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[Background of the present invention]

The present invention relates to a microdispersion system for enhancing the solubility and bioavailability of a therapeutic agent.

[0002] Unlike hydrophilic compounds, delivery of lipophilic therapeutic agents by conventional means is problematic. If the solubility is low, incomplete and / or capricious absorption may occur, and the absorption is capricious within or between patients. The insolubility of large lipophilic particles tends to reduce the rate of delivery because the therapeutic agent is poorly soluble in gastrointestinal fluids and crosses the epithelial barrier before it is excreted. In addition, degradation of unstable therapeutics by gastric juice may reduce therapeutic bioavailability to the point of treatment failure (Presco
tt, L .; F. , Novel Drug Delivery and it's
Therapeutic Application, John Wiley &
Sons, New York, 1989, p. 3-4).

[0003] Despite the difficulties associated with delivering hydrophilic therapeutic agents, the potential benefits of developing methods for the delivery of such therapeutic agents are great. Extensive studies have shown that the membrane permeability and effectiveness of therapeutic agents often increase with increasing lipophilicity (B
anker and Rhodes, Modern Pharmaceutical
s, Marcel Dekker, Inc. , New York, 1979, p.
p. 31-49; Hughes and Mitta, 1993, J. Am. Ocul
. Pharmac. 9: 299; Yokogawa et al. , 1990,
Pharm, Res. 7: 691; Hageluken et al. , 199
4, Biochem. Pharmac. 47: 1789). Therefore, the development of new systems for the delivery of lipophilic compounds can potentially enhance the therapeutic efficacy of treating a wide range of conditions.

[0004]

SUMMARY OF THE INVENTION In accordance with the present invention, it has been discovered that enhanced bioavailability of therapeutic agents, particularly poorly soluble therapeutic agents, can be obtained using a microdispersion system. It has also been discovered that greater sustained delivery of a therapeutic agent can be obtained with this microdispersion system. This microdispersion system is characterized by the formation of a discontinuous phase of droplets when the pharmaceutical composition of the invention contacts an aqueous environment, particularly a physiological fluid. As used herein, droplet means a discontinuous phase aggregate, including, for example, droplets, micelles or vesicles, as well as those in combination with particulates, such as therapeutic agent particles. Formation of the microdispersion improves the absorption of the therapeutic from the aqueous environment, thereby enhancing the bioavailability of the therapeutic.

[0005] The methods and compositions of the present invention are particularly applicable to oral administration of therapeutic agents and absorption of such agents in the gastrointestinal tract. However, the methods and compositions of the present invention can be applied to the administration of therapeutic agents in other aqueous environments.

[0006] The pharmaceutical composition of the present invention comprises at least one therapeutic agent, a microdispersed formulation, and optionally other adjuvants. The microdispersed formulation consists of a solid, semi-solid or liquid mixture of a polyglycolized glyceride component, a polyoxypropylene-polyoxyethylene block copolymer component, ethanol and optionally other auxiliaries.

[0007] The polyglycolized glyceride component of the microdispersed composition is caprylocaproyl macroglyceride (Labrasol ^™ , Larafac ^™ , Hydro).
(Known commercially as WL1219), Gelucire ^™ 44/13 and Gelucire ^™ 50/13 (available from Gattefosse), and can include any grade of saturated and unsaturated polyglycolized glycerides. . Preferred polyglycolized glycerides have a hydrophilic-lipophilic balance (HLB) of greater than 10.

[0008] Microdispersions include solid, semi-solid or liquid forms. Generally, the presence of a large percentage of caprylocaproyl glyceride in the composition allows for solid and / or liquid forms of the formulation. Each grade of polyglycolized glyceride and optionally d-α-troferyl polyethylene glycol 1000 succinate are combined to form a solid, semi-solid or liquid form. Commercially available caprylocaproyl macroglyceride compositions have a defined combination of mono-, di- and triglycerides and mono- and di-fatty acid esters of PEG. Caprylocaproyl macroglyceride compositions are C8, C10, C12, C1
4, C16 and C18 fatty acid chain lengths, any of which can comprise 1-99% of the fatty acid component of the composition. In general, the predominance of C8-C10 fatty acid chains in the composition gives a liquid to semi-solid formulation. The predominance of C12-C14 fatty acid chains in the composition gives a liquid, semi-solid or solid formulation. The predominance of> C14 fatty acid chain length in the composition gives a semi-solid or solid formulation. Therefore, the system can employ any combination of the above to obtain the desired solid, semi-solid or liquid form.

[0009] The polyoxypropylene-polyoxyethylene block copolymer component of the microdispersion composition is a polyoxypropylene-polyoxyethylene block copolymer of all grades, preferably a polyoxypropylene-polyoxyethylene block having an HLB greater than 10. It may include a copolymer. Preferred polyoxypropylene-polyoxyethylene block copolymers are, for example, Pluron
Plurons such as ic L44, Pluronic F68, Pluronic F108 and Pluronic F127 (available from BASF)
ic NF surfactant.

[0010] Each component (polyglycolized glyceride / polyoxypropylene-polyoxyethylene block polymer / ethanol) of the microdispersed blend of the present invention comprises (0
. Substantially including a wide weight ratio such as from 050 / 99.9 / 0.05) to (99.9 / 0.05 / 0.05) to (0.05 / 0.05 / 99.9). They can be combined in any weight ratio. The preferred weight ratio of polyglycolized glyceride / polyoxypropylene-polyoxyethylene block copolymer / ethanol is 8 / 0.5 / 1.5,7 / 2 / 1,6 / 3 / 1,6 / 1/3, 5/4
/ 1, 5/1/4, 4/3/3, 4/4/2, 3/6/1 and 2/6/2. This weight ratio is preferably configured to obtain a mixture having a melting point in the range of about 20 ° C to about 70 ° C, preferably in the range of about 50 ° C to about 70 ° C. When employed as part of a pharmaceutical composition of the present invention, the microdispersion formulation facilitates the formation of a microdispersion of droplets when the pharmaceutical composition contacts an aqueous environment containing physiological fluids. Droplet diameters can vary from about 0.05 μm to about 1500 μm. Preferably, the droplets have an average diameter of no more than about 500 μm, and more preferably, no more than about 50 μm. Smaller diameters increase the bioavailability of the therapeutic.

[0011] The pharmaceutical compositions of the present invention are characterized in that 1% or more of the total therapeutic agent content is present in solution in the system in a solid, semi-solid or liquid phase. The composition is also characterized in that a portion of the therapeutic agent can be present as a solid dispersion. Any proportion of the therapeutic agent present as a solid dispersion preferably has a particle size distribution in which about 90% of the particles have a diameter of 10 μm or less (D90 <10 μm). The solubilized therapeutic / dispersed therapeutic ratio is in the range of 1/90 to 100/0. Preferably, about 30% to about 100% of the therapeutic agent is in solution,
And more preferably, from about 60% to about 100% of the therapeutic agent is in solution.
The ratio of polyglycolized glycide / polyoxypropylene-polyoxyethylene block copolymer is selected to facilitate solubilization of the therapeutic agent based on polyglycolized glyceride / polyoxypropylene-polyoxyethylene block copolymer. The solubilized therapeutic / dispersed therapeutic ratio can be readily ascertained by use of techniques in solution calorimetry that are well known in the art. The crystallinity of a therapeutic agent is easily determined by X-ray diffraction. The diameter of the microdispersed droplets can be characterized by measuring any of the droplet volume, droplet diameter, or droplet number using techniques well known in the art. These techniques include, for example, laser light dispersion particle size analysis, coulter counter technology, and freeze etching technology.

The core component mixture of the microdispersed formulation (polyglycolized glyceride / polyoxypropylene-polyoxyethylene block copolymer / ethanol) is present in the pharmaceutical composition from about 0.10% to about 99.9%, preferably About 5% to about 90%,
And more preferably it may be present in the range of about 30% to about 80%. The balance of the pharmaceutical composition consists of the therapeutic agent and the adjuvant. The polyglycolized glyceride component is
Typically, it comprises about 1% to about 90%, and preferably about 40% to about 80% of the pharmaceutical composition. The polyoxypropylene-polyoxyethylene block copolymer component typically comprises from about 1% to about 50%, and preferably from about 3% to about 35% of the pharmaceutical composition. The ethanol component typically comprises from about 1% to about 30%, and preferably from about 5% to about 15% of the pharmaceutical composition.

[0013] Therapeutic agents that can be used in connection with the present invention include any therapeutically active compound. About 2
Therapeutic agents having an intrinsic solubility in water of not more than 0.0 g / l, in particular those having an intrinsic solubility of not more than about 10.0 g / l, and / or those having poor bioavailability previously described in the literature It is specifically contemplated as part of the present invention. The therapeutic agent can be present in the pharmaceutical composition in a range from about 0.10% to about 99.9%, preferably from about 5% to about 75%, and more preferably from about 30% to about 60%. .

Examples of therapeutic agents that can be used in connection with the present invention can include: Dihydropyridine compounds including, for example, nifedipine, felodipine, nicardipine;
Paclitaxel; Omperazole; Spironolactone; Furosemide; Terbutaline; Riboflavin; Gemfibrozil; Indomethacin; Ibuprofen; Phenytoin;
In addition, any therapeutic agent having an intrinsic solubility of about 10.0 g / l or less, and activity in any of the following fields is contemplated as part of the present invention. Activity in the cardiovascular system; immunosuppressive activity; cholesterol lowering activity; antihypertensive activity; antiepileptic activity; hormonal activity; hypoglycemic activity; antiviral activity; antihistamine activity, nasal decongestant activity; antimicrobial activity; Analgesic activity; antimycobacterial, anticancer activity; diuretic activity, antifungal activity, antiparasitic activity, activity as a central nervous system (CNS) stimulant, activity as a CNS inhibitor, 5-HT inhibitor Activity, anti-schizophrenic activity, anti-Alzheimer's activity, anti-psoriatic activity, anti-ulcer activity, activity as a proton pump inhibitor, anti-asthmatic activity, activity as a bronchodilator, and thrombolytic activity. The therapeutic agent can be, for example, a protein, peptide, cyclopeptide, steroid molecule, vitamin, oligonucleotide, or any small or large molecule, or a combination thereof.

[0015] The pharmaceutical compositions and microdispersed formulations of the present invention can include adjuvants. Adjuvants can be added to the pharmaceutical composition for a variety of reasons, including, for example, achieving the following objectives. Increasing the solubility of the therapeutic agent in the microdispersion composition; improving the chemical stability of the system; setting the melting point of the system; altering or suppressing or modifying the release profile of the therapeutic agent from the pharmaceutical composition; Enhanced attributes useful for processing and formulating pharmaceutical compositions such as tabletability. The adjuvant is about 5% of the weight of the pharmaceutical composition
To about 95%, preferably about 10% to about 70%.

Examples of suitable auxiliaries that can be used in connection with the present invention are: Glycerol; glyceryl monooleate; glyceryl monostearate; glyceryl palmitostearate; triglyceride; diglycerite; monoglyceride; diester of polyethylene glycol (PEG); monoester of PEG; Polyoxyethylene alkyl ether; polyoxyethylene castor oil derivative; polyoxyethylene sorbitan fatty acid ester; polyoxyethylene stearate; polyvinyl alcohol; sodium starch glycolate; sorbitan fatty acid ester; polyoxystearate Polyethylene glycol hydroxystearate; poly Anionic, cationic, amphiphilic compounds; lecithin; phospholipids; carbohydrates including, for example, lactose, maltodextrin, sucrose and starch; polyols, including, for example, sorbitol, mannitol and cyclitol; microcrystalline cellulose; Vitamins, including acids and niacinamides; and inorganic compounds, including, for example, calcium carbonate, dicalcium phosphate and any combination of the above.

Preferred adjuvants of the microdispersion formulation include a water-soluble tocopherol derivative, preferably d-α-tocopherol polyethylene glycol ester, and more preferably d-α-troferyl polyethylene glycol 1000 succinate. The water-soluble tocopherol derivative preferably comprises from about 1% to about 90%, and more preferably from about 20% to about 60% of the microdispersed composition. The preferred weight range of the tocopherol derivative in the final composition is from about 10% to about 70%.
%. Other tropherol-based supplements include ascorbyl palmitate and vitamin E acetate.

[0018] The invention also relates to a method for delivering one or more therapeutic agents to a physiological target site. The method comprises providing a pharmaceutical composition according to the invention and introducing a pharmaceutically effective amount of the pharmaceutical composition to a physiological target site. The drug composition forms a microdispersion when in contact with a physiological fluid at a physiological target site. Introduction of the pharmaceutical composition to a physiological target site can be, for example, topical, subcutaneous, intramuscular, intraperitoneal, nasal, respiratory, vaginal, transanal. Alternatively, it can be achieved by otic, oral or ocular administration.

The present invention also relates to a method of formulating a therapeutic agent. The method comprises providing a microdispersed composition comprising a polyglycolized glyceride, a polyoxypropylene-polyoxyethylene block copolymer and ethanol, and mixing the components of the microdispersed composition with a therapeutic agent, wherein at least 1% of the therapeutic agent is present. To produce a solubilized drug composition.

An example of a method for formulating the pharmaceutical composition of the present invention is as follows. The polyglycolized glyceride component and the polyoxypropylene-polyoxyethylene block copolymer component are heated until the mixture melts. The therapeutic agent, which has been ground or micronized to a particle size range where the D90 is less than 10 microns, is slowly added to the molten mixture with vigorous stirring while the mixture is in the molten state at a sufficient temperature.
Then absolute ethanol is added to the mixture with stirring.

Two alternative next steps include: (1) Cool the temperature of the mixture to room temperature, then homogenize the composition and, if necessary, then add other adjuvants to the mixture. (2)
If permitted by the nature of the therapeutic, the temperature of the mixture is maintained at about 20 ° C. above the melting point of the mixture with constant agitation to ensure homogeneity of the mixture.

After all components have been mixed, the formulation becomes liquid or it can set into a solid or semi-solid mass. The formulation can be spray coagulated in a spray drier or coagulated to a powder in a fluid bed drier. The formulation can also be coagulated onto the adjuvant in a spray drier, fluid bed drier, rotor mixer, high shear granulator, planetary mixer, blender, or any conventional food and drug processing equipment.

The compositions of the present invention may be formulated into conventional, special or novel pharmaceutical dosage forms, including, for example, tablets, capsules, powders for inhalation, suppositories, suspensions and emulsions. The compositions of the present invention can also be coagulated on solid drug dosage forms such as tablets, capsules and / or granules.

The entire disclosure of all patents, patent applications, and publications cited herein is hereby incorporated by reference. In particular, US Provisional Patent Application No. No. 60 / 063,338, U.S. Pat. 09 / 050,913, U.S. Provisional Patent Application No. 60 / 080,163
U.S. Provisional Patent Application No. No. 60 / 085,417, U.S. Provisional Patent Application No. 60/0
88,855, PCT application PCT / US99 / 13223, US provisional patent application No.
. 60 / 092,767 is incorporated herein by reference.

Without further consideration, using the above description, it is believed that one skilled in the art can utilize the invention to its fullest extent. The following preferred examples are therefore merely illustrative, and should not be construed as limiting the remainder of the disclosure.

In the following examples, all parts and percentages are by weight unless otherwise indicated.

[0027]

【Example】

Example 1 Production Method Caprylocaproyl macroglyceride (Labrasol ^™ , Labraf)
ac ^™ or Hydro WL1219) and / or lauroyl macroglyceride (Gelucire ^™ 44/14 or La
(Commercially known as Brafil ^™ M2130CS), d-α-tocopheryl polyethylene glycol 1000 succinate, and a polyoxypropylene-polyoxyethylene block copolymer (L44, liquid) are heated to melt the mixture. While maintaining the system at a sufficiently high temperature to keep the mixture in a molten state, the therapeutic agent is slowly added to the molten mixture with vigorous stirring. Therapeutic agents are preferably ground or micronized to a particle size range such that D90 is <10 microns. Then absolute ethanol is added to the mixture with stirring. The ratio of polyglycolized glyceride: polyoxypropylene-polyoxyethylene block copolymer: absolute ethanol is> 1% of therapeutic agent in polyglycolized glyceride / polyoxypropylene-polyoxyethylene block copolymer / absolute ethanol system, and Preferably, it is selected to facilitate 30-100% solubilization.

Next, two alternative steps are: (1) cooling the temperature of the mixture to room temperature, then homogenizing the composition and adding other adjuvants, if necessary, to the mixture; If permitted by the nature of the agent, the temperature of the mixture is maintained above the melting point of the mixture, 20 ° C., and constant stirring is carried out during the addition of the adjuvant to ensure homogeneity of the mixture. Adjuvants can be added to the microdispersion formulation or drug composition for a number of different purposes, including: Increase the solubility of the therapeutic agent; improve the chemical stability of the system; modify / control / modify the release profile of the therapeutic agent; attributes such as flowability, direct tabletability desired for processing and formulation of the dosage form And give other attributes.

After mixing all the components, the formulation is liquid or it may set into a solid or semi-solid mass. The formulation can be spray-agglomerated into a powder in a spray drier or a fluid bed drier. The formulation can also be coagulated to the adjuvant in a spray drier, fluidized bed drier, rotor mixer, high shear granulator, planetary mixer, blender, or any other food and pharmaceutical processing equipment.

The compositions of the present invention can be formulated into conventional, special or novel pharmaceutical dosage forms such as tablets, capsules, inhalable powders, suppositories, suspensions and emulsions. The compositions of the present invention can be coagulated onto solid drug dosage forms such as tablets, capsules and / or granules.

Example 2 Cyclosporin A (Dose: 100 mg / ml) Ingredient Amount (100 ml) Amount (1 L)シ ク ロ Cycloporin 10.0g 100.0g Vitamin E TPGS 10ml 100ml Labrazole 65ml 65ml Pluronic L44 5ml 50ml Absolute ethanol 10ml 100ml PEG200 10ml 100ml Vitamin E acetate 0.1ml 1.0ml Ascorbyl palmitate 0.1g 1.0g

Manufacturing operation: (1) Set the water bath to a temperature of 70 ± 2 ° C .; (2) Dissolve vitamin E TPGS and weigh 100 ml into a suitable container; (3) Dissolve the dissolved vitamin E TPGS Stir for 2 minutes using a low speed mechanical stirrer; (4) Add 650 ml of labrazole to Vitamin E TPGS with constant stirring; add 50 ml of Pluronic L-44 to the mixture with stirring; (6) Complete mixing of all ingredients Stir the mixture for 30 minutes to ensure that (7) reduce the temperature of the mixture to 50 ± 2 ° C. and allow sufficient time to stabilize the temperature of the mixture to 50 ± 2 ° C .; (8 ) Prepare 100g of cyclosporine and add cyclosporin slowly to the mixture with constant stirring over 30 minutes (Note: cyclosporine is a fine powder, clumped (9) If necessary, adjust the speed of the stirrer to obtain a uniform dispersion of the cyclosporin in the mixture; (10) maintain the temperature at 50 ± 2 ° C. and continue stirring the contents for 1 hour; 11) Turn off the heat source of the water bath; (12) Increase the speed of the stirrer until a vortex is formed in the solution; (13) Add 100 ml of absolute ethanol to the vortex of the mixture quickly while continuing to stir; (14) PEG into mixture with constant stirring
Add 200; (15) Vitamin E acetate 1 to the mixture with constant stirring
. 0 ml; (16) Ascorbyl palmitate with constant stirring
(17) Continue stirring for 15 minutes; (18) Turn off the stirrer; (
19) Cover the container to prevent loss of alcohol and allow the mixture to cool to room temperature, (20) filter the mixture through a # 60 mesh screen to remove excess particles, (21) Must be transparent with no dissolved particles (Note: air bubbles may be present in the solution and they should not be mistaken for undissolved particles).

Example 3 Astemizole Preparation (Dose: 10 mg / ml) Ingredient Amount (100 ml) Astemizole 10 g Vitamin E TPGS 5 ml Labrazole 75ml Pluronic L44 15ml PEG200 10ml Vitamin E acetate 0.1ml Ascorbyl palmitate 0.1g

The astemizole composition was prepared substantially according to the procedure for preparing the cyclosporin composition of Example 2.

Example 4 Azathioprine Formulation (Dose: 100 mg / ml) Ingredient Amount (100 ml) Azathioprine 10.0 g Labrazole 75 ml Pluronic L44 15ml PEG200 10ml Vitamin E acetate 0.1ml Ascorbyl palmitate 0.1g

The azathioprine composition was prepared substantially according to the procedure for preparing the cyclosporin composition of Example 2.

Example 5 Loratidine Preparation (Dose: 10 mg / ml) Ingredient Amount (100 ml) Loratidine 1.0 g Labrazole 55 ml Pluronic L44 20ml Absolute ethanol 15ml PEG200 10ml Vitamin E acetate 0.1ml Ascorbyl palmitate 0.1g

The loratidine composition was prepared substantially according to the procedure for preparing the cyclosporin composition of Example 2.

Example 6-Griseofulvin Formulation (Dose: 165 mg / ml) Ingredient Amount (100 ml) {} Griseofulvin 16.5 g Vitamin E TPGS 10ml Labrazole 60ml Pluronic L44 10ml PEG200 20ml Vitamin E acetate 0.1ml Ascorbyl palmitate 0.1g

The griseofulvin composition was prepared substantially according to the procedure for preparing the cyclosporin composition of Example 2.

Example 7-Diclofenac Formulation (Dose: 50 mg / ml) Ingredient Amount (100 ml) Diclofenac 5.0 g Vitamin E TPGS 10ml Labrazole 30ml Pluronic L44 30ml Absolute ethanol 10ml PEG200 20ml Vitamin E acetate 0.1ml Ascorbyl palmitate 0.1g

The diclofenac composition was prepared substantially according to the procedure for preparing the cyclosporin composition of Example 2.

Example 8-Minoxidil Formulation (Dose: 10 mg / ml) Ingredient Amount (100 ml) Minoxidil 1.0 g Labrazole 55 ml Pluronic L44 15 ml Gelucire 44/13 qs absolute ethanol 10 ml propylene glycol 10 ml vitamin E acetate 0.1 ml ascorbyl palmitate 0.1 g

The minoxidil composition was prepared substantially according to the procedure for preparing the cyclosporin composition of Example 2.

Example 9-Mitomycin C Composition (Dose: 20 mg / ml) Component Amount (100 ml) Mitomycin 2.0 g Labrazole 60ml Pluronic L44 15ml Absolute ethanol 15ml PEG200 10ml Vitamin E acetate 0.1ml Ascorbyl palmitate 0.1g

The mitomycin C composition was prepared substantially according to the procedure for preparing the cyclosporin composition of Example 2.

Component Amount (100 ml) Phenytoin 5.0 g Vitamin E TPGS 10 ml Labrazole 50 ml Pluronic L44 10 ml Absolute ethanol 20 ml PEG200 10 ml Vitamin E Acetate 0.1ml Ascorbyl palmitate 0.1g

The phenytoin composition was prepared substantially according to the procedure for preparing the cyclosporin composition of Example 2.

Example 11 Paclitaxel Formulation (Dose: 6 mg / ml) Ingredient Amount (100 ml) Paclitaxel 0.600 g Vitamin E TPGS 10ml Labrazole 50ml Pluronic L44 15ml Absolute ethanol 15ml PEG200 10ml Vitamin E acetate 0.1ml Ascorbyl palmitate 0.1g

The paclitaxel composition was prepared substantially according to the procedure for preparing the cyclosporin composition of Example 2.

Ingredient Amount (100 ml) Tamoxifen 1.0 g Vitamin E TPGS 5 ml Labrazole 55 ml Pluronic L44 10 ml Absolute ethanol 20 ml PEG 200 10 ml Vitamin E Acetate 0.2ml Ascorbyl palmitate 0.2g

The tamoxifen composition was prepared substantially according to the procedure for preparing the cyclosporin composition of Example 2.

Example 13-Evaluation of Oral Bioavailability The bioavailability of cyclosporin A in the formulation (test formulation) described in Example 2 above was compared to the bioavailability of cyclosporin A in the commercial product Neoral (control formulation) And compared. Both test and control formulations were administered to 6 male New Zealand white rabbits and a 2.5 ml blood sample was drawn from the rabbit ear lip vein before and after the following times. -5, 15, 30, 60
, 120, 180, 240, 360, 480 minutes and 24 hours.

After fasting the animals overnight, test and control formulations were administered orally at a dose of 100 mg / kg. This dose was delivered through a tube that was not pre-saturated with the dosing solution. The dosing solution was diluted about 1: 2 with water. The control animal is 306 mg of the control preparation.
(Cyclosporin A 32 mg) was administered, and the test animal was given 247 mg of the test preparation.
(Cyclosporin A 29 mg) was administered. Blood samples are extracted by organic extraction
And then Sawckuck et al. , Clin. Chem. , 1981
: 27, analyzed by HPLC analysis using a modification of # 8. Separation of cyclosporin A was performed on a phenomenex Lun of 150 mm x 4.6 mm inner diameter.
a Performed on C18 reverse phase column. The column was kept at 70 ° C. and the detector was set at 210 nm. The mobile phase was adjusted to pH 3.1 by the addition of 1 M phosphoric acid.
Acetonitrile 70% and water 30%. The sample run time was 35 minutes.

The area under the one-hour blood concentration curve (AUC) of the control animal was 590, 195 ± 111.
(484 ng min / ml). The highest concentration (Cmax) of 1745 ± 320 ng / ml was reached at 144 ± 30 minutes (Tmax). The area under the blood concentration hour curve (AUC) of the test animals was 606, 253 ± 177 (753 ng min / ml).
)Met. A maximum concentration (Cmax) of 821 ± 212 ng / ml was reached at 144 ± 36 minutes (Tmax). The relative oral bioavailability of the microdispersion system versus cyclosporin A in the Neoral system was 1.27, indicating a 27% greater bioavailability of cyclosporin A using the microdispersion system.

Although the Cmax for cyclosporin A was greater in control animals than in test animals, the microdispersion system used in test animals appeared to generate a broader concentration time profile in the absorption and post-absorption phases. In the terminal phase, up to at least 24 hours, cyclosporin A levels appear to be higher in test animals than in control animals. 24 of cyclosporin A in test animals
The time blood concentration was 19 compared to 117.7 ± 76.1 ng / ml in control animals.
It was 8 ± 60 ng. Therefore, in addition to the enhanced oral bioavailability of cyclosporin A, the microdispersion system of the present invention provides for a more sustained delivery of cyclosporin A.

Example 14-Cyclosporin A Composition Cyclosporin A 100 mg Dehydrated ethanol (U.S.P) 0.095 ml Pluronic ^™ F127 0.25 g Gelucire ^™ 4413 0.40 g Vitamin E acetate 0.0025 g Ascorbin palmitate 0.0025 g Propylene glycol 0.25g

[0058] The above formulation initially contained about 3 pluronic F127 and Gelucire4413.
It is manufactured by mixing at 8 to 40 ° C. Vitamin E acetate and ascorbyl palmitate are added at about the same temperature. Then cyclosporin A
Is added incrementally with sufficient agitation to dissolve or uniformly disperse the therapeutic agent. Next, the other ingredients are added. The resulting liquid can be filled as a liquid, or it can be filled, for example, in a gelatin capsule.

Example 15-Cyclosporin A composition Cyclosporin A 200 mg Dehydrated ethanol (USP) 0.08 g Pluronic ^™ L44 0.207 g Gelucire ^™ 44/14 0.312 g

Melt Gelucire and mix with Pluronic. Add cyclosporin A to the mixture and dissolve in the mixture using heat. Then ethanol is added to the mixture. The resulting mixture is a low viscosity clear solution after cooling to room temperature.

Example 16-Cyclosporin Composition Cyclosporin A 400 mg Dehydrated Ethanol (USP) 0.16 g Pluronic L44 0.414 g Gelucire ^™ 44/14

Gelucire was lightly heated to dissolve pluronicly and ethanol was added to the mixture. Cyclosporin A was added to the above solution while keeping the temperature of the mixture below 40 ° C. Cyclosporin A dissolved in a mixture of ethanol, Gelucire and pluronic, but in some cases a small percentage of cyclosporin was in the form of a sticky mass. The sticky mass began to dissolve with stirring and mild heating. The sticky mass could be prevented if cyclosporin A was added to the mixture little by little under stirring.

The above examples can be repeated with similar success by substituting the reactants and / or operating conditions of the invention as generally or specifically described for those used in the above examples. .

From the above description, those skilled in the art can easily ascertain the essential features of the present invention,
Various changes and modifications may be made to adapt the present invention to various applications and conditions without departing from its spirit and scope.

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Claims (22)

[Claims] 1. A polyglycolized glyceride component, (b) a polyoxypropylene-polyoxyethylene block copolymer component,
And (c) a microdispersed formulation for use as part of a pharmaceutical composition comprising ethanol. 2. A pharmaceutical composition comprising a microdispersed formulation according to claim 1 and at least one therapeutic agent. 3. The pharmaceutical composition according to claim 2, wherein the at least one therapeutic agent has a solubility in water of less than 20.0 g / l. 4. The formulation according to claim 1, wherein either the polyglycolized glyceride or the polyoxypropylene-polyoxyethylene block copolymer has a hydrophilic-lipophilic balance of greater than 10. 5. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition forms a microdispersion when in contact with an aqueous medium, and the droplets of the microdispersion have an average diameter of less than 500 μm. 6. The pharmaceutical composition according to claim 2, wherein 30% to 100% of the at least one therapeutic agent is solubilized. 7. The microdispersion formulation of claim 1, wherein the mixture of the polyglycolized glyceride component, the polyoxypropylene-polyoxyethylene block copolymer component, and ethanol comprises from 5% to 75% of the microdispersion formulation. object. 8. The pharmaceutical composition according to claim 2, wherein the mixture of the polyglycolized glyceride component, the polyoxypropylene-polyoxyethylene block copolymer component and ethanol comprises 5% to 75% of the pharmaceutical composition. . 9. The pharmaceutical composition according to claim 2, wherein the therapeutic agent comprises between 5% and 75% of the pharmaceutical composition. 10. The microdispersed formulation according to claim 1, further comprising at least one water-soluble tocopherol derivative. 11. The microdispersed formulation according to claim 10, wherein the at least one water-soluble tocopherol derivative is d-α-troferyl polyethylene glycol 1000 succinate. 12. The pharmaceutical composition according to claim 2, further comprising at least one water-soluble tocopherol derivative. 13. The pharmaceutical composition according to claim 12, wherein the at least one water-soluble tocopherol derivative is d-α-tocopheryl polyethylene glycol 1000 succinate. 14. The pharmaceutical composition according to claim 2, wherein the therapeutic agent has an intrinsic solubility in water of less than 20.0 g / l. 15. A method comprising providing a pharmaceutical composition according to claim 2 and introducing a pharmaceutically effective amount of said pharmaceutical composition to a physiological target site, said pharmaceutical composition comprising a physiological fluid at the target site. At least one characterized by forming a microdispersion when in contact
A method for delivering a therapeutic agent to a physiological target site. 16. The method according to claim 15, wherein the physiological target site is the gastrointestinal tract. 17. A method comprising providing a pharmaceutical composition according to claim 2 and introducing a pharmaceutically effective amount of said pharmaceutical composition to a physiological target site, said pharmaceutical composition comprising a physiological fluid at the target site. At least one characterized by forming a microdispersion when in contact
A method for delivering a therapeutic agent to a physiological target site. 18. The method according to claim 17, wherein the physiological target site is the gastrointestinal tract. 19. A method comprising providing a pharmaceutical composition according to claim 3 and introducing a pharmaceutically effective amount of said pharmaceutical composition to a physiological target site, said pharmaceutical composition comprising a physiological fluid at the target site. At least one characterized by forming a microdispersion when in contact
A method for delivering a therapeutic agent to a physiological target site. 20. The method according to claim 19, wherein the physiological target site is the gastrointestinal tract. 21. Providing a pharmaceutical composition according to claim 2 and introducing a pharmaceutically effective amount of said pharmaceutical composition to a physiological target site, said pharmaceutical composition comprising a physiological fluid at the target site. Upon contact, a microdispersion is formed, droplets of the microdispersion
A method of delivering at least one therapeutic agent to a physiological target site, wherein the at least one therapeutic agent has an average diameter of less than m. 22. The method according to claim 21, wherein the physiological target site is the gastrointestinal tract.