TW200922637A - Pharmaceutical composition with enhanced bioavailability - Google Patents

Abstract

The invention pertains to a self-emulsifying pharmaceutical composition containing a lipophilic drug, a surfactant, and a hydrophilic carrier. The invention also provides a method for making the pharmaceutical composition for increasing the bioavailability of a drug by self-emulsification.

Description

200922637 IX. Description of the invention: [Technical field to which the invention pertains] H An oral self-emulsifying pharmaceutical composition containing a lipophilic drug, a hydrophilic carrier, and a surfactant. The composition immediately self-emulsifies into microemulsions having a size (four) nm to about _nm upon contact with the gastrointestinal fluid. [Prior Art] η Oral administration (4) is the long-term and most commonly accepted path for the treatment of diseases: 'However, a total of about 50% of the drugs limit the possibility of oral administration due to high fat solubility, 14 , Eight. In addition, approximately 40% of newly developed drugs are fat soluble. Since most of the particles of the lipophilic drug are difficult to be infiltrated by the gastrointestinal fluid, they exhibit poor solubility and release volatility when administered in the conventional lozenge or capsule form, thus showing lower bioavailability. In addition, drug absorption in different individuals may vary significantly due to differences in gastrointestinal function and food intake/and therefore it is quite difficult to determine and control the dose. In view of the above, increasing the absorption rate of oral drugs is the key to solving the problem of low bioavailability of poorly soluble drugs. To date, the following methods have been used to improve the biological properties of poorly soluble drugs: a) Conversion of poorly soluble drugs to soluble salts or esters. b) reduce the particle size and increase the total surface area to enhance the dissolution of the drug. It is usually carried out mechanically. c) Increasing the solubility of the drug in water by adding a solubilizer. Solid dispersion (SDS) technology, which produces a uniformly dispersed solid dispersion by mixing or active ingredients and excipients. 122666.doc 200922637 The commonly used method is; glutinous method, t-melting method, Solvent_spraying blasting method. The advantages of this technology are in the remedy and utilization „ 仕 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于For example, although a weak acid or a weak base drug can be converted into a soluble salt for administration, the soluble salt may become difficult due to a change in pH in the gastrointestinal tract: weak acid or weak The drug is tested, thus leading to the sinking of the drug. Further, the amount of the carrier in the solid dispersion technique is usually large, and therefore, if the main component of the dose is required, a large volume is formed and it is difficult to swallow the money or the sac. Furthermore, since the carrier used is generally expensive and the cold beam drying or spray drying method used requires special equipment and processes, the production cost is quite high. Although the conventional solvent method (4) can be used, it is difficult to handle the co-precipitate which is still viscous. Recently, the 'melting method has been used to directly fill capsules. However, the moisture in the capsule shell may affect the stability of the solid dispersion. Furthermore, since the permeability of the poorly soluble drug in the gastrointestinal tract may not be high, it is important to avoid the crystallization of the drug because it cannot be absorbed immediately after the formation of the supersaturated solution. Recently, the use of fat-soluble matrix formulations to prepare oral formulations has received great attention, and a new type of "self-emulsifying/microemulsifying drug delivery system (SEDDS/SMEDDS)" has been developed. Technology, and it has been used to improve the water solubility and bioavailability of hydrophobic drugs after oral administration. Typically, SEDDS/SMEDDS consists of an oil phase, a surfactant, a co-surfactant or solubilizer, and a drug. The basic principle of the system is that when the 122666.doc 200922637 SEDDS/SMEDDS formulation is exposed to water, the oil-in-water microemulsion is spontaneously formed by force, enthalpy, dish and mechanical agitation. In %, the drug formulation can be dissolved in the base liquid without the aqueous phase. It can then be filled into soft/hard capsules to form a solid oral formulation. After oral administration and exposure to gastrointestinal fluids, the formulation is capable of self-emulsification to a microemulsion to facilitate dispersion, dissolution, stabilization, and absorption of the drug' thereby improving the bioavailability of the drug. Compared with the emulsion / / ί «agent, SEDDS / SMEDDS (four) not only has the same advantages and advantages that are beneficial to the solubility of hydrophobic drugs, but also overcomes the shortcomings of delamination of emulsions after prolonged placement. Since SEDDS/SMEDDs are thermodynamically stable systems, they are easy to store. In addition, SEDDS/SMEDDS is becoming an important area of pharmaceutical development due to its easy and convenient production process. The emulsion/microemulsion formed by SEDDS/SMEDDS showed good thermodynamic stability and optical transparency. The main difference between the above microemulsions and ordinary emulsions is the particle size of the emulsion droplets. The size of the emulsion of the common emulsion is between 1 〇μιη, and the droplet size of the microemulsion formed by SMEDDS is usually between 2 rnn and 100 nm (these droplets are called the droplets of nanoparticles). ). Due to the small particle size, the total surface area for absorption and dispersion is significantly greater than the total surface area of the solid dosage form, and it can easily penetrate the gastrointestinal tract and be absorbed. The bioavailability of the drug is thus improved. In addition to improving the bioavailability of hydrophobic drugs, SEDDS/SMEDDS is also capable of embedding peptide/protein drugs in the oil phase of the emulsion so that the drug is not broken down by enzymes in the gastrointestinal tract. Despite the above advantages, SEDDS/SMEDDS still has many disadvantages. SEDDS/SMEDDS consists of an oil phase, a surfactant, a solubilizer, and a pharmaceutical composition 122666.doc 200922637. Since the solubilizing agent is usually an organic solvent, it is extremely volatile and reduces in the solution or capsule' thereby causing phase equilibrium damage, drug precipitation or changes in the size of the droplet to affect the bioavailability of the drug. In addition, since the drug must be soluble in the oil phase system, only the first water-soluble ιν= substance is more suitable for the snail S/SMED. In addition, the common oils of castor oil are highly toxic. Since the oil excipient contained in SEDDS/SME is easily deteriorated by oxidation' and it is difficult to control the particle size of the emulsion formed by using the oil excipient, and the packaging and storage of SEDDS/SME requires strict control of humidity and Temperature, which increases production costs. Therefore, there is still a need to develop new dosage forms to improve the solubility and bioavailability of hydrophobic drugs. Khan The present invention provides a pharmaceutical composition for improving the solubility and bioavailability of a lipophilic drug. The system used in the present invention fully exhibits the function of SEDDS/SMEDDS in the absence of a conventional oil phase. Furthermore, the composition is easy to prepare and convenient to take. It also shows good stability during long-term storage: SUMMARY OF THE INVENTION The present invention is directed to providing a σ-medicine composition for enhancing the bioavailability of a medicament comprising a therapeutically effective amount of a lipophilic drug, a hydrophilic carrier, and a surfactant in the composition. The Hydrophilic Lipophilic Balance (HLB) value is from about 8 to about. Within the scope. Another object of the present invention is to provide an emulsion/microemulsion which is formed from the oral pharmaceutical composition of the present invention. Another object of the present invention is to provide a method for preparing an oral pharmaceutical composition of the present invention which comprises dissolving a drug in a hydrophilic solvent carrier 122666.doc 200922637 within a range of adding more than one. And adjusting the value to provide a method for enhancing the bioavailability of a lipid-based drug that undergoes treatment in the context of the present invention: 'The pharmaceutical composition of the present invention. ...to the patient orally, another target of the present invention is that the rabbit ancestor +i ^ ' is a method for administering a pharmaceutically active ingredient to a host to increase the medicinal active ingredient, and the method a) providing an oral pharmaceutical composition for oral administration of the oral administration of the composition, and administering b) the composition to the host, and b) ingesting the composition to contact the biological fluid and increasing the medicinal activity Bioavailability of ingredients. [Embodiment] Unless otherwise defined herein, the scientific and technical terms used in connection with the present invention shall have the meaning commonly understood by those skilled in the art. The meaning and _' of the term is clear; however, if there is any potential: ambiguity, the definitions provided herein take precedence over any dictionary or extrinsic definition. Unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular. The present invention provides an oral pharmaceutical composition for improving the solubility and bioavailability of a lipophilic drug comprising a pharmaceutically effective amount of a lipophilic drug, a hydrophilic solvent carrier and a surfactant, wherein the composition has a value of about 8 To the extent of about 15. When the pharmaceutical composition of the present invention is contacted with a gastrointestinal fluid, it spontaneously emulsifies in the absence of an oil phase for use in a conventional ternary system to form an emulsion/microemulsion containing the drug microemulsion therein. For example, the oil phase may be eucalyptus oil, corn oil, soybean oil, oil, Xiaoripo oil or 122666.doc -10· 200922637 medium chain triglyceride oil. The "effective amount of treatment" should be understood as the sound of 彳β / π > For the oral preparation of the present invention, the "operatively-effective amount" means that the sputum beam is effective in the blood to produce a therapeutic effect on the target organ after being absorbed into the body through the gastrointestinal (GI) wall. / Fertility dose of the farmer. Those skilled in the art will understand that the composition present in the composition may vary from case to case, including but not limited to the mode of administration, the size and age of the amine, and the like. In addition, this can be easily decided by the physician without any undue experimentation. Huasheng' is about 0.1% by weight of the composition.

5 〇 weight. /. The amount within the range exists and the amount within the J % range exists.仏 重 重 重 重 % % 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据曰 drugs, antacids, anti-inflammatory substances, shellfish-like blood official dilating agents, brain blood vessels according to mis-made du}—agents, sister Chunnan shovel, & Zhang agents, knowing the music, anti-tumor ^ ^ , decongestant, vitamins, stomach -, ', pain, vasodilators, antiarrhythmia, anti-migraine sputum, rod, year a ten, hand-carrying box anti-sputum blood agent and anti-thrombotic drugs, heat Agent, hypnotic agent, sedative, antiemetic... painkiller, solution V cancer, t, stop soil, stop nausea, anticonvulsant,

Nervous Sv.t '乍 Drugs for the Central Nervous System (Central ... Υ - NS) 'Hyperglycemic and hypoglycemic agents, thyroid glands and antithyroid agents, diuretics? A thyroid and nutritional supplements, anti-obesity 筚 '七七子吕松剂, mineral « or partial action in the mouth of the thousand:] sputum, cough The composition of the invention may contain the box 1 and its analogy. This 3 has a combination of more than one active ingredient. The drug is compared with 122666.doc 200922637. The best examples are CyCl〇Sp〇rine, tacrolimus, ibuprofen, ketoprofen, and Shixiao local ( Nifedipine), amlodipine or simvastatin The hydrophilic carrier used in the present invention must be non-toxic and have good physiological tolerance. In addition, the carrier should allow the drug to be incorporated therein. According to the present invention, hydrophilic carriers include, but are not limited to, ethanol, isopropanol, propylene glycol, and polyethylene glycol (such as PEG200, PEG300, PEG400, PEG600, PEG1000, PEG2000, PEG3000, PEG4000, PEG6000, or PEG8000). Any of the above mentioned carriers may be used alone or in combination with one or more carriers. The carrier is preferably present in the compositions of the present invention in an amount ranging from about 1% by weight to about 30% by weight of the composition, and more preferably in an amount ranging from about 2% by weight to about 20% by weight. Surfactants useful in the present invention can be any of those known in the art including, but not limited to, cationic surfactants, anionic surfactants, and nonionic surfactants. The surfactants useful in the present invention are HLB systems well known to those skilled in the art and should have an HLB value greater than about 2. The HLB value provides a means to rank the surfactant based on the balance between the hydrophilic portion and the lipophilic portion of the surfactant. That is, the higher the HLB value, the more hydrophilic the surfactant. Generally, the surfactants useful in the present invention have an HLB value in the range of from about 2 to about 18. Preferred examples of surfactants are PEG 40 hydrogenated castor oil, polysorbate, cocamidopropyl betaine, glyceryl cocoate, PEG 6 caprylic/capric glyceride, Polosham 122666.doc 200922637 (Poloxmer) ^ Labrafil M1944CS > Labrafil M2125CS, Labrasol, Cremophor, Crem〇ph〇r rh, and outside (10). Any of the surfactants mentioned above may be used alone or in combination with one or more surfactants. In the compositions of the present invention, the surfactant is preferably present in an amount ranging from about 5% by weight to about 9% by weight of the composition, and more preferably from about 20% by weight to about 85% by weight. The quantity exists. ί A necessary aspect of the pharmaceutical composition of the present invention is that it is thermodynamically stable when contacted with an aqueous solution (e.g., gastrointestinal tract-forming emulsion/microemulsion. The microemulsion disk thus formed is contacted with the gastrointestinal fluid of the mammal. Until the composition is in contact with the lunate fluid, the pot is a medicinal/microemulsion microemulsion, which is substantially uniform and consists of a ""< hole. The droplet size of the microemulsion is less than The pharmaceutical composition of the present invention can be prepared by stirring and mixing a waxy drug, a hydrophilic carrier and a surfactant, preferably about 8 nm, preferably about 1 nm. Preferably, the agent is mixed. And further adding to the chamber or a plurality of hydrophilic carriers to the beaker or flask, θ = obtaining a homogeneous solution. Then adding one or more drugs, then: two or two, until a clear solution is obtained to form HLB Values are between about 8 and about = mixed. Note that air should be prevented from entering the solution during mixing. For oral administration of a composition with a lipophilic drug, the compound is encapsulated in a sealed soft or hard capsule. Tian u solves the group (4) and then releases the contents of the substance-like substance γ intestinal material. The example is enteric soft or hard (four) capsule. The capsule is known to have an enteric coating of 122666.doc -13 - 200922637 A coating having a substance or combination of substances that resists dissolution in the gastric juice but disintegrates in the intestine. The invention is illustrated in more detail by the following non-limiting analytical methods and the results obtained therefrom: Example 1 Ingredient mg/ Capsule F(1)-1 F(I)-2 Cyclosporin 100 100 EtOH 117.6 141 Tween 80 758 758 Total 975.6 999 Add cyclosporine to Tween 80 and ethanol and mix, and stir the mixture until a clear solution is obtained. The formulations F(I)-1 and F(I)-2 obtained had HLB values of 14.0 and 13.9, respectively. A clear solution of the two formulations of 975.6 mg and 999 mg was filled into capsules for further testing. Example 2 Ingredient mg/capsule F(1)-3 Cyclosporin 100 EtOH 117 Labrasol 758 Total 975 Cyclosporin was added to Labrasol and ethanol and mixed, and the mixture was stirred until a clear solution was obtained. The obtained formulation F ( I)-3 has an HLB of 13.1 The 975 mg formulation clear solution was filled into capsules for further testing. 122666.doc -14- 200922637 Example 3 Ingredient mg/capsule F(II)-1 F(II)-2 F(II)-3 ring Sporomycin 100.0 100.0 100.0 EtOH 117.5 117.5 117.5 Labrafil M2125CS 84.5 189.5 324.5 Tween 80 758.0 758.0 758.0 Total 1060 1165 1300 Cyclosporin was added to Labrafil M2125CS, Tween 80 and ethanol and mixed, and the mixture was stirred until a clear solution was obtained. The obtained formulations F(II)-1, F(II)-2 and F(II)-3 have HLB values of 13.1, 12.2 and 11.3, respectively. The clarified solutions of the three formulations of 1060 mg, 1165 mg and 1300 mg were filled into capsules for further testing. Example 4 Ingredient mg/capsule F(III)-1 F(III)-2 F(III)-3 Cyclosporin 100.0 100.0 100.0 EtOH 117.5 117.5 117.5 Propylene glycol 189.5 324.5 454.5 Tween80 758.0 758.0 758.0 Total 1165 1300 1430

Cyclosporin was added to propylene glycol, Tween 80 and ethanol and mixed, and the mixture was stirred until a clear solution was obtained. The obtained formulations F(III)-1, F(III)-2 and F(III)-3 have HLB values of 13.0, 12.4 and 12.0, respectively. Three formulations of 1165 mg, 1 300 mg, and 1430 mg of the clear solution were filled into capsules for further testing. 122666.doc -15 - 200922637 Example 5 Ingredient mg/capsule F(IV)-1 F(IV)-2 F(IV)-3 Cyclosporin 100.0 100.0 100.0 EtOH 117.5 117.5 117.5 Labrafil M1944CS 84.5 189.5 324.5 Tween80 758.0 758.0 758.0 Total 1060 1165 1300 Add cyclosporine to Labrafil M1944CS, Tween 80 and ethanol and mix, and stir the mixture until a clear solution is obtained. The obtained ligands F(IV)-1, F(IV)-2 and F(IV)-3 have HLB values of 13.1, 12.2 and • 3, respectively. Three clear solutions of 1060 mg, 1165 mg, and 1300 mg were filled into capsules for further testing. Example 6 Ingredient mg/capsule F(V)-1 F(V)-2 F(V)-3 Cyclosporin 100.0 100.0 100.0 EtOH 117.5 117.5 117.5 Labrafil Ml944CS 36.0 166.5 242.0 Tween80 758.0 666.0 590.0 Total 1011.5 1050 1049.5 Ring Sporomycin was added to Labrafil M1944CS, Tween 80 and ethanol and mixed, and the mixture was stirred until a clear solution was obtained. What is the preparation obtained? (¥)-1, 卩〇)-2 and? (¥)-3 has HLB values of 13.6, 12.2, and 11.3, respectively. Three formulations of 1011.5 mg, 1050 mg, and 1049.5 mg of the clear solution were filled into capsules for further testing. 122666.doc -16- 200922637 Example 7 Ingredient mg/capsule tacrolimus F(I) Tacrolimus 1.0 EtOH 8.7 Labrafil Ml944CS 17.3 Tween80 43.0 Total 70 Adds tacrolimus to Labrafil Ml 944CS, Tween80 and ethanol It was mixed and the mixture was stirred until a clear solution was obtained. The formulation tacrolimus F(I) obtained had an HLB value of 11.3. A 70 mg formulation clear solution was filled into the capsule for further testing. Example 8 Ingredient mg/capsule Tacrolimus F(II) Tacrolimus 5.0 EtOH 43.5 Tween 80 301.5 Total 350 Tacrolimus was added to Tween 80 and ethanol and mixed, and the mixture was stirred until a clear solution was obtained. The obtained formulation tacrolimus F(II) has an HLB value of 14.1. A 350 mg formulation clear solution was filled into the capsule for further testing. Example 9 Ingredients mg/capsules Ketoprofen 100.0 EtOH 118.0 Tween 80 758.0 Total 976.0 122666.doc -17- 200922637 The ketoprofen was added to butyl ween 80 and ethanol and mixed with a standard mixture until a clear solution was obtained. The obtained formulation class j-lphin has an HLB value of Μ. A 976 mg formulation clear solution was filled into the capsule for further testing. Example 10 Dissolution Test The dissolution test was carried out by the following procedure: Instrument: Logan UDT-804 (USA)

ί. Media: 500 ml 〇_1N HC1 solution, prepared as follows: Add 85% guanidine 37% concentrated hydrochloric acid to 9 〇〇ml of deionized water, then uniformly stir and mix the solution, and finally add ions The water makes the total volume reach 丨B.

USP Apparatus 2 (Paddle): 50 rpm Temperature: 37 ± 0.5〇C Sampling time (min): 7, 15, 30, 45, 60, 90, and 12〇 Procedure: Inject 500 μM of .1N hci solution into 6 Each of the dissolution tanks to be preheated. Maintain the temperature of the water bath at 37 〇, c and set up the mixing device for the lysis tester according to your needs. Π. Measure the temperature of the solution by temperature measurement. Once the temperature reached 37 Torr. 5 ° C, a dissolution test was performed. 30 min, 45 ui. One of each formulation was placed in a dissolution tank. Iv. Collect samples at the following time points: · 7 min, 15 min min, 60 min, 90 min, and i2 〇 min. ν· A sample made of polyvinylidene fluoride (Poly(vinylidene Ι—), pvDF) has a pore size of 〇·45 called a sputum, and then the concentration of the drug is determined by the amount of HPLC 122666.doc 18 200922637 . HPLC measurements were performed using the following equipment and conditions: i. Mobile phase: deionized water: acetonitrile: methyl tert-butyl ether: phosphoric acid (v/v/v/v) = 440 : 5 10 : 45 : 1 mixture . The mixture was filtered through a ruthenium membrane made of nylon 66 having a pore size of 0.45 μm. The mixture is shaken by an ultrasonic oscillator for at least 30 minutes to remove the gas contained in the liquid. Ii·Pump (Pump L-7100, HITACHI, JAPAN) - Flow rate: L5 ml/min in. Detector (UV Detector L-7400, HITACHI, JAPAN) - Wavelength: 21 〇-nm iv. The sample volume was set on the autosampler (8 嶋 嶋 丨 丨 L_72〇〇, HITACHI, JAPAN) and the injection volume was set to 2 〇 μ1. V. ί column. 4.6-mmx 250 cm column containing USP packing L1. Vi. f column temperature: Place the column in (9) its column oven. The results of the dissociation test in Figures 1 to 5 show that the drug contained in the w drug product prepared according to the present invention can be effectively dissolved and released therefrom, and can be obtained by the HLB value of the periorbital drug delivery system. Control the dissolution. Example 11. Particle Size Measurement of Microemulsion The particle size of the microemulsion formed from the formulations of Examples 3 to 8 in 〇. 1 N HC1 solution (artificial gastric juice) was measured by the following procedure: 1· 500 〇 1 N HC1 (dissolved solution) was injected into the dissolution tank and heated to 37. . . Once 37 C ' was reached, 1 ml of each formulation was added to the trough. 122666.doc > 19- 200922637 iii. The mixture was stirred by a paddle at 50 rpm for 3 minutes. Iv. Remove about 3 ml of the mixture and add to the sample tank, then measure the formed microemulsion in a dynamic light scattering instrument (Zetasizer 3〇00, Malvern Inst·, UK) according to the instructions in the manual provided by the manufacturer. granularity. Table 1 shows the results of microemulsion particle size formed from the formulations of the present invention. Table 1 Formulation particle size (nm) (mean ± standard deviation) Cyclosporin F (I)-1 652.3 ± 11.8 — _ cyclosporine F (I)-2 ~ 733.8 ± 28.4 cyclosporine F (III)-1 733.6±34.0 'Cyclosporine^'(111)-2 601.4±13.8 ^baumycin f(iii)-3~~~ 570.6±13.8 Circumambucus F(V)-1 271.4± 18.9 Circumscribed Anhui F (V)-2 Γ236.4士4.0 Cyclosporine F(V)-3 230.4±12.5 Tacrolimus F(I) 290.3±9.0 9.5±2.7 Female Table 1 shows various The proportion of ethanol and the % surfactant of the single surfactant of Example 1 can spontaneously form microemulsion in artificial gastric juice. d There are various types and proportions of surfactants and the HLB value between 8 and 丨5. The cyclosporine formulations of 4 and 6 were able to form a microbial agent in artificial gastric juice. The formulations of Examples 7 and 9 with various drugs showed poor self-emulsifying ability. The above results indicate that the drug delivery system of the present invention can be applied to various drugs or active ingredients. Example 12 Stability Test The particle size of the microemulsion formed from the formulations of Examples 3 to 8 in oj NHCI solution (artificial gastric juice) was measured by the following procedure: Stability testing was performed according to ICH guidelines. The gel filled with f(v)_3 122666.doc -20- 200922637 was placed at 25 ° C / 60% ± 5% RH, 3 (TC / 60% ± 5% RH and 40 ° C / 75) %±5°/〇RH is different in three different temperature and humidity constant temperature and humidity chambers. After 0, 2 and 3 months of storage, the remaining content of main components is analyzed according to the above HPLC method. The test results are shown in Table 2. Storage time. - \ --- -- .............__ Drug content (%) 25 °C 30 °C 40 °C 0 months 2 months 100.5 — 100.5 100.5 101.0 100.9 3 months 100.8 —~~~ 100.7 100.5 -

As shown in Table 2, the active ingredient of the pharmaceutical composition of the present invention is very stable after long-term storage, even at 40. (The same is true at temperatures. Example 13. Oral bioavailability test

Organized in 3 healthy young male volunteers for each of the cyclosporine drugs containing F(I)-1 (hard capsule), F(I)-1 (soft capsule) and F(V).3 Availability testing. After overnight fasting, a single dose of the test formulation is administered to the donors _§_ before the dose (〇 h) and after the administration of H 1 · 3 3h, 1.67h, 2h, ? 〇, < 2.5h, 3h, 4h, 6h, 9h, 12h and 24h collect blood samples of the subject. The plasma concentration of cyclosporine was determined by high performance liquid chromatography combined with mass preparation (LC-Mass). Figure 6 shows the good oral bioavailability of cyclosporine in humans with the combination of (1)-1 and (V)-3. ^ References us 6,436,430 B1 US 6,3 12,704 B1 122666.doc •21 - 200922637 US 6,057,289 US 5,965,1 60 US 5,993,858 US 6,054,136 US 6,458,373 B1 US 6,596,306 B1 US 6,638,522 B1 US 7,094,804 B2 US 6,960,563 B2 Figure 1 shows the in vitro (ζ·« vz7ro) dissolution curve of Formulations (II)-1 to -3. Figure 2 shows the in vitro dissolution profile of Formulations (III)-1 to -3. Figure 3 shows the in vitro dissolution profile of Formulations (IV)-1 to -3. Figure 4 shows the in vitro dissolution profile of formulations (V)-1 to -3. Figure 5 shows the in vitro dissolution profile of tacrolimus formulations I and II. Fig. 6 is a graph showing the blood concentration versus time of the formulation (V)-3 soft capsule, the formulation (1)-1 soft capsule, and the formulation (I)-1 hard capsule. 122666.doc 22-

Claims (1)

200922637 X. Patent Application Range: 1 . An oral administration pharmaceutical composition for improving the bioavailability of a medicament, comprising a therapeutically effective amount of a lipophilic drug, one or more hydrophilic carriers and/or a plurality of surfactants, Wherein the composition has a Hydrophilic Lipophilic Balance (HLB) value in the range of from about 8 to about 15; with the proviso that the composition is free of the oil phase. 2. The pharmaceutical composition according to claim 1, wherein the drug is an immunizing agent, an anti-infective agent, an anti-sputum blood pressure agent or a hypolipidemic agent. 3. The pharmaceutical composition of claim 2, wherein the drug is cyclosporine, tacr〇Umus, ibuprofen, ketoprofen (ket〇pr〇fen) , nifedipine, amlodipine (a) or a simvastatin. 4. The pharmaceutical composition according to claim 1, wherein the hydrophilic carrier is selected from the group consisting of ethanol, isopropanol, and polyethyl A pharmaceutical composition comprising the diol (P〇lyethylene glycoside 1, pEG), glycerin, propylene glycol, and a mixture thereof. 5. The pharmaceutical composition according to claim 1, wherein the surfactant is a cationic surfactant, an anionic surfactant, 6. A non-ionic surfactant or a mixture thereof. 6. The pharmaceutical composition of claim 5, wherein the surfactant has an HLB value in the range of from about 2 to about 18. 7. The pharmaceutical composition of claim 6 wherein the interface The active agent is selected from the group consisting of PEG 40 hydrogenated castor oil, polysorbate, cocamidopropyl betaine, glyceryi c〇c〇ate, 122666.doc 200922637 PEG 6 octanoic acid / hydrazine Glycerides, poloxamers (p 〇1〇xmer), LabrafU M1944CS ^ Labrafil M2125CS > Labrasol > Cremophor EL, Cremophor RH, Brij, Span, and mixtures thereof. 8. Pharmaceutical composition according to any one of claims 1 to 7' Wherein, when the composition is contacted with an aqueous solution, the composition forms an emulsion/microemulsion having a particle size of less than about 800 nm. The pharmaceutical composition according to any one of claims 1 to 7, wherein the drug is the composition The pharmaceutical composition according to any one of the items 1 to 7 wherein the hydrophilic carrier is about i by weight of the composition, wherein the weight of the composition is from about 5% by weight to about 5% by weight. The pharmaceutical composition of any one of the present invention, wherein the surfactant is from about 1% by weight to about 9% by weight of the composition. 12. An emulsion/microemulsion formed from an orally administered pharmaceutical composition according to any one of claims 1 to 1. A method of preparing a pharmaceutical composition according to any one of claims 1 to 5 which comprises mixing a lipophilic drug, a hydrophilic carrier and a surfactant by mixing. 14. The method of claim 13, comprising the step of dissolving the drug in a mixture comprising the solvent carrier and the surfactant, thereby obtaining a composition having an HLB value in the range of from about 8 to about 15. 15. The method of claim 13, further comprising the step of encapsulating the composition into a soft or hard capsule order. 1 6. The method of claim 3, wherein the drug is cleaved by 4% sporomycin, tacrolimus 122666.doc 200922637 ammoniapine or svastatin, ibuprofen, ketoprofen, nifedipine 0 The method of claim 13, wherein the hydrophilic carrier is selected from the group consisting of ethanol, chloramphenicol, polyethylene glycol (PEG), propylene glycol, and mixtures thereof. 18. The method of claim 13, wherein the surfactant It is a cationic surfactant, an anionic surfactant, a nonionic surfactant or a mixture thereof. 1 9. The method of claim 8 wherein the surfactant has an HLB value in the range of from about 2 to about 18. The method of claim 19, wherein the surfactant is selected from the group consisting of pH. 4〇hydrogenated castor oil, polysorbate, cocoamidopropyl betaine, capric acid glycerol, PEG 6 caprylic/capric glyceride, poloxamer, [abrafil M1944CS ^ Labrafil M2125CS > Labrasol ^ Cremophor EL , a group consisting of Cremoph〇r RH, Brij, Span, and mixtures thereof. The method of any one of claims 13 to 20, wherein the drug is present in an amount of from about 0.1% by weight to about 5% by weight of the composition. The method of any one of claims 1 to 20, wherein the hydrophilic carrier is present in an amount of from about 1% by weight to about 3% by weight of the composition. The method of any one of claims 1 to 3 wherein the surfactant is present in an amount from about 10% to about 9% by weight of the composition. 122666.doc