CN1272785A - Micro-osmotic controlled drug delivery system - Google Patents

Abstract

Disclosed herein are pharmaceutical compositions utilizing microosmotic cores for the controlled release of therapeutic agents, and methods of their use and preparation. In particular, the present invention relates to therapeutic agents which are present partly in solid solution in the composition.

Description

Microosmotic drug release system

Background of the Invention

The present invention relates to the field of osmotic release systems for the controlled release of therapeutic agents. Osmotic release systems facilitate controlled release of pharmaceutical agents from dosage forms based on changes in osmotic pressure in the dosage form. Osmotic delivery systems are useful for delivering both poorly soluble and highly soluble therapeutic agents.

Summary of Invention

According to the present invention, a microosmotic drug controlled release system is developed. The micro-osmotic system comprises the following parts: a micro-osmotic core, a drug component, and if necessary, a controlled-release matrix and/or a coating layer.

The micro-osmotic core contains at least one osmotic agent and, if desired, a swelling agent and/or a gelling agent. The osmotic agent facilitates the entry of aqueous biological fluids into the micro-osmotic core. Osmotic agents include, for example, sorbitol, mannitol, xylitol, sodium chloride, or any other such well-soluble and pharmaceutically acceptable excipients. Preferred penetrants include, for example, spray-dried sorbitol, especially Sorbitol Instant (EM Industries, Hawthorne, NY), which has a surface area of ~1 ^m2 /g; spray-dried mannitol; state) of mannitol containing not less than about 85% of "δ" type mannitol; combinations of sorbitol-mannitol-xylitol, preferably, as in German patent application DE 196 47 282 A1, Sorbitol > 90%, Mannitol > 4%, Xylitol > 4% as described in P96 47282-DE and International Patent Applications WO44 39 858, PCT/EP95/04059.

The microosmotic core may also contain a swelling agent, if desired. The swelling agent causes volume expansion upon contact with aqueous biological fluids, thereby changing the volume of the micro-osmotic core. The swelling agent is preferably capable of expanding the volume to many times its dry state volume. Preferred swelling agents include, for example, sodium starch glycolate, croscarmellose sodium, cellulose and microcrystalline cellulose.

Optionally, the micro-osmotic core may also contain a gelling agent. The role of the gelling agent is to maintain the integrity of the swelling agent, thereby maintaining the integrity of the microosmotic core. The gelling agent is preferably a water soluble polymer. Preferred gelling agents include, for example, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP) and derivatives thereof, gum tragacanth, gum arabic, guar gum, Carrageenan and other carbohydrate-derived gums, alginic acid and its derivatives, and carbomers.

Micro-osmotic cores are small particles of about 2-3000 [mu]m (preferably about 200-3000 [mu]m, more preferably about 200-1500 [mu]m) in diameter. These microparticles may be minitablets, for example formed with a water-soluble lubricant such as PEG8000. Microosmotic cores can also be extruded and spheronized into pellets and/or spray condensed into microparticles. The penetrating agent/swelling agent/gelling agent may be combined in a weight ratio of 100/0/0 to 0.05/99.9/0.05 to 99.9/0.05/0.05 to 0.05/0.05/99.9. The preferred ratio of penetrating agent/swelling agent/gelling agent is: 1/8/1, 2/7/1, 3/6/1, 4/5/1, 6/2/2, 7/1/ 2, 8/1/1, 9/0.5/0.5, and 5/4/1.

The microosmotic core of the present invention is coated with a drug ingredient to obtain a medicated core. The term "coating" as used herein refers to any physical contact between the drug ingredient and the microosmotic core. For example, the micro-osmotic core may be fully or partially coated, or otherwise impregnated, with the drug ingredient. The drug-containing core has a diameter of about 2-3000 µm, preferably about 200-3000 µm, most preferably about 200-1500 µm. A pharmaceutical composition comprises at least one therapeutic agent. The therapeutic agent in the pharmaceutical composition can be, for example, a solid, a solid solution, a solid solution-dispersion, a microdispersion, a solution-suspension (eg, aqueous, alcoholic, or aqueous-alcoholic), or any combination thereof. Therapeutic agents can be mixed with selected excipients and/or binders. Solution-suspension therapeutics may optionally contain hydrophilic agents such as HPMC, HPC, PVP, sorbitol, and/or natural gums such as acacia, in addition to water, alcohol, or water-alcohol systems.

The term "solid solution" herein refers to a solution of a solid therapeutic agent. A solid solution of a therapeutic agent is characterized by the absence of a melting point peak at the melting point of the therapeutic agent, indicating the absence of a solid therapeutic agent. The term "solid solution-dispersion" as used herein refers to a system in which part of the therapeutic agent is a solid solution and part of the therapeutic agent is a well-dispersed solid. Preferably, more than 1% of the total therapeutic agent content is present in the system in solution, or in a solid, semi-solid, or liquid phase. The system is also characterized in that at least one therapeutic agent may be present as a solid dispersion. Any portion of the therapeutic agent present as a solid dispersion preferably has a particle size distribution such that about 90% of the particles are less than about 10 microns in diameter.

In a solid solution-dispersion, the ratio of dissolved therapeutic agent/dispersed therapeutic agent is from 1/99 to 100/0. Preferably, from about 30% to about 100% of the therapeutic agent is present in solution, and more preferably, from about 60% to about 90% of the therapeutic agent is present in solution. The ratio of the amount of therapeutic agent present in solid solution to the amount present in solid dispersion can be readily determined by thermal analysis techniques such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and differential Scanning microcalorimetry] to be determined. The crystallinity of a therapeutic agent can be readily determined by X-ray diffraction.

An example of a solid solution-dispersion system (especially for poorly water-soluble therapeutic agents) is, for example, U.S. Patent Application No. 09/050913 and U.S. Provisional Patent Application Nos. 60/080163, 60/085417, 60/085333 and Polyethylene glycol-treated saturated glycerides (saturated polyglycolyzed glycerides) described in 60/092767 (for example, ^Gelucire® , product of Gattefosse Company), polyoxypropylene-polyoxyethylene block copolymers (for example, ^Pluronic® NF surfactant, BASF company product) and the mixture of therapeutic agent. The polyethylene glycol-treated glyceride component of the pharmaceutical carrier composition can include all grades of polyethylene glycol-treated saturated and unsaturated glycerides, preferably including a hydrophilic-lipophilic balance (HLB) > 10 Glycerides treated with polyethylene glycol. Preferred polyethylene glycol-treated glycerides include, for example, ^Gelucire® 44/13 and ^Gelucire® 50/13. The mixture may also include all grades of polyoxypropylene-polyoxyethylene block copolymers, preferably polyoxypropylene-polyoxyethylene block copolymers with HLB>10. Preferred polyoxypropylene-polyoxyethylene block copolymers include, for example, ^Pluronic® L44, ^Pluronic® F68, ^Pluronic® F108 and ^Pluronic® F127. The polyethylene glycol-treated glyceride/polyoxypropylene-polyoxyethylene block copolymer may be combined in a weight ratio of about 0.10/99.9 to about 99.0/0.10. Preferred ratios are 1/9, 2/8, 3/7, 4/6, 6/4, 7/3, 8/2, 9/1 and 5/5. The polyethylene glycol-treated saturated glyceride/polyoxypropylene-polyoxyethylene block copolymer mixture preferably has a melting point of about 30-70°C, more preferably about 50-70°C. When using a polyethylene glycol-treated glyceride/polyoxypropylene-polyoxyethylene block copolymer mixture, the amount of the mixture in the final composition of the pharmaceutical ingredient is about 0.10-99.9%, preferably about 5-75% %. The amount of therapeutic agent in the final composition of the pharmaceutical ingredient is about 0.10-99.9%, preferably about 5-75%.

Examples of therapeutic agents that may be used in the present invention include: dihydropyridines (including, for example, nifedipine, felodipine, nicardipine), cyclic peptides (including, for example, cyclosporine), omeprazole, spironolactone , furosemide, terbutaline, riboflavin, gemfibrozil, indomethacin, ibuprofen, phenytoin, and glibenclamide. In addition, any therapeutic agent having an intrinsic solubility of less than about 10.0 g/L and having therapeutic activity in any of the following areas is contemplated as part of this invention: activity in the cardiovascular system, immunosuppressive activity, cholesterol-lowering activity, antihypertensive activity, antiepileptic activity, hormonal activity, hypoglycemic activity, antiviral activity, antihistamine activity, activity to relieve nasal congestion, antimicrobial activity, antiarrhythmic activity, analgesic activity, antimycobacterial activity, anticancer activity, Diuretic activity, antifungal activity, antiparasitic activity, activity as central nervous system (CNS) stimulant, activity as CNS depressant, activity as 5-HT inhibitor, antischizophrenia activity, anti-Alzheimer's disease Antiinflammatory activity, antipsoriatic activity, antiulcer activity, activity as a proton pump inhibitor, antiasthmatic activity, activity as a bronchodilator, and thrombolytic activity. Therapeutic agents can be, for example, proteins, peptides, cyclic peptides, steroidal molecules, vitamins, oligonucleotides, or any small or large molecule, or any combination of the foregoing.

In addition to one or more therapeutic agents, a pharmaceutical composition can include excipients, if desired. The excipient preferably accounts for about 5-95% by weight of the final composition of the pharmaceutical ingredient, more preferably about 10-70%. Examples of suitable excipients include, but are not limited to: ascorbyl palmitate, tocopheryl acetate, glycerin, glyceryl monooleate, glyceryl monostearate, glyceryl palmitosterate, triacid Glycerides, diglycerides, monoglycerides, stearic acid, magnesium stearate, talc, polyethylene glycol (PEG) diester, PEG monoester, polyethylene glycol, polyoxyethylene fatty acid Glycerides; Polyoxyethylene macrogol fatty acid glycerides and ethers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, Polyvinyl alcohol, sodium starch glycolate, sorbitan fatty acid ester, polyoxyl stearate, polyethylene glycol hydroxystearate, polyoxyethylene alcohols, anion, cation, amphoteric compound, egg Phospholipids, phospholipids, carbohydrates (including, for example, lactose, maltodextrin, sucrose, and starch), polyols (including, for example, sorbitol, mannitol, and xylitol), microcrystalline cellulose, vitamins (including, for example, ascorbic acid and niacinamide) , bioflavonoids (such as including quercetin, isoquercine, naringin, rutin, etc.), inorganic compounds (such as including calcium carbonate, dicalcium phosphate) and any combination of the above substances.

The microosmotic core (drug-containing core) coated with the drug ingredient can be coated with a suitable polymer and/or mixed with a polymer matrix system. The polymer coating or polymer matrix can serve to modify the therapeutic agent release characteristics of the drug-containing core. The polymer coating may comprise for example: hydrophilic polymers such as HPMC, HPC, cellulose derivatives, starch derivatives, PVP and PVP derivatives, carbomers; water insoluble polymers such as ethyl cellulose, cellulose acetate , polymethacrylate polymers (such as ^Eudragit® polymers) and pseudolatex dispersions of the aforementioned polymers; enteric polymers such as shellac, cellulose acetate phthalate; plasticizers such as sebacic acid Dibutyl esters, triacetin, acetyl tributyl phthalate; pearlescent pigments such as the Candurin ^™ pigment series (products of EM Industries, Hawthorne, NY). The drug-containing core can be coated by pharmaceutical techniques well known in the art, including techniques such as Worster coating, spin coating and/or pan coating.

The polymer matrix comprises at least one hydrophilic polymer such as cellulose and its derivatives [including eg HPMC, HEC, Carbomers (eg Carbopol P934, Carbopol P974)] and alginic acid and its derivatives. The hydrophilic polymer of the polymer matrix preferably has a molecular weight of about 100-4,000,000. The hydrophilic polymers are also preferably used in combination with at least one hydration enhancer which provides faster hydration of the hydrophilic polymers. Hydration enhancers include, for example, sorbitol, mannitol, xylitol, and microcrystalline cellulose, and any combination thereof. A preferred hydration enhancer is a proprietary spray-condensed sorbitol (commercially available as Sorbitol Instant from EM Industries, Hawthorne, NY) with a surface area of 1 m ² /g. Hydrophilic polymers of different molecular weights and chemistries can be combined to obtain the desired release profile of the therapeutic agent.

The drug-containing core can be dry blended with a polymer matrix, then granulated and/or processed into beads or pellets with a suitable solvent (e.g., aqueous and/or organic), or compressed into a tablet with a suitable lubricant agent. Lubricants suitable for tableting dry blends of drug-containing cores and polymer matrices include, for example, sodium stearyl fumarate, magnesium stearate, PEG 8000. Flow enhancers such as colloidal silicon dioxide may also be used as part of the tabletting step.

The product obtained from the above procedure (the product comprising a drug-containing core, which may be coated or uncoated, may be mixed with a polymer matrix to form a dry mixture, and optionally further into granules, beads, pellets or tablets) are further processed into the final dosage forms described below. As an example, granules, pellets, beads or dry blends can be compressed into tablets and the resulting tablets can be coated with a polymer coating, if desired, to modify the release profile of the therapeutic agent. The polymer coating is essentially the coating as described above. As another example, beads, pellets or granules may be coated with a polymeric coating substantially as described above. The coated beads, pellets or granules can then be filled into capsules or compressed into tablets with suitable pharmaceutical excipients.

In the present invention, the final dosage form may contain various types of drug-containing cores. For example, drug-containing cores containing the same therapeutic agent but with different release characteristics can be incorporated into the final dosage form. Different release profiles of drug-containing cores containing the same therapeutic agent can be obtained, for example, by varying the content of the microosmotic core or the polymer coating of the drug-containing core. Alternatively, medicated cores with different therapeutic agents may also be incorporated into the same final dosage form.

The present invention also relates to methods for the manufacture of pharmaceutical compositions. The method includes the following steps: forming a micro-osmotic core, coating the micro-osmotic core with a drug component to form a drug-containing core, and formulating the drug-containing core into the above-mentioned final dosage form if necessary.

The invention also relates to methods of delivering one or more therapeutic agents to a physiological target site. The method includes the steps of forming the following composition of the invention and introducing a pharmaceutically effective amount of the pharmaceutical composition to a physiological target site. The pharmaceutical composition can be introduced into the physiological target site, for example, by topical administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, nasal administration, pulmonary administration, vaginal administration, rectal administration, ear administration , oral or ocular administration. A preferred method of delivering at least one therapeutic agent to a physiological target site contemplated by the present invention is oral administration.

A brief description of the attached drawings

Figure 1 is a graph showing the in vitro release profile of felodipine in the tablet of Example 17.

Figure 2 is a graph showing the in vitro release profile of felodipine in the tablet of Example 18.

Figure 3 is a graph showing the in vitro release profile of felodipine in the tablet of Example 19.

4 is a graph showing the in vitro release profile of felodipine in the tablet of Example 20.

5 is a graph showing the in vitro release profile of felodipine in the tablet of Example 21.

6 is a graph showing the in vitro release profile of felodipine in the tablet of Example 22.

7 is a graph showing the in vitro release profile of felodipine in the tablet of Example 23.

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, the following preferred embodiments should be considered as illustrations only, rather than limiting the present invention.

Example

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

In Examples 17-23 below, the following ingredients were used.

1. Pruv ^TM ...sodium octadecyl fumarate, a product of Mendell

2. Avicel ^TM PH200... microcrystalline cellulose NF, product of FMC company

3. Sorbitol Instant P300...Sorbitol NF, product of Merck KGaA

4. Methocel ^TM E4M Premium CR...Hydroxypropyl methylcellulose NF, product of Dow Chemical Company

5. Methocel ^TM K100M...Hydroxypropyl methylcellulose NF, product of Dow Chemical Company

6. Triacetin ^TM ... triacetin, product of Spectrum Quality Products

7. ^Eudragit® NE30D... 30% aqueous dispersion of polyacrylate copolymer, product of Roehm

8. ^Eudragit® L30D... 30% aqueous dispersion of methacrylic acid/methacrylate copolymer, product of Roehm

9. PVP30... Polyvinylpyrrolidone (MW: 44,000-54,000), the trade name is Kollidon ^® 30, a product of BASF

10. Gelucire® ^50/13 ... [glycerides of saturated hydrogenated vegetable oils treated with polyethylene glycol, including glycerides and PEG-esters], product of Gattefosse

11. Pluronic ^® F68...polyoxypropylene-polyoxyethylene block copolymer, BASF company product Example 1: Preparation of micro-permeable core

The microosmotic core can be prepared from a variety of materials by any technique known in the art. Below are a few of these techniques and materials:

(1) Use crystalline or spray-condensed sorbitol as the micro-osmotic core;

(2) Sorbitol, sodium starch glycolate and HPMC are mixed, and PEG8000 is used as a lubricant to press into microtablets (for example, diameter<1mm);

(3) Sorbitol powder is mixed with sodium starch glycolate, and the mixture is extruded and spheroidized to form pellets;

(4) Sodium starch glycolate was spray-coagulated on sorbitol.

Micro-osmotic cores can be prepared by any of the methods described above or by any other technique known in the art, including granulation. Example 2: Preparation of Therapeutic Agents as Solid Solution-Dispersions

A mixture of polyethylene glycol-treated glycerides and polyoxypropylene/polyoxyethylene block copolymer was heated to a temperature 20°C above the melting point (-50°C). The therapeutic agent is gradually added to the molten mixture. Preferably, the therapeutic agent is micronized such that at least 90% of the particles are less than about 75 microns in diameter. The mixture was maintained at a temperature 20°C above the melting point of the mixture of polyethylene glycol-treated glycerides and polyoxypropylene/polyoxyethylene block copolymer. The ratio of polyethylene glycol-treated glyceride to polyoxypropylene/polyoxyethylene block copolymer is selected such that more than 1% (preferably 30-100%) of the therapeutic agent is soluble in the mixture. Embodiment 3: Controlled-release tablet containing nifedipine

Effectiveness (mg/piece) Effective 1. SorbitOl Instant P300 50 Microconuction Core 2. American Pharmaceutical 90 Active ingredients 3. Gelucire 50/13 90 Extinifier 4.Pluronic F68 90 Extract 5. HPMC E4M (CR grade) 300 hydrophilic polymer 6. Sorbitol Instant P300 75 hydraulic reinforcement agent 7. Micro crystal cellulose 75 hydraulic reinforcement agent 8. Magnesium magnesium 6.8 lubricant 6.8 lubricant

Sorbitol Instant P300 was used as the osmosis core. Gelucire 50/13, Pluronic F68 and nifedipine are processed together to obtain a pharmaceutical composition containing the therapeutic agent nifedipine, which exists as a solid solution-dispersion. The medicinal ingredients are then spray coagulated on the Sorbitol Instant. The medicated core prepared above was mixed with a polymer matrix containing Sorbitol Instant P300, HPMC E4M (CR grade), microcrystalline cellulose and magnesium stearate. The mixture of drug-containing core and polymer formulation is then compressed to obtain controlled release tablets. Embodiment 4: Controlled release tablet containing felodipine

Effectiveness (mg/tablet) Effective 1. SorbitOl Instant P300 50 osmotic agent 2. Sodium starch ethanol 20 oligomer 3. non -Luo Di Ping, American Pharmacopoeia 90 active ingredients 4. Gelucire 50/13 90 Fukin 5. Pluronic F68 90 Extinifier 6.HPMC E4M (CR grade) 300 hydrophilic polymer 7. Sorbitol Instant P300 75 hydraulic reinforcement agent 8. Micro crystal cellulose 75 hydraulic enhancer 9. Magnesium magnesium 6.8 lubricant 6.8 lubricant

Combining Sorbitol Instant P300 with Sodium Starch Glycolate to form a micro-osmotic core. Gelucire 50/13, Pluronic F68 and felodipine are mixed to obtain a pharmaceutical composition containing felodipine in solid solution. The drug ingredient is then spray-condensed onto the micro-osmotic core. The medicated core prepared above was mixed with Sorbitol Instant P300, HPMC E4M (CR grade), microcrystalline cellulose and magnesium stearate. The mixture of drug-containing core and polymer formulation is then compressed to obtain controlled release tablets. Embodiment 5: Controlled-release tablet containing phenytoin

Effectiveness (mg/tablet) Effective 1. SorbitOl Instant P300 50 osmotic agent 2. Sodium glycopyate 20 lymic agent 3.HPMC E4M 10 gel agent 4. Pharmaceutin 95 active ingredient 5.gelucire 50. 50.gelucire 50 /13 90 Extiniferous Volume 6.Pluronic F68 90 Extinifier 7.HPMC (K100) 300 hydrophilic polymer 8. Sorbitol Instant P300 150 hydraulic reinforcement 9. Magnesium Magnesium 6.8 Lubricant

Sorbitol Instant P300, HPMC E4M and Sodium Starch Glycolate are processed together into a micro-osmotic core. Gelucire 50/13, Pluronic F68 and phenytoin are processed together to obtain a solid solution of phenytoin in the matrix. The drug ingredient is spray-condensed onto the micro-osmotic core. The drug system micro-osmotic core prepared above was mixed with Sorbitol Instant P300, HPMC E4M (CR grade), microcrystalline cellulose and magnesium stearate. Compress the tablet with the above formula to obtain a controlled release tablet. Embodiment 6: Controlled-release tablets containing indomethacin

Effectiveness (mg/tablet) Effective 1. SorbitOl Instant P300 50 osmotic agent 2. Sodium Etanol Sodium 20 Snaping Agent 3.HPMC E4M 10 Gelgent 4. 吲哚 Meixin, American Pharmacopoeia 100 Active Component 5.PVP 5.PVP 90 excavant, adhesive 6.HPMC (K100) 300 hydrophilic polymer 7. Sorbitol Instant P300 150 hydraulic reinforcement agent 8. Magnesium Magnesium 6.8 Lubricant

Sorbitol Instant P300, HPMC E4M and Sodium Starch Glycolate are processed together into a micro-osmotic core. PVP and indomethacin were processed together to give a suspension in ethanol. The drug system is sprayed onto the micro-osmotic core. The drug system micro-osmotic core prepared above was mixed with Sorbitol Instant P300, HPMCE4M (CR grade), microcrystalline cellulose and magnesium stearate. Tablets were compressed with the above preparation to obtain controlled-release tablets. Embodiment 7: the controlled-release tablet containing chlorpheniramine

Effectiveness (mg/tablet) Effective 1. SorbitOl Instant P300 50 osmotic agent 2. Sodium starch ethanol 20 soluble agent 3.HPMC E4M 10 gel agent 4. Platrin 10 active ingredient 5.PVP 20 elixid agent agent agent , Adhesive 6.HPMC (K100) 300 hydrophilic polymer 7.sorbitolinstant P300 150 hydraulic enhancer 8. Micro crystal hard fatty acid salt 6.8 lubricant

Sorbitol Instant P300, HPMC E4M and Sodium Starch Glycolate are processed together into a micro-osmotic core. Process PVP and chlorpheniramine together to obtain an aqueous solution. The drug system is sprayed onto the micro-osmotic core. The drug system micro-osmotic core prepared above was mixed with Sorbitol Instant P300, HPMC E4M (CR grade), microcrystalline cellulose and magnesium stearate. Compress the tablet with the above formula to obtain a controlled release tablet. Embodiment 8: Controlled-release tablet containing diltiazem hydrochloride

Effectiveness (mg/tablet) Effective 1. SorbitOl Instant P300 160 osmotic agent 2. Sodium Etanol 40 Snaping Agent 3.hpmce4m 20 Plastic Coagulants 4. El Sulfurine 300 Activated Component 5.PVP 60 Further shape Agent, adhesive 6. Ethyl cellulose decentralized bodies appropriate amount of hydrophilic polymer 7. Affordotic acid dioxyl a moderate plasticizer 8. Powder powder anti -junction agent

Sorbitol Instant P300, HPMC E4M and Sodium Starch Glycolate are processed together into a micro-osmotic core. PVP and diltiazem hydrochloride are processed together to obtain an aqueous solution. The drug system is sprayed onto the micro-osmotic core. The drug system microosmotic cores prepared above were coated with ethylcellulose dispersion plasticized with dibutyl sebacate. Compress the tablet with the above formula to obtain a controlled release tablet. Embodiment 9: the capsule containing chlorpheniramine controlled-release pellets

Effectiveness (mg/tablet) Effective 1.SorbitOl Instant P300 50 osmotic agent 2. Sodium Etanol 20 oligomes 3.PVP 10 Gas Costric agent 4. Poemin 10 active ingredients 5.PVP 20 rectifiers, PVP 20 rectifiers, PVP 20 rectifying agent, Adhesive 6. EUDRAGIT RS30D Differential Affordable Hydivating Polymer 7. Affordotic Planted Plastic Plastic Plastic Plastic Plastic Plastic Plastic Powder

Sorbitol Instant P300, HPMC E4M and Sodium Starch Glycolate are processed together into a micro-osmotic core. Process PVP and chlorpheniramine together to obtain an aqueous solution. The drug system is sprayed onto the micro-osmotic core. The drug system microosmotic cores prepared above were coated with Eudragit RS30D (polymethacrylate copolymer) dispersion plasticized with dibutyl sebacate. The controlled-release pellets are filled into capsules. Embodiment 10: Controlled release tablet containing nifedipine

Effectiveness (mg/tablet) Effective 1. SorbitOl Instant P300 50 osmotic agent 2. Sodium starch ethanol 20 oligomer 3.hpmc E4M 10 gel agent 4. Nitzorpine, American Pharmacopoeia 90 active ingredient 5.pvp 90 Exting agent, adhesive 6. locust bean gum 175 hydrophilic polymer 7. Huangyuan collagen 175 hydrophilic polymer 8. Sorbitol Instant P300 150 hydraulic reinforcement agent 9. Calcium chloride 25. Magnesium Fatty Acid 6.8 Lubricant

Sorbitol Instant P300, HPMC E4M and Sodium Starch Glycolate are processed together into a micro-osmotic core. PVP and nifedipine were processed together to give a suspension solution in ethanol. The drug system is sprayed onto the micro-osmotic core. The drug system micro-osmotic core prepared above was mixed with Sorbitol Instant P300, locust bean gum, xanthan gum, calcium chloride and finally magnesium stearate. Compress the tablet with the above formula to obtain a controlled release tablet. Embodiment 11: Controlled-release tablet containing nifedipine

Effectiveness (mg/tablet) Effective 1. Sorbitol Instant P300 50 osmotic agent 2. Sodium of starch ethanol 20 oligomer 3. Pharmaceutical, American Pharmacopoeia 90 Active ingredients 4.PVP 90 Fuk, adhesive 5 .Hpmc (K100) 300 hydrophilic polymer 6. Sorbitol Instant P300 150 hydraulic reinforcement agent 7. Ethyl cellulose 100 hydrophilic polymers 8. Glycerin acetate 25 plasticizers 6.8 Lubricants

Sorbitol Instant P300 is processed together with sodium starch glycolate into a micro-osmotic core. PVP and nifedipine were processed together to give a suspension in ethanol. The drug system is sprayed onto the micro-osmotic core. The pharmaceutical system microosmotic core prepared above was mixed with Sorbitol Instant P300, HPMC (K100 grade), granulated with a granulation solvent consisting of ethyl cellulose and triacetin, dried, and the agglomerates were crushed , and finally mixed with magnesium stearate. Compress the tablet with the above formula to obtain a controlled release tablet. Embodiment 12: Controlled release tablet containing nifedipine

Effectiveness (mg/tablet) Effective 1. Sorbitol Instant P300 50 osmotic agent 2. Sodium of starch ethanol 20 oligomer 3. Pharmaceutical, American Pharmacopoeia 90 Active ingredients 4.PVP 90 Fuk, adhesive 5 .Hpmc (K100) 300 hydrophilic polymer 6. Sorbitol Instant P300 150 hydraulic reinforcement agent 7. Ethyl cellulose 100 hydrophobic polymer 8. Glycelacerotetate 25 plasticizer 9.hpmc E4M 10 hydrophilic hydrophilic Sexual polymer 10. Magnesium stearate 6.8 Lubricant

Sorbitol Instant P300 is processed together with sodium starch glycolate into a micro-osmotic core. PVP and nifedipine were processed together to give a suspension solution in ethanol. The drug system is sprayed onto the micro-osmotic core. Mix the microosmotic core of the pharmaceutical system prepared above with Sorbitol Instant P300, HPMC (K100 grade), make granules with a granulation solvent consisting of ethyl cellulose, HPMC E4M and triacetin, dry, and The mass is crushed and finally blended with magnesium stearate. Compress the tablet with the above formula to obtain a controlled release tablet. Embodiment 13: Controlled-release tablets containing nifedipine

Effectiveness (mg/tablet) Effective 1. Sorbitol Instant P300 50 osmotic agent 2. Sodium of starch ethanol 20 oligomer 3. Pharmaceutical, American Pharmacopoeia 90 Active ingredients 4.PVP 90 Fuk, adhesive 5 .Hpmc (K100) 300 hydrophilic polymer 6. Sorbitol Instant P300 150 hydraulic reinforcement agent 7. Ethyl cellulose 100 hydrophobic polymer 8. Glycelacerotetate 25 plasticizer 9.hpmc E4M 10 hydrophilic hydrophilic Sexual polymer 10. Magnesium stearate 6.8 Lubricant

Sorbitol Instant P300 is processed together with sodium starch glycolate into a micro-osmotic core. PVP and nifedipine were processed together to give a suspension in ethanol. The drug system is sprayed onto the micro-osmotic core. The pharmaceutical system microosmotic core prepared above was mixed with Sorbitol Instant P300, HPMC (K100 grade), granulated with a granulation solvent consisting of ethyl cellulose and triacetin, dried, and the agglomerates were crushed , and finally mixed with magnesium stearate. Compress the tablet with the above formula to obtain a controlled release tablet. The tablets were coated with a semipermeable polymer coating system consisting of ethylcellulose, HPMC E4M and triacetin. Embodiment 14: Controlled-release tablet containing nifedipine

Effectiveness (mg/tablet) Effective 1. Sorbitol Instant P300 50 osmotic agent 2. Sodium of starch ethanol 20 oligomer 3. Pharmaceutical, American Pharmacopoeia 90 Active ingredients 4.PVP 90 Fuk, adhesive 5 .Hpmc (K100) 300 hydrophilic polymer 6. Sorbitol Instant P300 150 hydraulic reinforcement agent 7.Eudragit NE30D 100 hydrophobic polymer 8. Guilizhaxite 25 plasticizer 9.hpmc E4M 10 hydrophilicity Polymer 10. Magnesium Stearate 6.8 Lubricant

Sorbitol Instant P300 is processed together with sodium starch glycolate into a micro-osmotic core. PVP and nifedipine were processed together to give a suspension in ethanol. The drug system is sprayed onto the micro-osmotic core. The micro-osmotic core of the drug system prepared above was mixed with Sorbitol Instant P300, HPMC (K100 grade) and prepared with a solvent for granulation consisting of Eudragit NE30D (polymethacrylate copolymer dispersion) and triacetin Granulate, dry, crush the mass and finally blend with magnesium stearate. Compress the tablet with the above formula to obtain a controlled release tablet. These tablets were coated with a semipermeable polymer coating system consisting of Eudragit NE30D (polymethacrylate copolymer dispersion), HPMC E4M and triacetin. Embodiment l5: the controlled-release tablet containing verapamil hydrochloride

Effectiveness (mg/tablet) Effective 1. Sorbitol Instant P300 220 osmotic agent 2. Sodium Etanol 40 Snaping Agent 3. Verapami Hydrochloride 240 Active Component 4.PVP 60 Equipment 5. Adhesive 5. HPMC (K100) 300 hydrophilic polymer 6. SORBITOL Instant P300 50 hydraulic enhanced agent 7.Eudragit NE30D 150 hydrophobic polymer 8.Eudragit L30D 100 hydrophobic polymer 9. Gui diic acid diode 75 plasticizer 10. HPMC E4M 10 Hydrophilic polymer 11. Magnesium stearate 6.8 Lubricant

Mix Sorbitol Instant P300 and Sodium Starch Glycolate to form a micro-osmotic core. PVP and verapamil hydrochloride are processed together to obtain an aqueous solution. The drug system is sprayed onto the micro-osmotic core. Divide the drug micro-osmotic core into two parts. One part of the micro-osmotic core of the pharmaceutical system prepared above was mixed with SorbitolInstant P300, HPMC (K100 grade) and granulated with Eudragit NE30D (polymethacrylate copolymer dispersion) and triacetin Granulate with solvent, dry and break up agglomerates. The other part of the micro-osmotic core of the drug system prepared above was mixed with Sorbitol Instant P300, HPMC (K100 grade) with Eudragit L30D (polymethacrylate copolymer dispersion) and glycerol triacetate Granulation uses a solvent to make granules, dries them, and breaks up the agglomerates. Combine the material obtained in steps c and d and mix with magnesium stearate. Compress the tablet with the above formula to obtain a controlled release tablet. These tablets were coated with a semipermeable polymer coating system consisting of Eudragit NE30D (polymethacrylate copolymer dispersion), HPMC E4M and triacetin. Embodiment 16: Capsules containing verapamil hydrochloride

Effectiveness (mg/tablet) Effective 1. SorbitOl Instant P300 220 osmotic agent 2. Sodium Etanol 40 Snaping Agent 3. Verapami Hydrochloride 240 Active Component 4.PVP 6 Exfibles, Adhesive 5. HPMC (K100) 300 hydrophilic polymer 6. Sorbitol Instant P300 50 hydraulic reinforcement agent 7.Eudragit NE30D 100 hydrophobic polymer 8.Eudragit L30D 150 hydrophobic polymer 9. Guilinic acid diode 75 plasticizer 10. Talc powder Anti-caking agent

Sorbitol Instant P300 is processed together with sodium starch glycolate into a micro-osmotic core. PVP and verapamil hydrochloride are processed together to obtain an aqueous solution. The drug system is sprayed onto the micro-osmotic core. Divide the drug micro-osmotic core into two parts. One part of the micro-osmotic core of the pharmaceutical system prepared above was mixed with SorbitolInstant P300, HPMC (K100 grade) and granulated with Eudragit NE30D (polymethacrylate copolymer dispersion) and triacetin Granulate with solvent, dry and break up agglomerates. These granules were then coated with Eudragit L30D (polymethacrylate copolymer) system plasticized with dibutyl sebacate. The other part of the micro-osmotic core of the drug system prepared above was mixed with SorbitolInstant P300, HPMC (K100 grade) to form pellets, which were prepared from Eudragit L30D (polymethacrylate copolymer dispersion) and glycerol triacetate Granulation of the ester composition Use a solvent to make granules, dry, and break up the agglomerates. The materials obtained in steps c and d are combined, mixed with talc and filled into capsules.

In Examples 17-23 below, the following felodipine matrix ingredients were used:

Felodipine, USP 1.5g

Gelucire 50/13 1.5g

Pluronic F68 1.5g

Sorbitol Instant P300 4.0g

Melt the Gelucire and Pluronic together. Dissolve felodipine in the mixture and add the solution to Sorbitol Instant P300 while stirring. Mix the mixture well and let it set. The coagulated mixture was then passed through a #20 mesh screen. Example 17: In Vitro Release Profile of Felodipine Tablets with Microosmotic Core

Excipients mg/tablet supplier

HPMC E4M 112.5 Dow Chemical

Sorbitol P300 66 EMI Corporation

Avicel PH200 209.48 FMC Corporation

Felodipine Matrix 60.98 EMI Corporation

Pruv 1 Mendell Corporation

HPMC, Sorbitol Instant, Avicel and Felodipine matrices were combined. Add Pruv to the above mixture and mix the mixture well. A sample (450 mg) of the above mixture was compressed into tablets using a Carver tablet press at a pressure of 2 tons. Put each piece into a rotating basket, stir with a paddle at 50 rpm, and measure its in vitro release characteristics in 900 mL of deionized aqueous solution containing 1% sodium lauryl sulfate. Samples of the solution were taken at different times, and their absorbance at 362 nm was measured. The measurement results are shown in the following table and Fig. 1 . time (hours) t ^1/2 %freed Standard Deviation 0 0 0 2 1.41421356 20.43 3.07 4 2 38.56 3.24 6 2.44948974 55.3 3.03 8 2.82842712 70.51 4.22 10 3.16227766 86.79 6.54 12 3.46410162 95.24 1.4 According to Higuchi equation: % = Kt ^1/2 + constant tablet r slope Intercept Felodipine 0.9739667 28.60726 -10.1986

According to zero-order release: tablet r slope Intercept Felodipine 0.9952701 8.042679 4.148214 Example 18: In Vitro Release Profile of Felodipine Tablets with Microosmotic Core

Excipients mg/tablet supplier

HPMC E4M Premium CR 112.5 Dow Chemical

Sorbitol P300 67.5 EMI Corporation

Avicel PH200 212.3 FMC Corporation

Felodipine Matrix 56.7 EMI Corporation

Pruv 1 Mendell Corporation

Operate in the same manner as in Example 17 above. The results of the measurements are shown in the table below and FIG. 2 . time (hours) t ^1/2 7-8KP% release standard deviation 6-7KP% release standard deviation 0 0 0 0 0 0 2 1.41 66.59 13.5 59.88 5.33 4 2 88.9 8.13 85.88 2.27 6 2.45 95.87 2.88 99.47 2.57 8 2.83 97.79 3.64 102.06 3.38 10 3.16 97.46 3.08 101.72 3.42 12 3.46

According to Higuchi equation: % = Kt ^1/2 + constant tablet r slope Intercept 7-8KP 0.98997 40.6174942 3.335371 6-7KP 0.99881 41.2926417 0.81378

According to zero-order release: tablet r slope Intercept 7-8KP 0.91526 15.496 16.352 6-7KP 0.95079 16.2205 12.646 Embodiment 19: In vitro release characteristics of felodipine tablet

Excipients mg/tablet supplier

E4M & K100M formula:

HPMC E4M 106.88 Dow Chemical

HPMC K100M 5.62 Dow Chemical

Sorbitol P300 73.39 EMI Corporation

Avicel PH200 227.76 FMC Corporation

Felodipine Matrix 30.36 EMI Corporation

Pruv 0.99 Mendell Corporation

E4M formula:

HPMC E4M 112.5 Dow Chemical

Sorbitol P300 73.39 EMI Corporation

Avicel PH200 227.76 FMC Corporation

Felodipine Matrix 30.36 EMI Corporation

Pruv 0.99 Mendell combined the ingredients of HPMC, Sorbitol Instant, Avicel and Hydrosolve-felodipine. Add Pruv to the above mixture and mix the mixture well. A sample (445 mg) of the above mixture was compressed into tablets using a Carver tablet press at a pressure of 2 tons. Put each piece into a rotating basket, stir with a paddle at 50 rpm, and measure its in vitro release characteristics in 900 mL of deionized aqueous solution containing 1% sodium lauryl sulfate. Samples of the solution were taken at different times, and their absorbance at 362 nm was measured. The results of the measurements are shown in the table below and in FIG. 3 . time (hours) t ^1/2 95%E4M& K100M 100% E4M% release standard deviation %freed standard deviation 0 0 0 0 0 0 2 1.41 14.63 2.13 15.99 6.15 4 2 41.5 3.86 42.53 7.24 6 2.45 63.26 6.21 64.29 5.4 8 2.83 75.85 6.79 78.23 5.23 10 3.16 90.14 6.24 88.78 4.66 12 3.46 96.6 6.56 95.92 3.06

According to Higuchi equation: % = Kt ^1/2 + constant tablet r slope Intercept E4M & K100M 0.95949 29.55133836 -10.80056 E4M 0.96362 29.5771156 -10.11314

According to zero-order release: tablet r slope Intercept E4M & K100M 0.99329 10.1065 -1.018 E4M 0.99509 10.238 -0.746 Example 20: In Vitro Release Profile of Felodipine Tablets

Excipients mg/tablet supplier

HPMC E4M 101.25 Dow Chemical

HPMC K100M 11.25 Dow Chemical

Sorbitol P300 73.39 EMI Corporation

Avicel PH200 227.76 FMC Corporation

Felodipine Matrix 30.36 EMI Corporation

Pruv 0.99 Mendell

Combine HPMC, Sorbitol Instant, Avicel and Hydrosolve-Felodipine components. Add Pruv to the above mixture and mix the mixture well. A sample (445 mg) of the above mixture was compressed into tablets using a Carver tablet press at a pressure of 2 tons. Put each piece into a rotating basket, stir with a paddle at 50 rpm, and measure its in vitro release characteristics in 900 mL of deionized aqueous solution containing 1% sodium lauryl sulfate. Samples of the solution were taken at different times, and their absorbance at 362 nm was measured. The results of the measurements are shown in the table below and in FIG. 4 . time (hours) t ^1/2 HydroSolve % release Standard Deviation 0 0 0 2 1.41 19.6 3.54 4 2 36.96 2.46 6 2.45 54.39 0 8 2.83 68.86 0.62 10 3.16 79.83 3.73 12 3.46 89.04 10.54

According to Higuchi equation: % = Kt ^1/2 + constant tablet r slope Intercept Felodipine 0.9779732566 26.8444051 -8.90112

According to zero-order release: tablet r slope Intercept T ₉₀ Felodipine 0.9922566 7.49071429 4.8671429 11.3651187 Example 21: In Vitro Release Profile of Felodipine Tablets

Excipients mg/tablet supplier

K100M formula:

HPMC K100M 50.75 Dow Chemical

Sorbitol P300 33.2 EMI Corporation

AvicelPH200 103.3 FMC Corporation

Felodipine Matrix 15.18 EMI Corporation

Pruv 0.45 Mendell

E4M & K100M formula:

HPMC E4M 40.6 Dow Chemical

HPMC K100M 10.15 Dow Chemical

Sorbitol P300 33.2 EMI Corporation

Avicel PH200 103.3 FMC Corporation

Felodipine Matrix 15.18 EMI Corporation

Pruv 0.45 Mendell

Combine HPMC, Sorbitol Instant, Avicel and Hydrosolve-Felodipine components. Add Pruv to the above mixture and mix the mixture well. A sample (203 mg) of the above mixture was compressed into tablets using a Carver tablet press at a pressure of 2 tons. Put each piece into a rotating basket, stir with a paddle at 50 rpm, and measure its in vitro release characteristics in 900 mL of deionized aqueous solution containing 1% sodium lauryl sulfate. Samples of the solution were taken at different times, and their absorbance at 362 nm was measured. The results of the measurements are shown in the table below and in FIG. 5 . time (hours) t ^1/2 K100M E4M & K100M% release standard deviation %freed standard deviation 0 0 0 0 0 0 2 1.41421 15.82 2.59 18.64 2.94 4 2 34.46 2.59 46.89 7.64 6 2.44949 57.63 10.31 71.75 5.45 8 2.82843 72.32 9.79 86.44 7.38 10 3.16228 79.82 10.66 89.83 11.11

According to Higuchi equation: % = Kt ^1/2 + constant tablet r slope Intercept K100M 0.9598 26.6965209 -9.402476 E4M & K100M 0.9655 31.1539762 -9.293658

According to zero-order release: tablet r slope Intercept K100M 0.9977 9.3225 -1.244 E4M & K100M 0.9953 11.2995 -0.454 Example 22: In vitro release profile of tablets made by hydrosolve Formulation I (10% Sorbitol): Excipient mg/tablet Supplier HPMC E4M 50.75 Dow Chemical Company Sorbitol P300 33.2 EMI Company Avicel PH200 103.3 FMC Company Lodipine Matrix 15.18 EMI Pruv 0.45 Mendell

Combine HPMC, Sorbitol Instant, Avicel and Hydrosolve-Felodipine components. Add Pruv to the above mixture and mix the mixture well. A sample (203 mg) of the above mixture was compressed into tablets using a Carver tablet press at a pressure of 2 tons. Put each piece into a rotating basket, stir with a paddle at 50 rpm, and measure its in vitro release characteristics in 900 mL of deionized aqueous solution containing 1% sodium lauryl sulfate. Samples of the solution were taken at different times, and their absorbance at 362 nm was measured. The results of the measurements are shown in the table below and in FIG. 6 . time (hours) t ^1/2 HydroSolve % release Standard Deviation 0 0 0 0 2 1.414213562 53.41 3.89 4 2 85.31 6.06 6 2.449489743 98.33 1.76 8 2.828427125 101.75 1.76 9 3 101.75 1.76 10 3.15227766

According to Higuchi equation: % = Kt ^1/2 + constant tablet r slope Intercept Felodipine 0.9907336 38.00593 1.6895071

According to zero-order release: tablet r slope Intercept Felodipine 0.9261162 12.421 18.076 Example 23: In vitro release characteristics of felodipine tablets Excipient mg/tablet Supplier HPMC E4M 62.19 Dow Chemical Company Sorbitol P300 30.45 EMI Company Avicel PH200 94.73 FMC Company Felodipine Matrix 15.18 EMI Company Pruv 0.45 Mendell Company

Combine HPMC, Sorbitol Instant, Avicel and Hydrosolve-Felodipine components. Add Pruv to the above mixture and mix the mixture well. A sample (203 mg) of the above mixture was compressed into tablets using a Carver tablet press at a pressure of 2 tons. Put each piece into a rotating basket, stir with a paddle at 50 rpm, and measure its in vitro release characteristics in 900 mL of deionized aqueous solution containing 1% sodium lauryl sulfate. Samples of the solution were taken at different times, and their absorbance at 362 nm was measured. The results of the measurements are shown in the table below and in FIG. 7 . time (hours) t ^1/2 HydroSolve % release 0 0 0 2 1.41421356 20.27 4 2 48.65 6 2.4494897 67.12

According to Higuchi equation: % = Kt ^1/2 + constant tablet r slope Intercept Felodipine 0.9723567 31.17882739 -9.19942

According to the zero-order release method: tablet r slope Intercept Felodipine 0.9897404 9.729285714 3.755238

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for the corresponding reactants and/or operating conditions in the preceding examples.

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, the foregoing preferred embodiments should be considered as illustrations only, and should not be regarded as any limitation to the present invention.

All patent applications, patents and publications cited herein are hereby incorporated by reference in their entirety.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims (21)

1. pharmaceutical compositions, it comprises:

The core of pastille, the core of this pastille scribble little infiltration core of one deck ingredient above being,

Wherein, described little infiltration core comprises at least a little penetrating agent, and described ingredient comprises at least a therapeutic agent.

2. pharmaceutical compositions as claimed in claim 1, wherein, at least a little penetrating agent is Sorbitol, mannitol, xylitol or sodium chloride.

3. pharmaceutical compositions as claimed in claim 1, wherein, described little infiltration core also comprises at least a sweller or at least a gellant.

4. pharmaceutical compositions as claimed in claim 1, wherein, at least a portion of at least a Patent Office in the described ingredient is solid solution.

5. pharmaceutical compositions as claimed in claim 4, wherein, described ingredient comprises glyceride composition and the polyoxypropylene-polyoxyethylene block copolymer composition of handling through Polyethylene Glycol.

6. pharmaceutical compositions as claimed in claim 5 wherein, is solid solution at least a portion d mixture of at least a therapeutic agent, and this mixture comprises glyceride composition and the polyoxypropylene-polyoxyethylene block copolymer composition of handling through Polyethylene Glycol.

7. pharmaceutical compositions as claimed in claim 6, wherein, the described a part of therapeutic agent that is solid solution accounts for the 30-100% of the therapeutic agent in the ingredient.

8. pharmaceutical compositions as claimed in claim 6, wherein, the core of described pastille is surrounded by the polymer coat.

9. pharmaceutical compositions as claimed in claim 6, wherein, the core of described pastille mixes with polymeric matrix.

10. pharmaceutical compositions as claimed in claim 6, wherein, the core of described pastille is surrounded by the macromolecule coat and mixes with polymeric matrix.

11. pharmaceutical compositions as claimed in claim 1, wherein, the diameter of the core of described pastille is 2 μ m to 3mm.

12. pharmaceutical compositions as claimed in claim 6, wherein, described therapeutic agent is a dihydropyridine compounds.

13. at least a therapeutic agent is released into the method for physiology target site, and it may further comprise the steps:

Provide claim 6 described pharmaceutical compositions;

The pharmaceutical compositions of pharmacy effective dose is imported the physiology target site.

14. method as claimed in claim 13, wherein, described physiology target site is an intestines and stomach.

15. at least a therapeutic agent is released into the method for physiology target site, and it may further comprise the steps:

Provide claim 7 described pharmaceutical compositions;

The pharmaceutical compositions of pharmacy effective dose is imported the physiology target site.

16. method as claimed in claim 15, wherein, described physiology target site is an intestines and stomach.

17. at least a therapeutic agent is released into the method for physiology target site, and it may further comprise the steps:

Provide claim 1 described pharmaceutical compositions;

The pharmaceutical compositions of pharmacy effective dose is imported the physiology target site.

18. the method for preparation pharmaceutical compositions, it may further comprise the steps:

Prepare little infiltration core,

Painting medicine composition on this little infiltration core.

19. method as claimed in claim 18, wherein, described ingredient comprises glyceride composition and the polyoxypropylene-polyoxyethylene block copolymer mixture of ingredients of handling through Polyethylene Glycol.

20. method as claimed in claim 19, wherein, at least a portion of at least a therapeutic agent is solid solution in mixture.

21. method as claimed in claim 20, wherein, the part of described at least a therapeutic agent accounts for 30-100%.

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