CN102166201B - Oral ciclosporin A sustained-release agent and preparation method thereof - Google Patents

Abstract

An oral cyclosporine A sustained-release preparation, which includes the following mass components: 1 part of cyclosporine A; 2.5-7.5 parts of povidone-K30; 0.15-4.82 parts of hypromellose 4000cPa.s; microcrystalline 0.1-3.94 parts of cellulose; 0-2.57 parts of hypromellose 15000cPa.s, 0.1-1.0 parts of phospholipids. The present invention combines the solid dispersion technology with the sustained-release hydrophilic gel skeleton technology, and prepares the insoluble drug cyclosporine A sustained-release preparation according to the principle of "dual-release drug" that is quick-release first and then slow-release. The solubility of cyclosporine A is improved, and the sustained-release preparations take effect quickly after oral administration, and then release steadily and slowly. Cyclosporine A sustained-release tablets reduce the peak and valley phenomenon of blood concentration, and the frequency of medication decreases. The invention discloses its preparation method.

Description

Oral cyclosporine A sustained-release preparation and preparation method thereof

technical field

The invention relates to an oral slow-release preparation of an insoluble drug and a preparation method thereof, in particular to an oral cyclosporine A sustained-release preparation and a preparation method thereof.

Background technique

Sustained/controlled release preparations (sustained/controlled release preparations) have the advantages of reducing the peak and valley phenomenon of blood concentration, reducing the number of medications and side effects, and improving patient compliance, etc., and are increasingly widely used in clinical practice. The preparation of slow/controlled release preparations usually requires dissolving the drug first, then adding slow/controlled release excipients, and using appropriate technology to make slow/controlled release preparations. Water-soluble drugs are easy to dissolve in water and can be easily made into slow/controlled release preparations. Currently, there are many varieties on the market. For poorly water-soluble drugs, if conventional slow/controlled release technology is used to prepare sustained-release preparations, due to the low solubility of the drug, less dissolution, and low drug concentration in the body, it is difficult to maintain the therapeutic concentration. Solubilization technology is usually required to increase the solubility of the drug first. Then use the solubilized materials as raw materials to prepare slow/controlled release preparations, that is, solubilize first and then slow release.

The solubilization technology of poorly soluble drugs mainly includes: solid dispersion technology, cyclodextrin inclusion technology, micellar solubilization, microemulsion solubilization, etc. Sustained/controlled release preparations for insoluble drugs can be divided into different types due to different drug release mechanisms: matrix preparations, osmotic pump preparations, membrane-controlled sustained-release preparations, sustained-release cyclodextrin inclusion complexes, sustained-release solid dispersions, etc. . Solid dispersion technology (solid dispersion, SD) is an effective method to improve the solubility and bioavailability of poorly soluble drugs. The significant advantage of using it to prepare sustained/controlled release preparations is that it can be directly prepared or made into an immediate release solid first. Dispersion, and then use the immediate-release solid dispersion as a raw material, and select slow/controlled release materials to prepare slow/controlled release preparations. (See: Ma Miaorui, Wu Mi, Zhang Lixia, Application of solid dispersion technology in sustained and controlled release preparations, Henan Chemical Industry, 2010, 27 (1): 3; Zhang Huiping, Xiang Daxiong, Luo Jieying, Liu Wei, Solid dispersion technology in pharmacy Research progress in Chinese Pharmaceutical Journal, 2007, 42 (11): 807; Zhen-ping Wei, Shi-rui Mao, Dian-zhou Bi, etal. Dissolution improvement of cisapride by solid dispersion with HPMC. Journal of Chinese Pharmaceutical Science . Industrial production.

Cyclosporine A (English name: Cyclosporine A, Cyclosporin A) its chemical name is cyclo[[(E)-(2S,3R.4R)-3-hydroxy-4-methyl-2(methylamino)-6- Octene]-L-2aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L- Alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl], molecular formula C ₆₂ H ₁₁₁ N ₁₁ O ₁₂ ; molecular weight 1202.63, has the following chemical structure,

Cyclosporin A is a lipophilic cyclic polypeptide extracted from the fungus (Tolypocladium Inflatum Gams) in 1772. It consists of 11 amino acids and is insoluble in water with a melting point of 148-151°C. In 1976, it was discovered that cyclosporin A has immunosuppressive effect, and it is a strong immunosuppressant. It was used in kidney transplant patients in 1978, and has been widely used in clinical organ transplantation since the 1980s to improve post-transplantation. Survival rate has become one of the most important immunosuppressants at present.

Cyclosporine A is currently marketed in the form of soft capsules, oral liquids and injections. It is emulsified in the body when it encounters water to form a microemulsion, which increases the apparent solubility of the drug and facilitates the absorption of the drug. Chinese patent 02112110 (disclosure date December 31, 2003) discloses the "microemulsified pre-concentrated oral liquid containing cyclosporin A" which is composed of cyclosporin A, absolute ethanol, polyoxyethylene hydrogenated castor oil, oil acid, propylene glycol. The oral liquid prepared by this formula is uniformly dispersed in water to form a nearly transparent microemulsion solution. But the disadvantage is that although the solubilizer polyoxyethylene castor oil contained in it is a good carrier of lipophilic drugs, it can produce a series of biological and physiological side effects, such as nephrotoxicity, allergic reactions, hyperlipidemia, and erythrocyte aggregation , Peripheral neuritis, etc.

Chinese patent 200710026135 (disclosure date: February 27, 2008) discloses "a self-microemulsifying soft capsule of cyclosporin A and its preparation method" which is composed of cyclosporine A, absolute ethanol, propylene glycol, polyoxygen Ethylene hydrogenated castor oil, Span-80 and medium-chain fatty acid triglycerides are heated and dissolved in a homogeneous emulsification pot to make soft capsules. The prepared soft capsule can overcome the bad properties of cyclosporine A such as low bioavailability, large difference in bioavailability among individuals, and the like. However, the preparation process of soft capsules is complicated, and liquid alcohol solvents are prone to volatilize through the capsule shell during storage, which accelerates the cross-linking and curing reaction of capsule shell gelatin and makes the disintegration time limit unqualified.

Chinese Patent No. 99102848 (disclosure date September 13, 2000) discloses "a pharmaceutical composition containing cyclosporine A" consisting of active ingredients, solvents or surfactant auxiliaries, solubilizers, and medium- and long-chain Saturated or unsaturated fatty acids, substituted carboxylic acids and other medicinal organic acids or a mixture of one or more acids or fish oil, although some improvements have been made in the process of this patented formula, but there are many defects in the formula components, which One defect will cause complicated preparation process and cost increase of corresponding products.

Relatively speaking, solid preparations are convenient to manufacture and easy to store in technology, but because the problem of too low solubility of cyclosporin A has not been solved, the most common solid dosage form in medicine has not yet appeared on the market.

The present invention combines the solid dispersion technology with the sustained-release hydrophilic gel skeleton technology, and prepares the insoluble drug cyclosporine A sustained-release preparation according to the principle of "dual-release drug" that is quick-release first and then slow-release, which significantly improves the cyclosporine A sustained-release preparation. The solubility of sporin A realizes the characteristics of rapid onset of effect of the sustained-release preparation after oral administration, and then stable and slow drug release.

Contents of the invention

The present invention selects water-soluble carrier material povidone (PVP), adopts solvent method to prepare cyclosporin A quick-release solid dispersion, utilizes solid dispersion technology to improve the solubility of insoluble drug cyclosporine A; The immediate-release solid dispersion was used as the raw material, and the matrix-type material hypromellose (HPMC) with sustained-release effect was selected, and the hydrogel matrix-type sustained-release preparation was prepared by wet granulation. Based on the "dual-release drug" mechanism of rapid release and sustained release, the present invention provides an oral cyclosporine A sustained-release drug with stable drug release, high bioavailability, less administration times, good patient compliance, and good stability. release preparations.

Technical scheme of the present invention is as follows:

An oral cyclosporine A sustained-release preparation, which comprises the following quality components:

Cyclosporine A 1 part; Povidone-K30 2.5-7.5 parts;

Hypromellose 4000cPa.s 0.15~4.82 parts; Microcrystalline cellulose 0.1~3.94 parts;

Hypromellose 15000cPa.s 0-2.57 parts, phospholipids 0.1-1.0 parts.

In the mass component composition of the above-mentioned oral cyclosporin A sustained-release preparation, 0.1-1.0 parts of phospholipids can be added in order to increase the solubility and in vivo absorption of cyclosporin A.

In the mass component composition of the oral cyclosporine A sustained-release preparation mentioned above, 0-2.57 parts of hypromellose 15000cPa.s and hypromellose 4000cPa.s can be added to the sustained-release matrix material.

The above-mentioned oral cyclosporine A sustained-release preparation can add 0.1 to 1.0 parts of poloxamer 188 in its mass component composition, the purpose of which is to make cyclosporine A have a better dissolution rate and bioavailability.

A method for preparing oral cyclosporine A sustained-release preparation, which consists of the following steps:

Step 1. Accurately weigh cyclosporine A, povidone-K30, phospholipids, and poloxamer 188 according to the above formula, dissolve them in absolute ethanol, put them in a water bath at 60°C, 90rmp rotary evaporation until nearly dry, and place them in a water bath at 70°C Completely evaporate the solvent, place in a -20°C refrigerator for 2 hours, then place in a 60°C vacuum oven for 12 hours, pulverize, pass through an 80-mesh sieve to obtain a solid dispersion, and set aside;

Step 2. Take the solid dispersion obtained in step 1, mix with hypromellose 4000cPa.s, hypromellose 15000cPa.s, and microcrystalline cellulose, add 70% syrup to prepare soft material, and pass through a 16-mesh sieve The obtained wet granules were baked in an oven at 60° C. for 30 minutes, taken out, sieved through a 16-mesh sieve for sizing, and compressed into tablets to obtain oral cyclosporine A sustained-release preparations.

The schematic flow sheet of preparation process of the present invention sees Fig. 1

In the oral cyclosporine A sustained-release preparation of the present invention, the water-soluble carrier materials in the prescription can be selected from PVP, polyethylene glycol (PEG), poloxamer 188, etc., and after screening, PVP-K30 is preferred; in order to increase cyclosporine A solubility and in vivo absorption, adding phospholipids to the solid dispersion; in order to increase the dissolution rate and bioavailability of the drug, add poloxamer 188; slow-release matrix materials can choose hypromellose (HPMC), sodium alginate , Carbomer, acrylic resin, etc. After screening, HPMC4000cPa.s is preferred, and HPMC15000cPa.s is used in appropriate amount. In order to meet the requirements of preparing tablets, it is preferable to add microcrystalline cellulose (MCC); the binder is preferably 70% syrup.

The beneficial effects of the present invention are:

1. The present invention combines the solid dispersion technology with the sustained-release hydrophilic gel matrix technology, and prepares the insoluble drug cyclosporine A sustained-release preparation according to the principle of "dual-release drug" of rapid release first and then slow release, which has significant advantages It improves the solubility of cyclosporine A, and realizes that the sustained-release formulation takes effect quickly after oral administration, and then releases the drug steadily and slowly. The experimental results are as follows: water, artificial gastric juice, artificial intestinal juice, and 0.1% SDS at pH 6.8 were used to conduct solubility tests on cyclosporin A raw material and drug-containing solid dispersion. The results showed that: compared with cyclosporine A raw material , the multiples of solubility increase of the drug-containing solid dispersion in the above four media are 3.17, 37.21, 21.26, and 112.54 in turn; the in vitro drug release curve of cyclosporin A solid dispersion in the dissolution medium is shown in Figure 2, and the results show: The cumulative drug release of the prepared solid dispersion in the dissolution medium reached 88.5%, reflecting the rapid release behavior. The cyclosporine A sustained-release tablet prepared by solid dispersion, its in vitro drug release curve is shown in Figure 3, the results show that: the sustained-release tablet has a constant release rate in the simulated in vivo medium, and the drug release in vitro conforms to the Higuchi kinetic equation, and the cumulative release in 24 hours The drug dosage is more than 80% (conforming to the quality requirements of sustained-release tablets), with obvious sustained-release characteristics.

2. The cyclosporine A sustained-release tablets prepared by the present invention can promote the in vivo absorption of cyclosporine A due to the addition of phospholipids when preparing the immediate-release solid dispersion, thereby improving the bioavailability of cyclosporine A sustained-release tablets In addition, cyclosporine A sustained-release tablets reduce the peak and valley phenomenon of blood concentration, and reduce the number of medications. Cyclosporine A sustained-release tablets and contrast preparations were orally administered to dogs, and the drug-time curve was measured, the results are shown in Figure 4.

3. The preparation method adopted in the present invention is simple, does not require special equipment, and the auxiliary materials are easy to obtain, the price is cheap, there are few influencing factors in the preparation process, the reproducibility is good, and it is easy for industrial production.

Description of drawings

Fig. 1 is a schematic flow chart of the preparation process of the present invention.

Fig. 2 is the in vitro release curve of cyclosporin A solid dispersion.

Fig. 3 is the in vitro drug release curve of the cyclosporin A sustained-release tablet of the present invention.

Fig. 4 is the drug-time curve of oral administration of cyclosporine A sustained-release tablet of the present invention and the same dose of the control preparation to Beagle dogs.

Detailed ways

Materials and equipment used in the following examples are:

Experimental materials: cyclosporine A (provided by Yangzijiang Pharmaceutical Group), phospholipids (Shanghai Taiwei Pharmaceutical Co., Ltd.), povidone-K30 (PVP-K30) (Shanghai Changwei Pharmaceutical Materials Co., Ltd.), poloxa Mu 188 (Shanghai Changwei Pharmaceutical Materials Co., Ltd.), hypromellose 4000cPa.s (HPMC4000cPa.s) (Shanghai Changwei Pharmaceutical Materials Co., Ltd.), hypromellose 15000cPa.s (HPMC15000cPa.s) (Shanghai Changwei Pharmaceutical Materials Co., Ltd.), microcrystalline cellulose (MCC), 70% syrup (Sinopharm Chemical Reagent Co., Ltd.), polyethylene glycol 4000 (PEG4000) (Qingdao Tianliyuan Biological Co., Ltd.), no Water ethanol (Chengdu Kelong Reagent Chemical Factory).

Experimental equipment: single-punch tablet press (Shanghai Tianxiang Pharmaceutical Machinery Factory), drug dissolution apparatus (D-800 Tianjin University Radio Factory), rotary evaporator (Heidolph Company, Germany), constant temperature water bath (Jiangsu Jintan Medical Instrument Factory) , stability test box (US 3M company), liquid chromatography (including: 510 pump, Shim-pak C ₁₈ column, 486 UV detector) (US Waters company), desktop high-speed refrigerated centrifuge (Biofuge Stratos Hereaus Germany) .

Example 1.

1. Accurately weigh 1g of cyclosporin A, 2.5g of povidone-K30, 0.1g of phospholipid, and 1.0g of poloxamer 188, add 20ml of absolute ethanol to dissolve, put in a water bath at 60°C, 90rmp rotary evaporation until nearly dry, The solvent was completely evaporated in a water bath at 70°C, placed in a -20°C refrigerator for 2 hours, then placed in a vacuum oven at 60°C for 12 hours, pulverized, and passed through an 80-mesh sieve to obtain a solid dispersion for future use.

2. Weigh 2.6g of solid dispersion, mix with hypromellose 4000cPa.s2.41g, microcrystalline cellulose 1g, add 70% syrup to prepare soft material, pass through a 16 mesh sieve to obtain wet granules, and store at 60°C After baking in an oven for 30 minutes, take it out, pass through a 16-mesh sieve for granulation, and press into tablets with a pressure of 4 to 5 kg to obtain about 20 sustained-release tablets.

3. The experimental results are as follows: Water, artificial gastric juice, artificial intestinal juice, and 0.1% SDS at pH 6.8 were used to test the solubility of cyclosporin A raw material and drug-containing solid dispersion. The results showed that: In contrast, the solubility enhancement times of the drug-containing solid dispersion in the above four media are 3.17, 37.21, 21.26, and 112.54 in turn; the in vitro drug release curve of the cyclosporine A solid dispersion in the dissolution medium is shown in Figure 2,

4. The in vitro release curve of cyclosporine A sustained-release tablets prepared by solid dispersion is shown in Figure 3. The results show that the release rate of the sustained-release tablets in the simulated in vivo medium is constant, and the in vitro drug release conforms to the Higuchi kinetic equation, 24h The cumulative drug release amount is more than 80% (meeting the quality requirements for sustained-release tablets), and has obvious sustained-release characteristics.

Example 2

1. Accurately weigh 1g of cyclosporine A, 3.5g of povidone-K30, 0.35g of phospholipids, and 0.45g of poloxamer 188, add 20ml of absolute ethanol to dissolve, put in a 60°C water bath, 90rmp rotary evaporation to nearly dry, The solvent was completely evaporated in a water bath at 70°C, placed in a -20°C refrigerator for 2 hours, then placed in a vacuum oven at 60°C for 12 hours, pulverized, and passed through an 80-mesh sieve to obtain a solid dispersion for future use.

2. Weigh 2.65g of solid dispersion, mix with hypromellose 4000cPa.s1g, hypromellose 15000cPa.s1.285g, microcrystalline cellulose 1.97g and mix evenly, add 70% syrup to prepare soft material, pass Wet granules were obtained through a 16-mesh sieve, dried in an oven at 60°C for 30 minutes, taken out, passed through a 16-mesh sieve for sizing, and compressed into tablets with a pressure controlled at 4 to 5 kg to obtain about 19 sustained-release tablets. The obtained sustained-release tablet has a constant release rate in the simulated in vivo medium, and the drug release in vitro conforms to Higuchi's kinetic equation, and the cumulative drug release amount reaches more than 80% in 24 hours, which has obvious sustained-release characteristics. After in vivo administration of Beagle dogs, its plasma drug concentration over time curve has obvious slow-release characteristics compared with the reference preparation. (See Figure 4)

Example 3

1. Accurately weigh 1g of cyclosporin A, 4.5g of povidone-K30, 0.55g of phospholipid, and 0.55g of poloxamer 188, add 20ml of absolute ethanol to dissolve, put in a 60℃ water bath, and 90rmp rotary evaporation to nearly dryness. The solvent was completely evaporated in a water bath at 70°C, placed in a -20°C refrigerator for 2 hours, then placed in a vacuum oven at 60°C for 12 hours, pulverized, and passed through an 80-mesh sieve to obtain a solid dispersion for future use.

2. Weigh 3.3g of solid dispersion, mix with hypromellose 4000cPa.s1.5g, hypromellose 15000cPa.s0.75g, microcrystalline cellulose 1.5g, add 70% syrup to prepare soft material , passed through a 16-mesh sieve to obtain wet granules, baked in an oven at 60°C for 30 minutes, took them out, passed through a 16-mesh sieve for sizing, and pressed into tablets with a pressure controlled at 4-5kg to obtain about 19 sustained-release tablets.

3. The solubility and in vitro drug release performance of cyclosporine A solid dispersion in dissolution medium are similar to embodiment 1.

4. Cyclosporine A sustained release tablet, its in vitro drug release performance is like embodiment 1.

Example 4

1. Accurately weigh 1g of cyclosporine A, 5.5g of povidone-K30, 0.65g of phospholipid, and 0.45g of poloxamer 188, add 20ml of absolute ethanol to dissolve, put in a water bath at 60°C, 90rmp rotary evaporation to near dryness, The solvent was completely evaporated in a water bath at 70°C, placed in a -20°C refrigerator for 2 hours, then placed in a vacuum oven at 60°C for 12 hours, pulverized, and passed through an 80-mesh sieve to obtain a solid dispersion for future use.

2. Weigh 3.8g of solid dispersion, mix with hypromellose 4000cPa.s2g, hypromellose 15000cPa.s0.5g, microcrystalline cellulose 0.05g and mix evenly, add 70% syrup to prepare soft material, pass Wet granules were obtained through a 16-mesh sieve, dried in an oven at 60°C for 30 minutes, taken out, passed through a 16-mesh sieve for sizing, and compressed into tablets with a pressure controlled at 4 to 5 kg to obtain about 19 sustained-release tablets.

3. The solubility and in vitro drug release performance of cyclosporine A solid dispersion in dissolution medium are similar to embodiment 1.

4. Cyclosporine A sustained release tablet, its in vitro drug release performance is like embodiment 1.

Example 5

1. Accurately weigh 1g of cyclosporine A, 6.5g of povidone-K30, 0.75g of phospholipid, and 0.75g of poloxamer 188, add 20ml of absolute ethanol to dissolve, put in a water bath at 60°C, 90rmp rotary evaporation to nearly dryness, The solvent was completely evaporated in a water bath at 70°C, placed in a -20°C refrigerator for 2 hours, then placed in a vacuum oven at 60°C for 12 hours, pulverized, and passed through an 80-mesh sieve to obtain a solid dispersion for future use.

2. Weigh 4.0g of solid dispersion, mix with hypromellose 4000cPa.s1.5g, hypromellose 15000cPa.s0.4g, microcrystalline cellulose 1.25g, add 70% syrup to prepare soft material , passed through a 16-mesh sieve to obtain wet granules, baked in an oven at 60°C for 30 minutes, took them out, passed through a 16-mesh sieve for granulation, and pressed into tablets with a pressure of 4-5kg to obtain about 17 sustained-release tablets.

3. The solubility and in vitro drug release performance of cyclosporine A solid dispersion in dissolution medium are similar to embodiment 1.

4. Cyclosporine A sustained release tablet, its in vitro drug release performance is like embodiment 1.

Example 6

1. Accurately weigh 1g of cyclosporin A, 7.5g of povidone-K30, 1.0g of phospholipid, and 0.1g of poloxamer 188, add 20ml of absolute ethanol to dissolve, put in a water bath at 60°C, 90rmp rotary evaporation to near dryness, The solvent was completely evaporated in a water bath at 70°C, placed in a -20°C refrigerator for 2 hours, then placed in a vacuum oven at 60°C for 12 hours, pulverized, and passed through an 80-mesh sieve to obtain a solid dispersion for future use.

2. Weigh 4.9g of solid dispersion, mix with hypromellose 4000cPa.s0.5g, hypromellose 15000cPa.s0.125g, microcrystalline cellulose 0.5g, add 70% syrup to prepare soft material , passed through a 16-mesh sieve to obtain wet granules, baked in an oven at 60°C for 30 minutes, took them out, passed through a 16-mesh sieve for sizing, and pressed into tablets with a pressure controlled at 4-5kg to obtain about 20 sustained-release tablets.

3. The solubility and in vitro drug release performance of cyclosporine A solid dispersion in dissolution medium are similar to embodiment 1.

4. Cyclosporine A sustained release tablet, its in vitro drug release performance is like embodiment 1.

Claims (3)

1. an oral cyclosporine A sustained-release preparation, characterized in that it comprises the following quality components: Cyclosporine A 1 part; Povidone-K30 2.5-7.5 parts; Hypromellose 4000cPa.s 0.15~4.82 parts; Microcrystalline cellulose 0.1~3.94 parts; Hypromellose 15000cPa.s 0～2.57 parts, Phospholipids 0.1～1.0 parts; It is prepared as follows: Step 1. Accurately weigh cyclosporin A, povidone-K30, and phospholipids according to the above formula, dissolve them in absolute ethanol, put them in a 60°C water bath, and 90rmp rotary evaporation to nearly dryness, completely evaporate the solvent in a 70°C water bath, and place Place in -20°C refrigerator for 2 hours, then place in 60°C vacuum oven for 12 hours, pulverize, pass through 80-mesh sieve to obtain solid dispersion, and set aside; Step 2. Take the solid dispersion obtained in step 1 and mix it with hypromellose 4000cPa.s, hypromellose 15000cPa.s and microcrystalline cellulose according to the above components, and then add 70% syrup to prepare soft material. Pass through a 16-mesh sieve to obtain wet granules, bake in an oven at 60°C for 30 minutes, take them out, pass through a 16-mesh sieve for granulation, and compress into tablets to obtain oral cyclosporine A sustained-release preparations. 2. The oral cyclosporine A sustained-release preparation according to claim 1, characterized in that: 0.1-1.0 parts of poloxamer 188 is added to its mass component composition. 3. A method for preparing the oral cyclosporine A sustained-release preparation as claimed in claim 2, characterized in that it consists of the following steps: Step 1. Accurately weigh cyclosporin A, povidone-K30, phospholipids, and poloxamer 188 according to the formula described in claim 2, and dissolve them in absolute ethanol, then put them in a 60°C water bath, and 90rmp rotary evaporation to nearly dryness. Completely evaporate the solvent in a water bath at 70°C, place in a -20°C refrigerator for 2 hours, then place in a vacuum oven at 60°C for 12 hours, pulverize, pass through an 80-mesh sieve to obtain a solid dispersion, and set aside; Step 2. Take the solid dispersion obtained in step 1 and mix it with hypromellose 4000cPa.s, hypromellose 15000cPa.s and microcrystalline cellulose according to claim 2, and then add 70% syrup to prepare soft Material, passed through a 16-mesh sieve to obtain wet granules, dried in an oven at 60°C for 30 minutes, taken out, passed through a 16-mesh sieve for granulation, and compressed into tablets to obtain an oral cyclosporine A sustained-release preparation.

Images