A special controlled-release oral preparation based on compound lactose and its preparation method

Abstract

The present invention belongs to the field of biomedicine technology, and specifically relates to a special controlled-release oral preparation based on compound lactose and a preparation method thereof. The method comprises the following steps: grinding lactose, sieving lactose, and anhydrous lactose are mixed evenly to obtain a compound lactose carrier, and then the drug is loaded on the compound lactose carrier, and a coating is applied to obtain a special controlled-release oral preparation based on compound lactose. The present invention coats a layer of coating with a sustained-release effect on the surface of the compound lactose carrier, and can control the drug release rate by responding to the microenvironment. In addition, the present invention also analyzes the physical properties of grinding lactose, sieving lactose, and anhydrous lactose, such as particle size, crystallinity, solubility, etc., and designs the lactose compounding ratio based on the drug release requirements, thereby realizing accurate control and optimization of the drug rate. The controlled-release oral preparation of the present invention also has the advantages of strong stability and high encapsulation rate.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and specifically relates to a special controlled-release oral preparation based on compound lactose and a preparation method thereof. Background Art

[0002] Controlled-release preparations have been an important development direction of the pharmaceutical industry at home and abroad in recent years. Controlled-release preparations refer to a dosage form in which the drug can slowly dissolve after entering the human body and maintain a relatively stable blood drug concentration in the body. The drug release process is easily affected by external factors, so it is necessary to reasonably control the drug solubility and drug dissolution rate so that the actual effect of the drug can reach the expected level. This type of controlled-release preparation has the advantages of fewer dosing times, longer duration of action, higher bioavailability, and fewer side effects, and has become a hot topic in modern drug preparation research.

[0003] At present, the controlled-release preparations used in clinical practice mainly include tablets, capsules or coated preparations, pellets and liposome preparations, oral liquids, and injectable controlled-release preparations. Among them, tablets are the most commonly used dosage form in clinical practice; capsules or coated preparations can prevent drugs from being affected by light, air, and moisture and destroying the efficacy, and can also cover up the bad smell of drugs and improve drug compliance; pellets and liposome preparations can not only play a controlled-release role, but also improve the efficacy, reduce toxic side effects, solidify liquid drugs, and facilitate storage; oral liquids use liquid preparations as carriers, have a large dispersion, and high bioavailability; injectable controlled-release preparations mainly achieve the purpose of sustained and controlled release through local injection. However, the solubility of different drugs varies greatly, and there are currently no reports on controlled-release oral preparations that can meet a variety of drug delivery needs, that is, existing controlled-release oral preparations cannot meet a variety of drug delivery needs. Based on the above problems, it is urgent to develop a new type of controlled-release oral preparation to meet a variety of drug delivery needs. Summary of the invention

[0004] The first object of the present invention is to provide a method for preparing a special controlled-release oral preparation based on compound lactose, which is simple to prepare and easy to operate and suitable for industrial production.

[0005] The second object of the present invention is to provide a special controlled-release oral preparation based on compound lactose to accurately control the release rate of the drug.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is:

[0007] A method for preparing a special controlled-release oral preparation based on compound lactose, comprising the following steps:

[0008] The ground lactose, sieved lactose and anhydrous lactose are mixed evenly to prepare a compound lactose carrier, and then the drug is loaded on the compound lactose carrier and coated to prepare a special controlled-release oral preparation based on the compound lactose;

[0009] The preparation process of the coating is as follows:

[0010] I. mixing a water-soluble polyol polymer material and a water-soluble polyamine polymer material uniformly, dissolving them in deionized water, and then adding polyvinyl pyrrolidone-co-vinyl acetate and polyacrylic acid to obtain a mixed solution 1;

[0011] II. Under catalyst conditions, diisocyanate is added to the mixed solution 1 of step I to obtain a mixed solution 2;

[0012] III. The mixed solution 2 of step II is added to the precipitant to obtain a gel-like substance, the gel-like substance is dissolved in an organic solvent, and a cross-linking agent is added under acidic conditions to obtain a mixed solution 3;

[0013] IV. Add the mixed solution 3 of step III to deionized water to prepare a coating.

[0014] Furthermore, the mass ratio of the water-soluble polyol polymer material, the water-soluble polyamine polymer material, polyvinyl pyrrolidone-co-vinyl acetate, polyacrylic acid, diisocyanate, and cross-linking agent is 1: (0.5-1.5): (0.5-1.5): (0.5-1.5): (2-5): (1.5-3).

[0015] Furthermore, the water-soluble polyol polymer material is selected from one of polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl cellulose, and polyethylene aniline; the water-soluble polyamine polymer material is selected from one of polylysine, poly(vinylamide-co-diallylamine), polyethylene glycol-modified polyamine, polyethyleneimine, and polyetheramine; and the cross-linking agent is selected from one or two of 1,4-butanediol diglycidyl ether, propylene glycol diglycidyl ether, triglycerol polyether, and aminoethyl ether glyceryl ether.

[0016] Furthermore, the diisocyanate is selected from one or two of dimethyl sulfoxide isocyanate, methacrylate isocyanate, and dipropylene glycol diisocyanate, the amount of the catalyst used accounts for 0.2%-2% of the amount of diisocyanate used, and the catalyst is selected from one of dibutyltin diacetic acid, tri-n-butylphosphine, and triphenylphosphine.

[0017] Furthermore, in step (III), the volume ratio of the mixed solution 2 to the precipitant is 1:(2-4), the precipitant is selected from one of methanol, ethanol, and propanol, the organic solvent is selected from one or two of dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, and acetone, and the pH value under the acidic conditions is 3-6.

[0018] Furthermore, the mass ratio of the ground lactose, sieved lactose and anhydrous lactose is (1-3): (3-6): (1-3).

[0019] Furthermore, the mass ratio of the drug, the compound lactose carrier, and the coating is 1:(1-3):(0.2-1.5), and the drug is a drug for treating cardiovascular and cerebrovascular diseases.

[0020] Furthermore, the drug is ginkgolide.

[0021] Furthermore, the controlled-release oral preparation is in the form of a tablet or a capsule.

[0022] A special controlled-release oral preparation based on compound lactose is prepared by the above-mentioned preparation method.

[0023] Compared with the prior art, the beneficial effects of the present invention are mainly:

[0024] (1) The present invention coats a layer of sustained-release coating on the surface of the composite lactose carrier, and the coating is obtained by isocyanating water-soluble polyol polymer materials, water-soluble polyamine polymer materials, polyvinyl pyrrolidone-co-vinyl acetate, polyacrylic acid and diisocyanate under the catalytic action of a catalyst, introducing a large number of amino groups and hydroxyl groups, and the amino groups and hydroxyl groups undergo condensation reaction with a cross-linking agent under acidic conditions, and finally obtaining a coating with a cross-linked structure. The coating with the above structure can control the drug release rate by responding to the microenvironment.

[0025] (2) The present invention analyzes the physical properties of ground lactose, sieved lactose, and anhydrous lactose, such as particle size, crystallinity, solubility, etc., designs the lactose compounding ratio based on the drug release requirements, and thus achieves precise control and optimization of the drug rate. DETAILED DESCRIPTION

[0026] The technical scheme of the present invention is further described below in conjunction with specific embodiments. However, it should be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the present invention. The specific conditions not specified in the examples are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, unless otherwise specified, are conventional products obtained through commercial channels.

[0027] Example 1

[0028] This embodiment provides a method for preparing a special controlled-release oral preparation based on compound lactose, and the detailed preparation process is as follows:

[0029] Weigh 1g of ground lactose, 3g of sieved lactose, and 1g of anhydrous lactose, and mix them evenly to prepare a composite lactose carrier. Then, 2.5g of ginkgolide and 2.5g of the composite lactose carrier are mixed through a 100-mesh sieve, loaded into a wet granulator, the speed is adjusted to 300rpm, and mixed for 3 times, each time for 10min, to load the ginkgolide on the composite lactose carrier, dissolve 2.5g of the coating in 95% ethanol solution to obtain a coating solution (20wt%), and use the above coating solution to coat the composite lactose carrier loaded with ginkgolide by fluidized bed spray drying, and tablet press to prepare a tablet controlled-release oral preparation.

[0030] The preparation process of the coating is as follows:

[0031] I. 10 g of polyvinyl alcohol and 10 g of polylysine were mixed evenly, dissolved in 500 mL of deionized water, and then 5 g of polyvinyl pyrrolidone-co-vinyl acetate and 5 g of polyacrylic acid were added to obtain a mixed solution 1;

[0032] II. To the mixed solution of step I 1 was added 20 g of dimethyl sulfoxide isocyanate, 0.2 g of dibutyltin diacetic acid to obtain a mixed solution 2;

[0033] III. The mixed solution 2 of step II was added to 1 L of methanol to obtain a gel-like substance, the gel-like substance was dissolved in dimethyl sulfoxide, and 15 g of 1,4-butanediol diglycidyl ether was added at pH 5 to obtain a mixed solution 3;

[0034] IV. Add the mixed solution 3 of step III to 2 L of deionized water, filter, wash, and dry in a vacuum drying oven at 60°C for 24 hours to obtain a coating.

[0035] This embodiment also provides a special controlled-release oral preparation based on compound lactose, which is prepared by the above method.

[0036] Example 2

[0037] This embodiment provides a method for preparing a special controlled-release oral preparation based on compound lactose, and the detailed preparation process is as follows:

[0038] Weigh 0.4 g of ground lactose, 1 g of sieved lactose, and 0.4 g of anhydrous lactose, and mix them evenly to prepare a composite lactose carrier. Then, 0.6 g of ginkgolide and 1.2 g of the composite lactose carrier are mixed through a 100-mesh sieve, loaded into a wet granulator, the speed is adjusted to 300 rpm, and mixed for 3 times, each time for 10 min. The ginkgolide is loaded on the composite lactose carrier, 0.12 g of the coating is dissolved in 95% ethanol solution to obtain a coating solution (20 wt%), and the composite lactose carrier loaded with ginkgolide is coated with the above coating solution by fluidized bed spray drying, and filled into capsules to prepare a capsule controlled-release oral preparation.

[0039] The preparation process of the coating is as follows:

[0040] I. 10 g of polyvinyl pyrrolidone and 5 g of polyvinyl aniline were mixed evenly, dissolved in 500 mL of deionized water, and then 10 g of polyvinyl pyrrolidone-co-vinyl acetate and 10 g of polyacrylic acid were added to obtain a mixed solution 1;

[0041] II. To the mixed solution of step I 1 was added 30 g of isocyanate methacrylate and 0.06 g of triphenylphosphine to obtain a mixed solution 2;

[0042] III. The mixed solution 2 of step II was added to 1.5 L of ethanol to obtain a gel-like substance, the gel-like substance was dissolved in a mixed solution of tetrahydrofuran and acetone, and 20 g of aminoethyl ether glycerol ether was added at pH 3 to obtain a mixed solution 3;

[0043] IV. Add the mixed solution 3 of step III to 2 L of deionized water, filter, wash, and dry in a vacuum drying oven at 60°C for 24 hours to obtain a coating.

[0044] This embodiment also provides a special controlled-release oral preparation based on compound lactose, which is prepared by the above method.

[0045] Example 3

[0046] This embodiment provides a method for preparing a special controlled-release oral preparation based on compound lactose, and the detailed preparation process is as follows:

[0047] Weigh 1.2 g of ground lactose, 2.4 g of sieved lactose, and 1.2 g of anhydrous lactose, and mix them evenly to prepare a composite lactose carrier. Then, 1.2 g of ginkgolide and 3.6 g of the composite lactose carrier are mixed through a 100-mesh sieve, loaded into a wet granulator, the speed is adjusted to 300 rpm, and mixed for 3 times, each time for 10 min, to load the ginkgolide on the composite lactose carrier, dissolve 1.8 g of the coating in 95% ethanol solution to obtain a coating solution (20 wt %), and use the above coating solution to coat the composite lactose carrier loaded with ginkgolide by fluidized bed spray drying, and tablet press to prepare a tablet controlled-release oral preparation.

[0048] The preparation process of the coating is as follows:

[0049] I. 10 g of hydroxypropyl cellulose and 15 g of polyetheramine were mixed evenly, dissolved in 500 mL of deionized water, and then 15 g of polyvinyl pyrrolidone-co-vinyl acetate and 15 g of polyacrylic acid were added to obtain a mixed solution 1;

[0050] II. To the mixed solution of step I 1 was added 50g of a mixture of isocyanate methacrylate and dipropylene glycol diisocyanate, 1g of tri-n-butylphosphine to obtain a mixed solution 2;

[0051] III. The mixed solution 2 of step II was added to 2L of propanol to obtain a gel-like substance, the gel-like substance was dissolved in N,N-dimethylformamide, and 30g of a mixture of propylene glycol diglycidyl ether and triglycerol polyether was added at pH 6 to obtain a mixed solution 3;

[0052] IV. Add the mixed solution 3 of step III to 2 L of deionized water, filter, wash, and dry in a vacuum drying oven at 60°C for 24 hours to obtain a coating.

[0053] This embodiment also provides a special controlled-release oral preparation based on compound lactose, which is prepared by the above method.

[0054] Comparative Example 1

[0055] The difference between this comparative example and Example 1 is that no polylysine is added in step I of the coating preparation process.

[0056] Comparative Example 2

[0057] The difference between this comparative example and Example 1 is that no polyvinyl alcohol is added in step I of the coating preparation process, and the amount of polylysine is adjusted to 20 g.

[0058] Comparative Example 3

[0059] The difference between this comparative example and Example 1 is that no polylysine is added in step I of the coating preparation process, and the amount of polyvinyl alcohol is adjusted to 20 g.

[0060] Comparative Example 4

[0061] This comparative example is different from Example 1 in that polyvinyl pyrrolidone is used to replace polyvinyl pyrrolidone-co-vinyl acetate in step I of the coating preparation process.

[0062] Comparative Example 5

[0063] The difference between this comparative example and Example 1 is that no polyvinyl pyrrolidone-co-vinyl acetate is added in step I of the coating preparation process.

[0064] Comparative Example 6

[0065] The difference between this comparative example and Example 1 is that no polyvinyl pyrrolidone-co-vinyl acetate is added in step I of the coating preparation process, and the amount of polyacrylic acid is adjusted to 10 g.

[0066] Comparative Example 7

[0067] The difference between this comparative example and Example 1 is that no polyacrylic acid is added in step I of the coating preparation process, and the amount of polyvinyl pyrrolidone-co-vinyl acetate is adjusted to 10 g.

[0068] Comparative Example 8

[0069] The difference between this comparative example and Example 1 is that 5 g of sieved lactose is used to prepare a single carrier, and the rest is the same as Example 1.

[0070] Comparative Example 9

[0071] The difference between this comparative example and Example 1 is that 1.5 g of ground lactose and 3.5 g of sieved lactose are used to prepare the ground lactose and sieved lactose composite carrier, and the rest is the same as Example 1.

[0072] The properties of the controlled-release oral preparation prepared by the present invention are tested as follows.

[0073] 1. Dissolution of Controlled Release Oral Preparations

[0074] The dissolution of ginkgolide in the controlled-release oral preparations prepared in Examples 1-3 and Comparative Examples 1-9 was tested, and the specific process was as follows:

[0075] The controlled-release oral preparations prepared in Examples 1-3 and Comparative Examples 1-9 were dissolved in 1 L of water, and samples were taken at 0 h, 2 h, 4 h, 8 h, 12 h, 18 h, and 24 h, respectively. The solubility of ginkgolide in each sample was detected by HPLC. The results are shown in Table 1.

[0076] Table 1

[0077] Group / Dissolution (%) 0h 2h 4h 8h 12h 18h 24h Example 1 0 15.4 29.3 48.6 72.7 87.9 96.8 Example 2 0 14.6 28.9 48.0 72.1 87.4 96.2 Example 3 0 14.1 27.6 47.9 71.3 86.5 95.6 Comparative Example 1 0 32.5 53.7 82.6 97.4 99.2 / Comparative Example 2 0 28.6 51.9 80.7 96.5 98.4 / Comparative Example 3 0 30.3 53.1 81.4 96.9 98.7 / Comparative Example 4 0 23.4 42.2 70.5 93.6 98.1 99.8 Comparative Example 5 0 40.5 58.6 87.9 99.3 / / Comparative Example 6 0 39.4 57.3 87.1 98.9 / / Comparative Example 7 0 37.0 56.4 85.6 98.7 / / Comparative Example 8 0 21.3 37.7 64.2 91.1 97.9 99.6 Comparative Example 9 0 19.5 35.8 62.4 89.6 97.8 98.3

[0078] It can be seen from Table 1 that the ginkgolide in the controlled-release oral preparation provided by the present invention can be stably and continuously released in vivo. Further analysis of the reasons shows that the present invention is to introduce a large amount of amino and hydroxyl groups by isocyanate reaction of water-soluble polyol polymer materials (polyvinyl alcohol), water-soluble polyamine polymer materials (polylysine), polyvinyl pyrrolidone-co-vinyl acetate, polyacrylic acid and isocyanate under the catalytic action of a catalyst, and finally obtain a coating with a cross-linked structure by condensation reaction of amino and hydroxyl groups with a cross-linking agent under acidic conditions. The coating with the above structure can control the drug release rate by responding to the microenvironment. In addition, the compounding of lactose of different particle sizes and crystallinity can further achieve accurate control and optimization of drug rate.

[0079] 2. Stability of controlled-release oral preparations

[0080] The stability of the controlled-release oral preparations prepared in Examples 1-3 and Comparative Examples 1-9 was tested, and the specific process was as follows:

[0081] The controlled-release oral preparations prepared in Examples 1-3 and Comparative Examples 1-9 were subjected to long-term and accelerated experiments. The conditions for the long-term experiment were set as follows: temperature of 30°C and relative humidity of 70%, and the conditions for the accelerated experiment were set as follows: temperature of 40°C and relative humidity of 80%. The content of ginkgolide in the controlled-release oral preparations was detected at certain time periods, and the stability was evaluated by the change in the content of ginkgolide. The calculation formula was as follows: (mass after storage / mass before storage)×100%. The results are shown in Table 2.

[0082] Table 2

[0083]

[0084]

[0085] It can be seen from Table 2 that after long-term and accelerated experiments, the controlled-release oral preparation of the present invention has a higher drug content than that of Comparative Examples 1-9, that is, the controlled-release oral preparation of the present invention has high stability.

[0086] 3. Encapsulation efficiency of controlled release oral preparations

[0087] The encapsulation efficiency of the controlled-release oral preparations prepared in Examples 1-3 was tested, and the specific process was as follows:

[0088] The controlled release oral preparation prepared in Example 1-3 was dissolved in 50 mL of anhydrous ethanol and stirred at 80 rpm for 20 min. The concentration of ginkgolide in the solution was detected. Encapsulation efficiency = (drug loading / drug amount) × 100%. The results are shown in Table 3.

[0089] Table 3

[0090] Group Encapsulation rate (%) Example 1 96.7 Example 2 93.6 Example 3 92.4

[0091] It can be seen from Table 3 that the controlled-release oral preparation prepared by the present invention has a high encapsulation rate. That is, the present invention can achieve a high drug coverage rate and can accurately quantify the content of the drug in the preparation, which is conducive to the application of controlled-release drug preparations.

[0092] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them. The basic principles and main features of the present invention have been described above with specific implementation schemes. On the basis of the present invention, some modifications or replacements may be made thereto, but these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of protection claimed by the present invention.

Claims

1. A method for preparing a special controlled-release oral preparation based on compound lactose, characterized in that: The following steps are involved: The ground lactose, sieved lactose and anhydrous lactose are mixed evenly to prepare a compound lactose carrier, and then the drug is loaded on the compound lactose carrier and coated to prepare a special controlled-release oral preparation based on the compound lactose; The preparation process of the coating is as follows: I. mixing a water-soluble polyol polymer material and a water-soluble polyamine polymer material uniformly, dissolving them in deionized water, and then adding polyvinyl pyrrolidone-co-vinyl acetate and polyacrylic acid to obtain a mixed solution 1; II. Under catalyst conditions, diisocyanate is added to the mixed solution 1 of step I to obtain a mixed solution 2; III. The mixed solution 2 of step II is added to the precipitant to obtain a gel-like substance, the gel-like substance is dissolved in an organic solvent, and a cross-linking agent is added under acidic conditions to obtain a mixed solution 3; IV. The mixed solution 3 of step III is added to deionized water, filtered and dried to obtain a coating; The mass ratio of the water-soluble polyol polymer material, the water-soluble polyamine polymer material, polyvinyl pyrrolidone-co-vinyl acetate, polyacrylic acid, diisocyanate, and crosslinking agent is 1: (0.5-1.5): (0.5-1.5): (0.5-1.5): (2-5): (1.5-3); The water-soluble polyol polymer material is selected from polyvinyl alcohol or hydroxypropyl cellulose, the water-soluble polyamine polymer material is selected from one of polylysine, polyethylene aniline, and polyether amine, and the cross-linking agent is selected from one or two of 1,4-butanediol diglycidyl ether, propylene glycol diglycidyl ether, triglycerol polyether, and aminoethyl ether glyceryl ether; The diisocyanate is selected from one or two of dimethyl sulfoxide isocyanate, methacrylate isocyanate, and dipropylene glycol diisocyanate; the amount of the catalyst used accounts for 0.2%-2% of the amount of the diisocyanate used; the catalyst is selected from one of dibutyltin diacetic acid, tri-n-butylphosphine, and triphenylphosphine; the mass ratio of the ground lactose, sieved lactose, and anhydrous lactose is (1-3): (3-6): (1-3); the mass ratio of the drug, the compound lactose carrier, and the coating is 1: (1-3): (0.2-1.5), and the drug is a drug for treating cardiovascular and cerebrovascular diseases; the drug is ginkgolide; The dosage form of the controlled-release oral preparation is tablet or capsule.

2. The method for preparing the special controlled-release oral preparation based on compound lactose according to claim 1, characterized in that: In step III, the volume ratio of the mixed solution 2 to the precipitant is 1:(2-4), the precipitant is selected from one of methanol, ethanol, and propanol, the organic solvent is selected from one or two of dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, and acetone, and the pH value under the acidic conditions is 3-6.

3. A special controlled-release oral preparation based on compound lactose, characterized in that: The preparation method according to claim 1 or 2 is used for preparation.

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