CN115919793A - Orlistat capsule preparation and preparation method thereof - Google Patents

Abstract

The invention discloses an orlistat capsule preparation which is prepared by uniformly mixing orlistat and a carrier, preparing solid dispersion powder by spray drying, uniformly mixing the solid dispersion powder and auxiliary materials, granulating by a wet method, extruding, rounding, drying, sieving, adding a lubricant, mixing and filling into capsules. The orlistat and the carrier are prepared into solid dispersion powder by spray drying, the spray drying has strong mixing property, good continuous operability and lower process temperature, the uniformity of the particle size of the solid dispersion powder can be ensured, the solid dispersion powder and the auxiliary materials are prepared into pellets by adopting wet granulation and extrusion spheronization technologies, the problems that the production is difficult to smoothly carry out and the dissolution behavior of the product is influenced due to the excessively low melting point of the orlistat are solved, the industrialized mass production is realized, the solubility, the temperature resistance and the moisture resistance of the orlistat and the release degree of the orlistat in vivo are improved, and the bioavailability of the drug is ensured to meet the requirements of clinical use.

Description

Orlistat capsule preparation and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to an orlistat capsule preparation and a preparation method thereof.

Background

Orlistat is the best weight-reducing product sold worldwide at present, a strong and long-acting specific gastrointestinal lipase inhibitor, through blocking the human body to the absorption of fat in the food directly, make human body's ingested heat energy and fat less than consuming, thus the fat in vivo is reduced naturally, achieve the goal of losing weight. Compared with other weight-losing products, orlistat does not enter blood circulation, does not act on central nerves, and has fewer side effects.

However, orlistat belongs to group iv in the biopharmaceutical classification system, is a drug with poor water solubility, has low solubility, is not beneficial to release of orlistat after oral administration, causes reduction of bioavailability, and affects clinical efficacy. Common preparation technologies for solving the problem of poor water solubility of the insoluble drug include nano crystallization, micronization, solid dispersion technology and the like. Although the nano crystallization technology can obviously improve the water solubility of orlistat and improve the bioavailability, orlistat has poor stability and is easy to recrystallize, so that the storage time is short, and the industrial mass production is difficult, so that the nano crystallization technology is only suitable for small-batch production in laboratories. The limited extent of particle size reduction of the drug by micronisation techniques can lead to difficulties in handling subsequent formulations, increased hydrophobicity of the powder and possible re-agglomeration, leading to reduced wettability of the powder. However, the conventional methods for preparing solid dispersions include a solvent method, a melting method, a solvent-melting method, etc., but the conventional methods have complicated preparation processes, and all require the drug and the carrier to be prepared in a molten state, which easily causes thermal decomposition of the drug and the carrier, thereby limiting the wide application of the methods.

Orlistat is white to off-white crystalline powder, odorless, and has a melting point of 40-48 ℃, and when the temperature is higher than the melting point, orlistat dissolves into oily liquid and then is subjected to crystal transformation. We found during the production of orlistat formulations: 1. because the melting point of orlistat is low, heat is inevitably generated in the production process due to the action of mechanical friction force during batch production, and if the temperature exceeds the melting point of orlistat, orlistat in a preparation product is melted, so that the product properties are changed, the production is difficult to smoothly carry out, and the dissolution behavior of the product is influenced; 2. the orlistat is difficult to place under high temperature conditions due to the low melting point of the orlistat, and because the high temperature conditions can cause partial melting of the orlistat, the dissolution rate is reduced, so that the stability of the product and the bioavailability in vivo are influenced; 3. orlistat capsules are sensitive to humidity and easy to absorb moisture, and the dissolution rate of the drug can be obviously reduced under high humidity conditions, thereby greatly influencing the stability of the product.

Disclosure of Invention

The invention aims to solve the technical problem that aiming at the defects of the prior art, the orlistat capsule preparation and the preparation method thereof are provided, the solubility of orlistat and the release degree of orlistat in vivo can be improved, and the bioavailability of the drug is ensured to meet the requirements of clinical use.

The technical scheme adopted by the invention for solving the technical problems is as follows: an orlistat capsule is prepared by uniformly mixing orlistat and a carrier, preparing solid dispersion powder by spray drying, uniformly mixing the solid dispersion powder and auxiliary materials, granulating by a wet method, extruding, rolling, drying, sieving, adding a lubricant, mixing, and filling into capsules.

The orlistat capsule preparation is prepared by preparing the orlistat and the carrier into solid dispersion powder through spray drying, wherein the spray drying has the advantages of strong mixing property, good continuous operability and lower process temperature, and can ensure the uniformity of the particle size of the solid dispersion powder.

Preferably, the weight ratio of each component of the capsule preparation in the prescription is as follows: 40-60% of orlistat, 3-10% of carrier and 37-50% of auxiliary material, wherein the carrier is polyvinylpyrrolidone, and the weight ratio of orlistat to carrier in the prescription is 1 (0.1-3).

Preferably, the auxiliary materials comprise a surfactant, a filler, a disintegrating agent and a binder. The improvement of the process is combined with the optimization of the types of the auxiliary materials, so that the stability of the medicine can be further improved, and the dissolution behavior of the medicine is not obviously changed.

Preferably, the surfactant is one of poloxamer 188, sodium lauryl sulfate and polysorbate 80, and sodium lauryl sulfate is further preferred.

Preferably, the filler is one of lactose, cyclodextrin, pregelatinized starch, microcrystalline cellulose and mannitol, and more preferably microcrystalline cellulose.

In order to improve the moisture resistance of the product, the disintegrating agent is preferably one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch. Preferably, the disintegrant is croscarmellose sodium, and the problems of reduced disintegration performance, reduced dissolution rate and poor stability of the product caused by moisture absorption can be effectively improved.

Preferably, the binder is one of polyvinylpyrrolidone and hydroxypropyl cellulose, and is further preferably polyvinylpyrrolidone K30.

Preferably, the lubricant is one of talc, magnesium stearate and sodium stearyl fumarate, and further preferably talc.

The preparation method of the orlistat capsule preparation comprises the following steps:

1) After mixing orlistat and a carrier uniformly, adding the mixture into a water-containing ethanol solution, and stirring the mixture until the mixture is clear to obtain a medicine-containing mixed solution, wherein the ratio of the volume of the ethanol to the total weight of orlistat and the carrier is 1mL (1-2) mg, the volume ratio of ethanol to water in the water-containing ethanol solution is (2-4) to 1, and the further preferable ratio is 3;

2) Spray drying the medicine-containing mixed solution, wherein the process conditions of the spray drying are as follows: drying at the air inlet temperature of 30-40 ℃, and sieving to obtain orlistat solid dispersion powder;

3) Mixing orlistat solid dispersion powder and auxiliary materials uniformly, granulating by a wet method to obtain a wet soft material, pouring the wet soft material into an extrusion spheronizer for extrusion and spheronization, wherein the extrusion speed is 40-60 r/min, the spheronization speed is 300-600 r/min, and the spheronization time is 20-120 s to obtain pellets; then drying the pellets, wherein the drying temperature is not more than 35 ℃; then sieving the pellets by using 16-mesh and 60-mesh screens in sequence to obtain 16-60-mesh pellets; finally, the sieved pellets are mixed with a lubricant in a hopper of a mixer, and the mixture is filled into capsules.

Compared with the prior art, the invention has the following advantages:

(1) The orlistat capsule preparation has the advantages of simple preparation process, easy operation, good reproducibility, high production efficiency and capability of realizing industrial batch production of the orlistat capsule preparation;

(2) The orlistat is prepared into pellets, and the orlistat is loaded by the carrier, so that the stability of the orlistat is high under normal storage conditions, and the orlistat cannot be recrystallized under the action of the carrier;

(3) The orlistat capsule preparation has good temperature resistance and moisture resistance, can not melt under high temperature conditions, can not reduce the disintegration performance under high humidity conditions, and can not influence the dissolution behavior of products.

Drawings

FIG. 1 is a comparison graph of appearance inspection of the content of original preparation and capsule of the examples and the comparative examples;

FIG. 2 is a 0-day dissolution profile of orlistat capsules prepared from the original formulation and the examples and comparative examples;

FIG. 3 is a graph showing the dissolution of orlistat capsules prepared by the original formulation and examples and comparative examples after leaving the capsules under high humidity (92.5% RH) for 28 days;

FIG. 4 is a graph showing the dissolution profile of orlistat capsules prepared by the original formulation and examples and comparative examples after being left at high temperature (40 ℃ C.) for 28 days.

Detailed Description

The invention is described in further detail below with reference to the following examples of the drawings.

The prescription of the orlistat capsule formulation of example 1 and the effects of the components are shown in table 1.

TABLE 1

Name(s)	Function of	Dosage of
			Orlistat	Active ingredient	150g
Microcrystalline cellulose	Filler	102g
			Croscarmellose sodium	Disintegrating agent	18g
Sodium dodecyl sulfate	Surface active agent	9g
			Polyvinylpyrrolidone K30	Carrier	15g
Polyvinylpyrrolidone K30	Adhesive agent	6g
			Talcum powder	Lubricant, static electricity removal	0.3g

The method for preparing the orlistat capsule formulation of example 1, comprising the steps of:

1) After orlistat and a carrier (15 g of polyvinylpyrrolidone K30) are uniformly mixed, adding the mixture into 180mL of aqueous ethanol solution, and stirring the mixture until the mixture is clear to obtain a medicine-containing mixed solution, wherein the ratio of the volume of the ethanol to the total weight of orlistat and the carrier is 1mL (1-2) mg, and the volume ratio of ethanol to water in the aqueous ethanol solution is 3;

2) Spray drying the mixed solution containing the medicine, wherein the process conditions of the spray drying are as follows: drying at 35-40 deg.c and sieving with 60 mesh sieve to obtain orlistat solid dispersion powder;

3) After mixing orlistat solid dispersion powder, microcrystalline cellulose and croscarmellose sodium uniformly, adding a proper amount of clear aqueous solution containing 9g of sodium dodecyl sulfate and 6g of polyvinylpyrrolidone K30, mixing uniformly and granulating by a wet method to obtain a wet soft material, pouring the wet soft material into an extrusion spheronizer for extrusion and spheronization, wherein the extrusion speed is 40-60 r/min, the spheronization speed is 300-600 r/min, and the spheronization time is 20-120 s to obtain pellets; then drying the pellets, wherein the drying temperature is not more than 35 ℃; then sieving the pellets by using 16-mesh and 60-mesh screens in sequence to obtain 16-60-mesh pellets; finally, mixing the sieved pellets with the talcum powder in a hopper of a mixing machine, and filling capsules with the filling amount of 118-123 mg.

The prescription of orlistat capsule preparation of example 2 and the effects of each component are shown in table 2.

TABLE 2

Name (R)	Function of	Dosage of
			Orlistat	Active ingredient	150g
Microcrystalline cellulose	Filler	102g
			Carboxymethylstarch sodium salt	Disintegrating agent	18g
Sodium dodecyl sulfate	Surface active agent	9g
			Polyvinylpyrrolidone K30	Carrier	15g
Polyvinylpyrrolidone K30	Adhesive agent	6g
			Talcum powder	Lubricant, static electricity removal	0.3g

The method for preparing orlistat capsule formulation of embodiment 2, comprising the steps of:

1) After orlistat and a carrier (15 g of polyvinylpyrrolidone K30) are uniformly mixed, adding the mixture into 180mL of aqueous ethanol solution, and stirring the mixture until the mixture is clear to obtain a medicine-containing mixed solution, wherein the ratio of the volume of the ethanol to the total weight of orlistat and the carrier is 1mL (1-2) mg, and the volume ratio of ethanol to water in the aqueous ethanol solution is 3;

2) Spray drying the mixed solution containing the medicine, wherein the process conditions of the spray drying are as follows: drying at 35 deg.C, and sieving with 60 mesh sieve to obtain orlistat solid dispersion powder;

3) After mixing orlistat solid dispersion powder with microcrystalline cellulose and carboxymethyl starch sodium uniformly, adding a proper amount of clear aqueous solution containing 9g of sodium dodecyl sulfate and 6g of polyvinylpyrrolidone K30, mixing uniformly and granulating by a wet method to obtain a wet soft material, pouring the wet soft material into an extrusion spheronizer for extrusion and spheronization, wherein the extrusion speed is 40-60 r/min, the spheronization speed is 300-600 r/min, and the spheronization time is 20-120 s to obtain pellets; then drying the pellets, wherein the drying temperature is not more than 35 ℃; then sieving the pellets by using 16-mesh and 60-mesh screens in sequence to obtain 16-60-mesh pellets; finally, mixing the sieved pellets with the talcum powder in a hopper of a mixer, and filling capsules with the capsule filling amount of 118-123 mg.

The prescription of orlistat capsule formulation of example 3 and the effect of each component are shown in table 3.

TABLE 3

Name(s)	Action	Amount of the composition
			Orlistat	Active ingredient	150g
Lactose	Filler	102g
			Croscarmellose sodium	Disintegrating agent	18g
Sodium dodecyl sulfate	Surface active agent	9g
			Polyvinylpyrrolidone K30	Carrier	15g
Polyvinylpyrrolidone K30	Adhesive agent	6g
			Talcum powder	Lubricant, static electricity removal	0.3g

The method for preparing orlistat capsule formulation of embodiment 3, comprising the steps of:

1) After orlistat and a carrier (15 g of polyvinylpyrrolidone K30) are uniformly mixed, adding the mixture into 180mL of aqueous ethanol solution, and stirring the mixture until the mixture is clear to obtain a medicine-containing mixed solution, wherein the ratio of the volume of the ethanol to the total weight of orlistat and the carrier is 1mL (1-2) mg, and the volume ratio of ethanol to water in the aqueous ethanol solution is 3;

2) Spray drying the medicine-containing mixed solution, wherein the process conditions of the spray drying are as follows: drying at 35 deg.C, and sieving with 60 mesh sieve to obtain orlistat solid dispersion powder;

3) Mixing orlistat solid dispersion powder with lactose and croscarmellose sodium uniformly, adding a proper amount of clear aqueous solution containing 9g of sodium dodecyl sulfate and 6g of polyvinylpyrrolidone K30, mixing uniformly and granulating by a wet method to obtain a wet soft material, pouring the wet soft material into an extrusion rounding machine for extrusion and rounding, wherein the extrusion speed is 40-60 r/min, the rounding speed is 300-600 r/min, and the rounding time is 20-120 s to obtain pellets; then drying the pellets, wherein the drying temperature is not more than 35 ℃; then sieving the pellets by using 16-mesh and 60-mesh screens in sequence to obtain 16-60-mesh pellets; finally, mixing the sieved pellets with the talcum powder in a hopper of a mixer, and filling capsules with the capsule filling amount of 118-123 mg.

For comparison, orlistat capsule formulations of comparative example 1, comparative example 2 were prepared using known conventional methods and compared with the original commercially available formulations. The original trituration was from GlaxoSmithKline Consumer Healthcare, spec: 60mg, batch number: 35998.

the formulation of orlistat capsule preparation of comparative example 1 and the effects of each component are shown in table 4.

TABLE 4

Name (R)	Function of	Dosage of
			Orlistat	Active ingredient	150g
Microcrystalline cellulose	Filler	108g
			Croscarmellose sodium	Disintegrating agent	18g
Sodium dodecyl sulfate	Surface active agent	9g
			Polyvinylpyrrolidone K30	Adhesive agent	15g
Talcum powder	Lubricant, static electricity removal	0.3g

The preparation method of orlistat capsule formulation of comparative example 1, comprising the steps of:

1) After orlistat, microcrystalline cellulose and croscarmellose sodium are uniformly mixed, a proper amount of clear aqueous solution containing 9g of sodium dodecyl sulfate and 15g of polyvinylpyrrolidone K30 is added, the mixture is uniformly mixed and granulated by a wet method to obtain a wet soft material, the wet soft material is poured into an extrusion spheronizer for extrusion and spheronization, the extrusion speed is 40-60 r/min, the spheronization speed is 300-600 r/min, and the spheronization time is 20-120 s to obtain pellets;

2) Drying the pellets at a temperature of not more than 35 ℃; then sieving the pellets by using 16-mesh and 60-mesh screens in sequence to obtain 16-60-mesh pellets; finally, mixing the sieved pellets with the talcum powder in a hopper of a mixer, and filling capsules with the capsule filling amount of 118-123 mg.

The prescription of orlistat capsule formulation of comparative example 2 and the effects of each component are shown in table 5.

TABLE 5

Name (R)	Function of	Dosage of
			Orlistat	Active ingredient	150g
Microcrystalline cellulose	Filler	108g
			Sodium starch glycolate	Disintegrating agent	18g
Sodium dodecyl sulfate	Surface active agent	9g
			Polyvinylpyrrolidone K30	Adhesive agent	15g
Talcum powder	Lubricant, static electricity removal	0.3g

The method for preparing the orlistat capsule formulation of comparative example 2, comprising the steps of:

1) After orlistat, microcrystalline cellulose and carboxymethyl starch sodium are uniformly mixed, a proper amount of clear aqueous solution containing 9g of sodium dodecyl sulfate and 15g of polyvinylpyrrolidone K30 is added, the mixture is uniformly mixed and granulated by a wet method to obtain a wet soft material, the wet soft material is poured into an extrusion spheronizer for extrusion and spheronization, the extrusion speed is 40-60 r/min, the spheronization speed is 300-600 r/min, and the spheronization time is 20-120 s to obtain pellets;

2) Drying the pellets at a temperature of not more than 35 ℃; then sieving the pellets by using 16-mesh and 60-mesh screens in sequence to obtain 16-60-mesh pellets; finally, mixing the sieved pellets with the talcum powder in a hopper of a mixing machine, and filling capsules with the filling amount of 118-123 mg.

The original formulation, examples 1 to 3, and comparative examples 1 to 2 were subjected to appearance inspection, and dissolution behavior thereof was measured, respectively, and the results are shown in table 6. The comparison of the appearance inspection of the capsule contents of the original preparation and examples and comparative examples is shown in FIG. 1, the dissolution profile of 0 day is shown in FIG. 2, the dissolution profile of 28 days when the capsule is left under high humidity (92.5% RH) conditions is shown in FIG. 3, and the dissolution profile of 28 days when the capsule is left under high temperature (40 ℃) conditions is shown in FIG. 4.

TABLE 6

The comparison can be concluded as follows:

1. comparative examples 1 to 2 and comparative examples 1 to 2 show that the disintegrant which is croscarmellose sodium is more helpful to improve the problems of reduced disintegration performance, reduced dissolution rate and poor stability of the product caused by moisture absorption than carboxymethyl starch sodium;

2. comparative examples 1 and 3 show that the use of microcrystalline cellulose as filler increases pellet moldability more than lactose and the pellet roundness is high;

3. compared with the comparative example 1, the preparation method of the invention can improve the problems that the orlistat on the surface of the pellet melts due to the fact that the orlistat generates heat during mass production because the melting point of the orlistat is too low, and further the product properties are changed, so that the production is difficult to smoothly carry out, and can increase the stability of the orlistat product under the high-temperature condition.

Claims (10)

1. The orlistat capsule preparation is characterized by being prepared by uniformly mixing orlistat and a carrier, then preparing solid dispersion powder by spray drying, uniformly mixing the solid dispersion powder with auxiliary materials, granulating by a wet method, extruding, rounding, drying, sieving, adding a lubricant, mixing and filling into capsules.

2. The orlistat capsule preparation according to claim 1, wherein the weight ratio of the components in the capsule preparation in the prescription is as follows: 40-60% of orlistat, 3-10% of carrier and 37-50% of auxiliary material, wherein the carrier is polyvinylpyrrolidone, and the weight ratio of orlistat to carrier in the prescription is 1 (0.1-3).

3. The orlistat capsule formulation of claim 2, wherein the excipients comprise a surfactant, a filler, a disintegrant, and a binder.

4. The orlistat capsule formulation of claim 3 wherein the surfactant is one of poloxamer 188, sodium lauryl sulfate, and polysorbate 80.

5. The orlistat capsule formulation of claim 3, wherein the filler is one of lactose, cyclodextrin, pregelatinized starch, microcrystalline cellulose, and mannitol.

6. The orlistat capsule formulation of claim 3, wherein the disintegrant is one of crospovidone, croscarmellose sodium, and sodium starch glycolate.

7. The orlistat capsule formulation of claim 6, wherein the disintegrant is croscarmellose sodium.

8. The orlistat capsule formulation according to claim 3, wherein the binder is one of polyvinylpyrrolidone and hydroxypropylcellulose.

9. The orlistat capsule formulation of claim 1, wherein the lubricant is one of talc, magnesium stearate and sodium stearyl fumarate.

10. The process for preparing orlistat capsule formulation according to any one of claims 1 to 9, comprising the steps of:

1) After orlistat and carrier are mixed evenly, the mixture is added into aqueous ethanol solution and stirred to be clear, and medicine-containing mixed solution is obtained, wherein the ratio of the volume of the ethanol to the total weight of orlistat and carrier is 1mL (1-2) mg, and the volume ratio of ethanol to water in the aqueous ethanol solution is (2-4): 1;

2) Spray drying the medicine-containing mixed solution, wherein the process conditions of the spray drying are as follows: drying at the air inlet temperature of 30-40 ℃, and sieving to obtain orlistat solid dispersion powder;

3) Mixing orlistat solid dispersion powder and auxiliary materials uniformly, granulating by a wet method to obtain a wet soft material, pouring the wet soft material into an extrusion spheronizer for extrusion and spheronization, wherein the extrusion speed is 40-60 r/min, the spheronization speed is 300-600 r/min, and the spheronization time is 20-120 s to obtain pellets; then drying the pellets, wherein the drying temperature is not more than 35 ℃; then sieving the pellets by using 16-mesh and 60-mesh screens in sequence to obtain 16-60-mesh pellets; finally, the sieved pellets are mixed with a lubricant in a hopper of a mixer, and the mixture is filled into capsules.

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