CN103222964B - Orlistat oral preparation and preparation method thereof - Google Patents

Abstract

An orlistat oral preparation and a preparation method thereof. The invention discloses an orlistat tablet, which is composed of an orlistat acrylic resin solid dispersion, a disintegrant and other pharmaceutically acceptable adjuvants, the orlistat acrylic resin solid The dispersion is prepared by supercritical fluid rapid expansion method, and D90<10μm. The present invention uses supercritical technology to micronize raw materials, and at the same time coats the surface of orlistat with a layer of inert material, which successfully solves the problem of low dissolution rate of preparations prepared in the prior art, and solves the problem of stickiness in the tableting process. Chong problem.

Description

Orlistat oral preparation and preparation method thereof

technical field

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an orlistat oral preparation and a preparation method thereof.

Background technique

Orlistat is a long-acting and potent specific gastrointestinal lipase inhibitor that inactivates the enzymes by forming a covalent bond with the active serine sites of gastric and pancreatic lipases in the lumen of the stomach and small intestine. Fat in food cannot be decomposed into free fatty acids, so fat cannot be absorbed and utilized, thereby reducing calorie intake and controlling body weight. The drug does not need to be absorbed systemically to exert its efficacy, and is rarely absorbed through the gastrointestinal tract, so its blood concentration is extremely low. There is no accumulation in the body with the therapeutic dose of this product. The metabolic site is in the wall of the gastrointestinal tract, and the elimination half-life is about 14 to 19 hours. About 97% of this product is excreted with feces, of which 83% is excreted in the original form. It can be applied clinically to obesity and hyperlipidemia.

The chemical name of orlistat: N-formyl-L-leucine(s)-1[(2s,3s)3-hexyl-4oxy-2-epoxypropylmethyl]dodecyl ester, Also known as tetrahydrolipstatin (THL), it is a semi-synthetic lipstatin derivative with the following structural formula:

Orlistat is white to off-white crystalline powder; odorless, easily soluble in methanol, ethanol, acetonitrile, chloroform, almost insoluble in water, almost insoluble in 0.1mol/L hydrochloric acid solution. The melting point is 40-48°C. Due to the low melting point of orlistat, it is prone to hydrolytic degradation and thermal degradation in humid air or dry air above 35°C, and problems such as adhesion, bonding and re-aggregation are prone to occur during the process; and orlistat It is relatively fluffy and has poor fluidity, and it cannot even be smoothly filled into capsules or compressed into tablets. The dissolution rate of the prepared preparation is low and cannot meet the treatment requirements.

CN102552168A discloses a pharmaceutical composition containing orlistat and a preparation method thereof. Orlistat and hydrophilic excipients are ground and mixed at a low temperature of -45°C to -15°C to obtain mixed granules, and then mixed with pharmaceutically acceptable 0-100 parts of the accepted auxiliary materials are mixed evenly, and made into capsules, tablets or granules. It solves the defects of adhesion and bonding phenomenon and low dissolution rate that are easy to occur in the process of orlistat preparation, ensures better dissolution rate of orlistat preparation, and improves product quality. However, this method requires low-temperature grinding equipment. Although it can be pulverized and mixed, it still cannot guarantee the problem of sticking during tablet compression or capsule filling, and the controllability of the large-scale production process is not high.

CN102362863A discloses a preparation containing orlistat and a preparation method thereof. The orlistat melt is coated on the surface of blank tablets or blank pellets, which solves the problem of stickiness caused by orlistat melting during the production process. The problem of flushing was solved, while the preparation maintained good stability and dissolution rate. Although the problem of sticking and punching has been avoided, the surface of the tablet or pellet is rough and not smooth after coating, and the orlistat raw material is easy to fall off from the surface of the tablet or pellet.

CN101791296B discloses an orlistat tablet and a preparation method thereof. After inclusion of orlistat and cyclodextrin, it is compressed into a tablet with pharmaceutically acceptable adjuvants. The tablet solves the problem of Orlistat The problem of sticking and punching of sestat by conventional process can significantly improve the chemical and physical stability of orlistat, mask the unpleasant taste of orlistat, and improve the compliance of oral administration for patients who are difficult to swallow. The dissolution rate improves the curative effect of orlistat. However, this process requires a cumbersome inclusion process, and the process is relatively complicated.

The Chinese patent "composition containing tetrahydro-trypsin" (application number 98800369.4) applied by the original research enterprise Roche discloses a composition containing orlistat, orlistat, stabilizer (polyvinyl ketone, lactose, hypromellose, hypromellose) and pharmaceutical excipients (surfactants, diluents, disintegrants, talcum powder), prepared pellets by extrusion spheronization, and controlled the particle size of these particles The diameter is in the range of 0.25mm to 2mm, and then prepared into a suitable oral solid preparation-capsule, tablet or bagged dosage form, to solve the problem of adhesion and bonding during the process. Extrusion and spheronization equipment are required during production, and during the capsule filling process, the free orlistat on the surface melts and sticks due to friction and heat.

US7393545 discloses a soluble cellulose tablet of a lipase inhibitor, which has the following problems: a large amount of methyl cellulose is used as a carrier, resulting in a large tablet weight, which increases the difficulty of medication for patients. It’s not good, it didn’t fundamentally solve the problem of sticking and punching in the tableting process, but the content of orlistat was reduced by increasing the weight of the tablet.

WO2009050720 discloses a pharmaceutical composition containing orlistat, which improves the dissolution rate and bioavailability of the drug. Fluidized bed equipment is used. The process is as follows: (a) preparing an aqueous solution of a water-soluble polymer material containing a surfactant; (b) dispersing the orlistat powder in the solution; (c) spraying the orlistat suspension on the surface of pharmaceutically acceptable pharmaceutical excipients, and finally processing it into a preparation form. However, in the process of spraying the suspension on the surface of the granular excipients, it is impossible for all orlistat raw material surfaces to be covered by the polymer, and a part of orlistat must be attached to the outer surface of the particles. During the tableting process, it will also stick to the punch due to the heat of the punch.

In addition, for the dissolution test of orlistat tablets prepared by the above technology, surfactants were added to the dissolution medium to improve the in vitro dissolution rate. However, there is no surfactant in the human gastrointestinal tract, and the tablets prepared by the above technology The dissolution rate still needs to be improved.

Contents of the invention

In view of the deficiencies in the prior art, the object of the present invention is to provide a solid oral preparation of orlistat with smooth surface and good dissolution rate by studying the physical and chemical properties of orlistat and screening the prescription process through a large number of tests and its preparation method.

The drug dissolution rate is closely related to the particle size and crystal form of the drug. The small particle size dissolves quickly, and the amorphous form dissolves faster than the crystalline form. Therefore, the present invention intends to make orlistat into an amorphous micronized form, but due to the low melting point of orlistat, conventional pulverization is difficult to realize, and low-temperature pulverization is difficult to industrialize. In order to realize the purpose of the present invention, the inventor finally obtained the following technical scheme through a large number of experimental studies:

A kind of orlistat tablet, this tablet is made up of orlistat acrylic resin solid dispersion, disintegrant and other pharmaceutically acceptable adjuvants, described orlistat acrylic resin solid dispersion adopts super Prepared by critical fluid rapid expansion method, D90<10μm.

Preferably, in the orlistat tablet, the weight ratio of orlistat to acrylic resin is 1:0.5-3.

Further preferably, the orlistat tablet, wherein the weight ratio of orlistat to acrylic resin is 1:1-2.

Still further preferably, the orlistat tablet, wherein the weight ratio of orlistat to acrylic resin is 1:1.5.

The disintegrant is selected from one or more of sodium carboxymethyl starch, crospovidone, hydroxypropyl cellulose, starch and croscarmellose sodium.

The disintegrant is preferably crospovidone.

The pharmaceutically acceptable auxiliary material is selected from one or more of microcrystalline cellulose, lactose, mannitol, povidone, pregelatinized starch, silicon dioxide, talcum powder and magnesium stearate.

A method for preparing the above-mentioned orlistat tablet, comprising the following steps:

(1) dissolving acrylic resin and orlistat in ethanol;

(2) Supercritical _CO2 and the solution of step (1) are decompressed through a nozzle of 10 microns in aperture, and the decompression time is ^10-5 seconds to form orlistat acrylic resin solid dispersion fine powder with particle size less than 10 μm;

(3) Mix the solid dispersion fine powder obtained in step (2) with microcrystalline cellulose and crospovidone evenly, granulate, dry, add magnesium stearate, mix evenly and press into tablets.

The present invention uses supercritical technology to micronize raw materials, and at the same time coats the surface of orlistat with a layer of inert material, which successfully solves the problem of low dissolution rate of preparations prepared in the prior art, and solves the problem of stickiness during tablet compression. Chong problem. That is: the present inventor creatively combined the supercritical fluid rapid expansion method to prepare micropowder raw materials and the solid dispersion technology, and adopted the supercritical fluid rapid expansion method to prepare orlistat acrylic resin solid dispersion, and prepared orlistat Then, the solid dispersion is uniformly mixed with pharmaceutically acceptable excipients, granulated, dried, and pressed into tablets to obtain a product that can dissolve rapidly and have a smooth surface without adding surfactants in the dissolution medium. Orlistat tablets have achieved unexpected effects.

Description of drawings

Figure 1 is the DSC spectrum of orlistat raw material.

Figure 2 is the DSC spectrum of acrylic resin.

Figure 3 is the DSC spectrum of a 1:1 mixture of orlistat acrylic resin.

Figure 4 is the DSC spectrum of orlistat acrylic resin 1:1 solid dispersion.

specific embodiment

The following are specific examples of the present invention, and further describe the technical solution of the present invention, but the protection scope of the present invention is not limited to these examples. All changes or equivalent substitutions that do not depart from the concept of the present invention are included in the protection scope of the present invention.

Example 1

1. Solid Dispersion Preparation

Orlistat 120g

Acrylic resin 60g

Absolute ethanol 600g

Dissolve the prescribed amount of orlistat and acrylic resin in absolute ethanol, and on the supercritical fluid equipment, pass the supercritical fluid CO2 to quickly decompress through a nozzle with an aperture of 10 microns, and the decompression time is ^10-5 seconds. The orlistat acrylic resin solid dispersion was prepared by a supercritical fluid rapid expansion method, and the D90 of the dispersion was less than 10 μm.

2. Preparation of Orlistat Tablets

Mix the solid dispersion with microcrystalline cellulose and crospovidone evenly, add an appropriate amount of pure water, granulate, dry, and pass the dry granules through a 20-mesh sieve, then mix evenly with the prescribed amount of magnesium stearate, and tablet it. have to.

Example 2

1. Solid Dispersion Preparation

Orlistat 120g

Acrylic resin 360g

Absolute ethanol 2000g

Dissolve the prescribed amount of orlistat and acrylic resin in absolute ethanol, and on the supercritical fluid equipment, pass the supercritical fluid CO2 to quickly decompress through a nozzle with an aperture of 10 microns, and the decompression time is ^10-5 seconds. The orlistat acrylic resin solid dispersion was prepared by a supercritical fluid rapid expansion method, and the D90 of the dispersion was less than 10 μm.

2. Preparation of Orlistat Tablets

Mix the solid dispersion with microcrystalline cellulose and crospovidone evenly, add an appropriate amount of pure water, granulate, dry, and pass the dry granules through a 20-mesh sieve, then mix evenly with the prescribed amount of magnesium stearate, and tablet it. have to.

Example 3

1. Solid Dispersion Preparation

Orlistat 120g

Acrylic resin 180g

Absolute ethanol 1000g

Dissolve the prescribed amount of orlistat and acrylic resin in absolute ethanol, and on the supercritical fluid equipment, pass the supercritical fluid CO2 to quickly decompress through a nozzle with an aperture of 10 microns, and the decompression time is ^10-5 seconds. The orlistat acrylic resin solid dispersion was prepared by a supercritical fluid rapid expansion method, and the D90 of the dispersion was less than 10 μm.

2. Preparation of Orlistat Tablets

Mix the solid dispersion with microcrystalline cellulose and crospovidone evenly, add an appropriate amount of pure water, granulate, dry, and pass the dry granules through a 20-mesh sieve, then mix evenly with the prescribed amount of magnesium stearate, and tablet it. have to.

comparative example

1. Orlistat raw material processing

Orlistat 120g

Absolute ethanol 1000g

Dissolve the prescribed amount of orlistat in absolute ethanol, and pass supercritical fluid CO2 through supercritical fluid equipment, and quickly pass through a nozzle with a pore size of 10 microns, and D90<10 μm.

2. Preparation of Orlistat Tablets

Mix the processed orlistat raw material with microcrystalline cellulose and crospovidone evenly, add an appropriate amount of pure water, granulate, dry, pass the dry granules through a 20-mesh sieve, and then mix evenly with the prescribed amount of magnesium stearate , ready to be pressed into tablets.

Verification Example

(1) Confirmation of orlistat crystal form

Preparation of Orlistat Acrylic Resin 1:1 Solid Dispersion

Orlistat 120g

Acrylic resin 120g

Absolute ethanol 100g

Dissolve the prescribed amount of orlistat and acrylic resin in absolute ethanol, and on the supercritical fluid equipment, pass the supercritical fluid CO2 to quickly decompress through a nozzle with an aperture of 10 microns, and the decompression time is ^10-5 seconds. The orlistat acrylic resin solid dispersion was prepared by a supercritical fluid rapid expansion method, and the D90 of the dispersion was less than 10 μm.

The crystal form of orlistat was verified by DSC. See Figure 1-4 for the map. It can be seen from the figure: after orlistat and acrylic resin form a solid dispersion, the endothermic peak of orlistat on the DSC spectrum disappears, which indicates that the dispersion is formed; while the endothermic peak of orlistat in the mixture still exists .

(2) Dissolution assay (Chinese Pharmacopoeia 2010 edition two appendix XC second method), with pH 1.2 hydrochloric acid solution 900ml as dissolution medium, rotating speed is 75 rpm, through 45 minutes, sampling determination. Get the solution 10ml to filter, according to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix VD determination).

Example 10min dissolution rate 45min dissolution rate Example 1 78.2% 98.2% Example 2 82.3% 99.6% Example 3 81.0% 98.9% Comparative Example 1 5.1% 5.2%

It can be seen from the table that the tablet prepared by the present invention dissolves faster in gastric acid; although Comparative Example 1 can be micronized to less than 10 μm, the raw material of orlistat is in a crystalline form because solid dispersion technology is not used. , poor dissolution.

Claims (7)

1. an orlistat tablets, it is characterized in that: this tablet is comprised of orlistat acrylic resin solid dispersion, disintegrating agent and other pharmaceutically acceptable adjuvants, described orlistat acrylic resin solid dispersion adopts using supercritical fluid quick expansion method to be prepared from, D90 < 10 μ m.

2. orlistat tablets according to claim 1, is characterized in that: the weight ratio of orlistat and acrylic resin is 1: 1-2.

3. orlistat tablets according to claim 1, is characterized in that: the weight ratio of orlistat and acrylic resin is 1: 1.5.

4. orlistat tablets according to claim 1, is characterized in that: described disintegrating agent is selected from one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, hydroxypropyl cellulose, starch and cross-linking sodium carboxymethyl cellulose.

5. orlistat tablets according to claim 1, is characterized in that: described disintegrating agent is polyvinylpolypyrrolidone.

6. orlistat tablets according to claim 1, is characterized in that: described pharmaceutically acceptable adjuvant is selected from one or more in microcrystalline Cellulose, lactose, mannitol, polyvidone, pregelatinized Starch, silicon dioxide, Pulvis Talci and magnesium stearate.

7. a method of preparing orlistat tablets claimed in claim 1, is characterized in that: comprise the following steps:

(1) acrylic resin, orlistat are dissolved in ethanol;

(2) by supercritical CO ₂with the nozzle that the solution of step (1) is 10 microns by aperture reduces pressure, decompression time 10-5 second, form the orlistat acrylic resin solid dispersion fine powder that granularity is less than 10 μ m;

(3) by the solid dispersion fine powder of step (2) gained and microcrystalline Cellulose, polyvinylpolypyrrolidone mix homogeneously, granulate, dry, add magnesium stearate, mix tabletting and get final product.