WO2013029198A1

WO2013029198A1 - Adefovir dipivoxil solid formulation and preparation method therefor

Info

Publication number: WO2013029198A1
Application number: PCT/CN2011/001440
Authority: WO
Inventors: 周世旺; 朱建强; 田青松
Original assignee: 天津泰普药品科技发展有限公司
Priority date: 2011-08-29
Filing date: 2011-08-29
Publication date: 2013-03-07

Abstract

An Adefovir Dipivoxil solid formulation and preparation method therefor. The method includes heating a pharmaceutical solvent and an inclusion agent for dissolution, leaving it for cooling to the room temperature, then mixing with Adefovir Dipivoxil, and suctioning the solvent to give Adefovir Dipivoxil granules, and further mixing with a pharmaceutical additive for uniform tableting or capsulation, wherein the Adefovir Dipivoxil granules are 0.5-3 parts, the pharmaceutical additive is 1-25 parts, and the Adefovir Dipivoxil granules comprise Adefovir Dipivoxil of 0.5-1 parts and the inclusion agent of 0.05-0.15 parts.

Description

Description Adefovir dipivoxil solid preparation and preparation method thereof

The invention belongs to the technical field of pharmaceutical preparations, and relates to the preparation of adefovir dipivoxil preparation, more specifically to an amorphous or crystalline adefovir dipivoxil solid preparation and a preparation method thereof.

Background technique '

Adefovir dipivoxi is a new anti-hepatitis B virus (HBV) drug and another oral anti-HBV drug following lamivudine. Adefovir dipivoxil is a nucleotide analogue of adenosine monophosphate, a prodrug of adefovir that competitively inhibits HBV polymerase and halts the prolongation of HBV DNA strands. The drug was approved for FDA approval in the US in September 2002.

From the beginning of He Weili's production approval for the first adefovir dipivoxil product in China, adefovir dipivoxil products have sprung up in just three years, Daiding, Mingzheng, Adixian, A-Gump Ding, Jiu Le, You He Ding and other products have been listed in China, occupying a place in the hepatitis B drug market. However, as adefovir dipivoxil preparation, there are the following difficulties in the preparation process:

(1) Adefovir dipivoxil bulk drug comprises: amorphous or crystalline. At present, there are types I, II, III, IV, V, etc., and how to maintain the stability of the crystalline form of the drug substance is a crucial issue. Because the stability of the crystal form after preparation directly affects its solubility, it affects bioavailability and efficacy.

(2) All types of APIs are sensitive to moisture and heat, and the substances will increase under high temperature and high humidity conditions.

(3) Most of the adefovir dipivoxil-type raw materials are needle-like and have poor fluidity; the pulverization process is prone to static electricity and the fluidity is even worse. Direct compression is prone to problems such as splitting and uneven content.

(4) Direct contact with adefovir dipivoxil has irritating and damage to the skin surface, and it has certain difficulties for the protection of production personnel. .

At present, the preparation methods of adefovir dipivoxil preparations mainly include: (1) conventional wet granulation tableting method, the disadvantage is that the granules undergo a high temperature and high humidity, the related substances will increase significantly; (2) direct pressure of raw materials and auxiliary materials The method of tableting, due to poor fluidity, the result of direct compression is prone to splinter and uneven content; (3) The method of dry granulation tableting, although the tableting is improved compared to the straight ramming, the raw material granules Surface treatment is not complete, also ^" sticky and cracked Description

The possibility of film production, and increase the processing process, is not suitable for large-scale preparation of the preparation; (4) hot-melt granulation, the main drug is added to other auxiliary materials, and then mixed with polyethylene glycol or povidone, the general temperature is 55 Above °C (polyethylene glycol or povidone melt), the result will increase the related substances.

Summary of the invention

SUMMARY OF THE INVENTION The object of the present invention is to overcome the shortcomings and deficiencies of the prior art and to provide a novel adefovir dipivoxil solid preparation and a preparation method thereof. To achieve the above object, the present invention provides the following technical solutions:

A solid preparation of adefovir dipivoxil, characterized in that it consists of encapsulated adefovir dipivoxil granules and a medicinal adjuvant; wherein the inclusion of adefovir dipivoxil granules refers to an agent and a drug It is dissolved by heating with a solvent, mixed with adefovir dipivoxil after cooling, and then removed by a medicinal solvent.

The solid preparation according to the present invention, wherein the halo ratio of the adefovir dipivoxil granules to the medicinal adjuvant is: 0.5-3 parts of adefovir dipivoxil granules, 1-25 parts of medicinal excipients; The composition of the encapsulated adefovir dipivoxil granules is: adefovir dipivoxil 0.5-1 part, and the inclusion agent 0.05-0.15 part.

The solid preparation according to the present invention, wherein the temperature at which the inclusion agent and the pharmaceutically acceptable solvent are dissolved by heating is 35-90 ° C; wherein the pharmaceutical auxiliary materials are lactose, mannitol, microcrystalline cellulose, pregelatinized starch, and hydroxyl Propylcellulose, hydroxypropylmethylcellulose, magnesium stearate or silica; the inclusion agent is polyethylene glycol or povidone; polyethylene glycol or povidone with hydroxypropyl cellulose, hydroxypropyl One or two mixtures of methyl cellulose; the pharmaceutically acceptable solvent is methanol, ethanol, acetone, chloroform or dichloromethane; the solid preparation is a tablet, capsule or granule.

The solid preparation of the present invention, wherein the polyethylene glycol is polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene glycol 6000 or polyethylene glycol 10000; povidone is poly Vesone K12, povidone K17 or povidone oxime 30.

It is particularly emphasized that the adefovir dipivoxil of the present invention comprises adefovir dipivoxil, an amorphous or crystalline adefovir dipivoxil bulk drug disclosed in the prior art. The crystalline form of adefovir dipivoxil refers to: I, II, III, ^/ or . For the preparation of amorphous adefovir dipivoxil, see CN1374314A; for the preparation of crystals of I, II, III and IV, see CN1251592A; and for the crystal of V, see the description of ZL02148744.

The present invention further discloses a method for preparing a solid preparation of adefovir dipivoxil, which is characterized by the following steps: Instruction manual

(1) selecting a pharmaceutically acceptable solvent in a proportion of 0.5-3 parts by weight, adding a binder, stirring, dissolving at 35-90 ° C, and allowing to cool to room temperature;

(2) then adding 0.5-1 part of adefovir dipivoxil, stirring and hooking; evaporating the solvent (preferably 30-35 V) below 35 ° C, and then obtaining the encapsulated adefovir dipivoxil granule;

(3) The obtained adefovir dipivoxil granules are uniformly mixed with a medicinal adjuvant to prepare a solid preparation.

The invention selects acetone (or chloroform) as a medicinal solvent, and adds polyethylene glycol (or povidone); polyethylene glycol (or povidone) and hydroxypropyl cellulose, hydroxypropyl methyl cellulose Kind or two kinds of mixture; add ^ dissolve, let cool to room temperature, then add adefovir dipivoxil, stir evenly; evaporate acetone (or chloroform) on a suitable equipment, sieved to get coated adefovir The ester polyethylene glycol (or povidone) granules are then tableted or encapsulated with other excipients.

The preparation method of the present invention is different from the hot-melt granulation in that: conventional hot-melt granulation requires mixing the main drug, other auxiliary materials and polyethylene glycol to heat above 55 ° C (polyethylene glycol or The povidone melts, and as a result, the adefovir dipivoxil-related substance increases as the temperature increases. The preparation method of the invention comprises the steps of: heating polyethylene glycol (or povidone) in a solvent to dissolve at room temperature, and then mixing with a sieved (conventional method) adefovir dipivoxil at 35 ° C. The solvent is removed to obtain the encapsulated adefovir dipivoxil polyethylene glycol (or povidone) particles, which ensures the stability of adefovir dipivoxil (including amorphous or crystalline), making adefovir The quality of the ester does not change and the relevant substances do not increase (see the comparative test results in Tables 2 and 3).

The present invention focuses on the following key issues:

1) Solvent selection: Adefovir dipivoxil is insoluble in water and soluble in ethanol, methanol, acetone and chloroform. Only the best preparation with ethanol or acetone, the optimum ratio of addition is about 1-3 times of the raw material adefovir dipivoxil;

2) Selection of inclusion agent: Optional polyethylene glycol 2000, 3000, 4000, 6000, 10000 (or povidone K12, Κ17, Κ30) may also be polyethylene glycol or povidone and hydroxypropyl cellulose , one or two mixtures of hydroxypropylmethylcellulose, preferably added in an amount of from about 3% to 20% of adefovir dipivoxil;

3) Selection of pharmaceutical excipients: The inventors examined excipients such as lactose, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, magnesium stearate, and silica, and the results showed that the above auxiliary materials and Ade Fuvirate has good compatibility.

The preparation process of the adefovir dipivoxil tablet of the invention is tested by crystal form and related substance test, and is now V-shaped crystal The crystallization is an example, and the method and results are as follows:

(1) Determination of the type: by X powder diffraction

Table 1, X powder diffraction method measurement results

The results show that: the particle diffraction angle 2 Θ value of the raw materials is reflected in the raw materials, indicating that the crystal form has no change.

Determination of related substances: USP standard, HPLC method; the results are as follows:

Table 2. Results of related substances of crystalline adefovir dipivoxil tablets prepared by the present invention (%)

The results show that: there is almost no change in the related substances in the preparation process of the invention, and the process is good, which is obviously superior to the hot melt granulation.

We used the preparation of the present invention to compare the stability of the preparation with the direct compression: at a high temperature of 60 ° C, a high humidity of RH 92%, a high temperature and high humidity (40 ° C, RH 75%), and the exposure was as follows:

Table 4. % increase in water absorption test of tablets made by the two processes

Project direct tableting agent granules high humidity RH92% 6.26 3.25 High temperature and high humidity (40 ° C, RH 75%) 4.88 2.35

Table 5, Comparison of results of tablet stability between the two processes

The results of the method of the present invention and direct compression showed that the materials involved in the two processes were comparable, but the hygroscopicity of the tablets of the present invention was lowered and the stability was remarkably improved.

The above test shows that: the crystal form of the raw material of the invention has no change before and after the preparation; the related substances are not increased; the flowability of the particles is enhanced; the stability is also obviously improved; the skin irritation to the production personnel is also greatly reduced; The preparation is more suitable for large-scale industrial production.

detailed description:

For the sake of simplicity and clarity, the invention will be further illustrated by the following examples. The raw materials used in it are all commercially available.

Example 1

Type I Adefovir I 10g

Ethanol 5ml

Polyethylene glycol 4000 lg

Hydroxypropyl cellulose 2g

Lactose 108g

Microcrystalline cellulose 36g

Magnesium stearate 3g

Process: Adefovir dipivoxil is sieved (60 mesh) according to the above weight; standby; polyethylene glycol, hydroxypropyl fiber After stirring and dissolving in ethanol at 80 ° C, let cool to room temperature, add adefovir dipivoxil, stir, evaporate the solvent at 35 ° C, and let cool to room temperature; obtain adefovir dipivoxil admixture particles, and then with other excipients After mixing, tableting or loading example 2

Type II Adefovir Cool 10g

Acetone 10ml

Polyethylene glycol 6000 1. 5g

Mannitol 108g

Microcrystalline cellulose 36g

Magnesium stearate 3g

Process: Adefovir dipivoxil is sieved (60 mesh) for use according to the above weight; take polyethylene glycol in acetone at 55 ° C, stir and heat to dissolve, then let cool to room temperature, add adefovir dipivoxil, stir and heat, The solvent was evaporated to dryness at 32 ° C to obtain adefovir dipivoxil admixture granules, which were then mixed with other excipients, and then tableted or capsuled.

Example 3

Type III adefovir dipivoxil 10g

Chloroform 15ml

Polyethylene glycol 10000 2g

Lactose 108g

Microcrystalline cellulose 36g

Pregelatinized starch 8g. Magnesium stearate 3g

Process: Adefovir dipivoxil is sieved (60 mesh) according to the above weight; use polyethylene glycol in chloroform at 65 ° C, stir and heat to dissolve, then let cool to room temperature, add adefovir dipivoxil, stir, 32 ° C Evaporate the solvent to obtain adefovir dipivoxil admixture granules, and then mix with other excipients, then tablet or capsule.

Example 4

Type IV adefovir dipivoxil 10g Methanol 20ml

Polyethylene glycol 4000 2. 5g

Hydroxypropylmethylcellulose 2g

Lactose 108g

Microcrystalline cellulose 36g

Pregelatinized starch 8g

Magnesium stearate 3g

Process: Adefovir dipivoxil is sieved (60 mesh) according to the above weight; standby; polyethylene glycol, hydroxypropylmethylcellulose is stirred and dissolved in methanol at 65 ° C, allowed to cool to room temperature, added adefovir The ester is stirred evenly, and the solvent is evaporated to dryness at 35 ° C to obtain adefovir dipivoxil admixture granules, which are then mixed with other auxiliary materials, and then tableted or filled. Example 5

V-type adefovir dipivoxil 10g

Ethanol 10ml

Polyethylene glycol 6000 2g

Hydroxypropylmethylcellulose 2g

Lactose 108g

Microcrystalline cellulose 36g

Pregelatinized starch 8g

Magnesium stearate 3g

Process: Adefovir dipivoxil is sieved (60 mesh) according to the above weight; use polyethylene glycol, hydroxypropylmethyl cellulose to dissolve in ethanol (about 80 ° C), let cool to room temperature, add Ade Fuwei ester, stir well, 3 (TC evaporated to dry solvent, get adefovir dipivoxil admixture particles, and then mix with other excipients, then tablet or capsule. Example 6

Type II adefovir dipivoxil 10g

Acetone 15ml ■ Polyethylene glycol 6000 0. 85g ,

Brother book

Hydroxypropyl cellulose 0.75g

Lactose HOg

Microcrystalline cellulose 36. 5g

Magnesium stearate 3. 5g.

The medicinal solvent (acetone), the inclusion agent (polyethylene glycol and hydroxypropyl cellulose), dissolved by heating at 60 ° C, allowed to cool to room temperature; then mixed with adefovir dipivoxil; stirred evenly, 35 Ό evaporated The solvent, the adefovir dipivoxil admixture granules, and then mixed with other excipients, tableted or capsuled.

Example 7

V-type adefovir dipivoxil 10g

Acetone 15ml

Povidone K30 lg

Mannitol HOg

Microcrystalline cellulose 36. 5g . Pregelatinized starch 8. 5g

Magnesium stearate 3. 5g ₀

The medicinal solvent (acetone) and the inclusion agent (Povidone K30) are dissolved by heating at 60 ° C, and then allowed to cool to room temperature; then mixed with adefovir dipivoxil; stirred evenly, and the solvent is evaporated to dryness at 32 ° C. Fuwei ester inclusion agent granules, then mixed with other excipients, compressed or encapsulated

Example 8

Amorphous adefovir dipivoxil 10g

Methanol 15ml

Povidone K17 0. 5g

Lactose HOg

Microcrystalline cellulose 36. 5g

Magnesium stearate 3. 5g ₀

The medicinal solvent (methanol) and the inclusion agent (Povidone K17) are dissolved by heating at 60 ° C, and then allowed to cool to room temperature; Description

Mix with adefovir dipivoxil; Stir well, evaporate the solvent at 30 ° C to obtain adefovir dipivoxil admixture granules, then mix with other excipients, and then compress or encapsulate.

Example 9

V-type adefovir dipivoxil 10g

Ethanol 15ml

Povidone K12 2g

Lactose 110g

Microcrystalline cellulose 36. 5g

Magnesium stearate 3. 5g.

The medicinal solvent (ethanol) and the inclusion agent (Povidone K12) are dissolved by heating at 60 ° C, and then allowed to cool at room temperature; then mixed with adefovir dipivoxil; stirred and hooked, and evaporated to dryness at 32 ° C. The defovirtide ester granules are then mixed with other excipients and then compressed or encapsulated.

Claims

Claim

A solid preparation of adefovir dipivoxil, which is characterized in that it consists of encapsulated adefovir dipivoxil granules and a medicinal adjuvant; wherein the inclusion of adefovir dipivoxil granule means an inclusion agent It is prepared by heating and dissolving with a medicinal solvent, mixing with adefovir dipivoxil after cooling, and then removing the medicinal solvent.

The solid preparation according to claim 1, wherein the weight ratio of the adefovir dipivoxil granules to the medicinal adjuvant is: 0.5-3 parts of adefovir dipivoxil granules, 1-25 parts of medicinal adjuvants; The composition of the encapsulated adefovir dipivoxil granules is: adefovir dipivoxil 0.5-1 part, and the inclusion agent 0.05-0.15 part.

The solid preparation according to claim 1 or 2, wherein the temperature at which the inclusion agent and the pharmaceutically acceptable solvent are dissolved by heating is 35-90 ° C; wherein the pharmaceutical auxiliary is lactose, mannitol, microcrystalline cellulose, pre- Gelatinized starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium stearate or silica; the inclusion agent is polyethylene glycol or povidone; polyethylene glycol or povidone and hydroxypropyl One or a mixture of cellulose, hydroxypropylmethylcellulose; the pharmaceutically acceptable solvent is methanol, ethanol, acetone, chloroform or dichloromethane; and the solid preparation is a tablet, capsule or granule.

The solid preparation according to any one of claims 1 to 3, wherein the polyethylene glycol is polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene glycol 6000 or polyethylene glycol. Alcohol 10000; Povidone is povidone K12, povidone K17 or povidone oxime 30.

The solid preparation according to any one of claims 1 to 3, wherein the adefovir dipivoxil refers to an adefovir dipivoxil of an amorphous or crystalline form.

6. The solid preparation according to claim 5, wherein the crystalline form of adefovir dipivoxil refers to I, II, III, V.

7. A process for the preparation of a solid preparation of adefovir dipivoxil according to any one of claims 1 to 3, which is characterized in that the following steps are carried out:

(1) selecting a pharmaceutically acceptable solvent in a proportion of 0.5-3 parts by weight, adding a binder, stirring, heating at 35-90 ° C, and allowing to cool to room temperature;

(2) Then adding 0.5-1 part of adefovir dipivoxil, stirring uniformly; evaporating the solvent below 35 ° C to obtain the encapsulated adefovir dipivoxil granule;