WO2012088992A1

WO2012088992A1 - Process for preparing solid medicine preparation and solid medicine preparation therefrom

Info

Publication number: WO2012088992A1
Application number: PCT/CN2011/083285
Authority: WO
Inventors: 郑斯骥; 谭波; 傅麟勇; 袁少卿; 曹智慧
Original assignee: 上海中西制药有限公司
Priority date: 2010-12-28
Filing date: 2011-12-01
Publication date: 2012-07-05
Also published as: CN102552161A; CN102552161B

Abstract

Disclosed is a process for preparing a solid medicine preparation and a solid medicine preparation therefrom. The preparation process uses an acid-alkali solventing-out dispersion technique comprising the steps of: dissolving a water insoluble and/or indissolvable acid active medicine ingredient in an alkaline solution containing an alkalizing agent to produce a medicine-containing alkaline solution; then uniformly mixing an auxiliary material and the medicine-containing alkaline solution to perform a wet granulation. The process avoids the disadvantages caused by a mechanical crushing treatment, such as serious pollution, large losses and potential safety hazards, by which the effect of reducing the particle size of the water insoluble and/or indissolvable acid active medicine ingredients can be achieved during preparation, and the solid produced has an excellent solventing-out characteristic, stability and content uniformity.

Description

Preparation method of pharmaceutical solid preparation and obtained medicine solid preparation technical field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of a solid pharmaceutical preparation and a obtained solid preparation of the medicament. Background technique

In the field of pharmaceutical preparations, the particle size of the pharmaceutically active ingredient is closely related to the preparation process and quality of the solid preparation, and the reduction of the particle size is the key to improving the dissolution and content uniformity of the pharmaceutical preparation. In the preparation process of a specific pharmaceutical preparation, the particle size of a suitable pharmaceutically active ingredient is usually selected depending on the dissolution characteristics of the drug and the permeability of the biofilm. For example, if the solubility is poor, drug dissolution is a drug that absorbs the rate-limiting process, and a smaller particle size can be selected to promote drug absorption. In the preparation process of a pharmaceutical solid preparation, selective control of the particle size of the pharmaceutically active ingredient is often involved.

At present, most of the selection and control of the particle size of the active ingredient of the drug are achieved by selecting different mechanical pulverization methods and pulverization process conditions. The universal pulverizer is a pulverizer widely used in the field of medicine. The effect of crushing materials is mainly on impact force and shearing force. It is suitable for a variety of medium-hardness dry materials. The average particle size after treatment is generally 100. About micrometers.

However, the treatment method of mechanical pulverization has problems such as a lot of dust, a polluted environment, and a large loss. For some highly active drugs, it is easy to cause adverse reactions in the mechanical pulverization process, and there are serious safety hazards. For example, inhalation of a lower dose of sedative sleeping pills powder can quickly produce hypnotic effects. When these drugs are pulverized, it is highly prone to cause an operator's rapid hypnosis and cause a safety accident. For example, when pulverizing some highly active hormones or anti-tumor drugs, inhaling or contacting a certain amount of the drug powder can easily cause a serious drug reaction by the operator.

For some poorly soluble drugs, the average particle size reaches about 100 microns, and the dissolution characteristics of the prepared solid preparations are not satisfactory. In the process of mechanical pulverization treatment, for a high active pharmaceutically active ingredient having a low content (e.g., 5 wt%) in a solid preparation, it also relates to the problem of dispersion uniformity of its mixing with an auxiliary material. Usually, a method of gradually diluting the pharmaceutically active ingredient and the auxiliary material in an equal amount is used to uniformly disperse the pharmaceutically active ingredient in the solid preparation. However, the method is cumbersome in process operation, and also causes many problems such as dust, environmental pollution, large loss, and safety hazards in labor protection.

In addition, the preparation of solid preparations also needs to consider whether the various properties of the product can meet the needs. For example, is it possible to ensure a better content uniformity? For example, stability is the focus of the quality of the solid preparation, including the chemical stability of the active ingredient, the content of impurities, the stability of the solid preparation, and the stability of dissolution during storage of the solid preparation, whether it is in the medicine Within the standard limits.

Therefore, in view of the above-mentioned drawbacks of the prior art, it is urgent to seek a preparation method which can avoid the above-mentioned drawbacks of the mechanical pulverization treatment method and which can ensure various properties of the solid preparation. Summary of the invention

The technical problem to be solved by the present invention is to overcome the conventional method for preparing a solid preparation by mechanically pulverizing and controlling the particle size of the pharmaceutically active ingredient, which causes environmental pollution, has serious safety hazards, and has large loss, and the obtained solid pharmaceutical preparation The solubility is not ideal, and the water-insoluble or poorly water-soluble acidic drug provides a simpler operation, less pollution, no such safety hazard, and can ensure that the prepared solid preparation has excellent dissolution characteristics. , a method for preparing a solid pharmaceutical preparation having stability and content uniformity, and a solid pharmaceutical preparation obtained.

In order to solve the above technical problems, the present inventors have taken a different approach, uniquely using Acid-Base Solventing-out Dispersion (A-BSoD), which dissolves water-insoluble and/or poorly water-soluble acidic with an alkaline solution. The drug, which is then returned to the solid state during the granulation process, avoids many of the drawbacks of mechanical comminution. Further, the inventors have unexpectedly found that the water-insoluble and/or poorly water-soluble acidic pharmaceutical solid preparation obtained by the method has excellent dissolution characteristics, stability, and content uniformity.

The method for preparing a pharmaceutical solid preparation of the present invention comprises the steps of: insoluble water and/or water The soluble acidic pharmaceutical active ingredient is dissolved in an alkaline solution containing an alkalizing agent to prepare a medicated alkaline liquid; thereafter, the auxiliary material and the medicated alkaline liquid are uniformly mixed to perform wet granulation.

In the present invention, the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is selected from various existing pharmaceutically active ingredients satisfying the above properties, including an amphoteric active ingredient having both an acidic group and a basic group. . In the art, most of the acidic pharmaceutically active ingredients are weak acid active ingredients. The present invention preferably has a high activity and a low content in a solid preparation (generally 20% or less, preferably 10% or less, more preferably 5% or less, and a percentage by mass) of water-insoluble or poorly water-soluble acidity. Pharmaceutical active ingredient. More specifically, the present invention is preferably, but not limited to, glipizide, folic acid, bumetanide, diclofenac, isocarbopurine, benzfluorothiazide, p-fluorothiazide, methotrexate, vitamin H , hexaerythritol, indapamide, furosemide, thioguanine, allopurinol, gliclazone, simvastatin, leflunomide, hydrochlorothiazide or phenobarbital.

Based on the conventional content of the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient in the solid preparation, the mass percentage of the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient in the wet-processed dry material can be determined during the preparation. In addition to the water-insoluble and/or poorly water-soluble acidic drug active ingredients, other pharmaceutically active ingredients may be added to prepare a compound solid preparation.

In the present invention, the alkalizing agent refers to a reagent capable of completely dissolving a water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient in an alkaline solution containing an alkalizing agent. According to common knowledge in the art, the basifying agent should be a pharmaceutically acceptable agent compatible with water insoluble and/or poorly water soluble acidic pharmaceutical active ingredients. In the present invention, the compatibility means coexistence without adverse effects. The alkalizing agent may be a single alkalizing agent or a complex alkalizing agent composed of two or more components, and may be selected from various bases such as inorganic bases and/or organic bases, strong bases and/or weakeners. The base is preferably selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, meglumine, diethanolamine and triethanolamine. The basifying agent described below is particularly preferred in the present invention:

When the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is indapamide, the alkalizing agent is sodium hydroxide, potassium hydroxide or sodium ethoxide, most preferably sodium hydroxide.

When the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is glipizide, the alkalization The agent is sodium hydroxide or potassium hydroxide, and the most preferred is sodium hydroxide.

When the water-insoluble and/or water-insoluble acidic pharmaceutical active ingredient is folic acid, the alkalizing agent is sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium carbonate or potassium carbonate, and most preferably sodium hydroxide or carbonic acid. sodium.

When the water-insoluble and/or water-insoluble acidic pharmaceutical active ingredient is methotrexate, the alkalizing agent is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

When the water-insoluble and/or water-insoluble acidic pharmaceutical active ingredient is benzfluorothiazide, the alkalizing agent is sodium hydroxide or potassium hydroxide.

The alkalizing agent is used in an amount at least the minimum amount which can completely dissolve the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient, preferably 1 to 1.5 times the minimum amount, and most preferably 1 to 1.05. Times. The amount of the alkalizing agent which can dissolve the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is related to various factors such as the type of alkalizing agent, the type of solvent, the water-insoluble and/or poorly water-soluble acidic drug in the alkalizing agent. The number of negative ions combined with the acid center of the active ingredient and the preparation conditions of the medicated alkaline solution (such as temperature, time, feeding sequence, stirring method) and the like. Here, the acidic center means a group or a portion of the water-insoluble and/or water-insoluble acidic drug active ingredient which can bind to a negative ion in the alkalizing agent molecule. Therefore, the above minimum amount refers to the minimum amount of an alkalizing agent which can be dissolved by a certain alkali-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient under the same solvent and medicated alkaline solution. The minimum amount can be determined by a simple conventional method: in the same solvent and the medicated alkaline solution, the amount of the alkalizing agent is gradually increased to dissolve a certain water-insoluble and/or poorly water-soluble acidic drug. The active ingredient, when completely dissolved, is the minimum amount. The present inventors have found through a large number of experiments that, in particular, the molar ratio of the alkalizing agent to the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is generally from 0.1 to 2.5, and most of from 0.9 to 1.5, and the present invention is particularly preferred. The amount of alkalizing agent:

For indapamide, sodium hydroxide or sodium ethoxide having a molar amount of 0.7 to 1.1 times is particularly preferred. For glipizide, sodium hydroxide having a molar amount of 0.95 to 1.1 times is particularly preferable.

For folic acid, sodium hydroxide having a molar amount of 1.8 to 2.1 times or a molar amount of 0.95 to 1.1 is particularly preferable. Times sodium carbonate or potassium carbonate.

For methotrexate, sodium hydroxide having a molar amount of 1.4 to 1.6 times or sodium carbonate having a molar amount of 0.85 to 1.1 times is particularly preferable.

For the benzfluorothiazine, sodium hydroxide having a molar amount of 0.9 to 1.6 times is particularly preferable.

In the present invention, the solvent in the alkalizing agent-containing alkaline solution may be water, an organic solvent or a mixture of water and an organic solvent. According to common knowledge in the art, the solvent selected should be an ion dissociable solvent in the alkalizing agent. For example, when the alkalizing agent is an inorganic substance, water or a mixed liquid of water and an organic solvent may be selected; and when the alkalizing agent is an organic substance, it may be a mixed liquid of water, water and an organic solvent, or an organic solvent. If the pharmaceutically active ingredient is superior to the solubility in water in some organic solvents, it is preferred to select a mixture of water and the organic solvent to facilitate dissolution of the active ingredient of the drug, and to reduce the amount of alkalizing agent or solvent, which is advantageous for The operation of the subsequent granulation step. The organic solvent is selected according to the principle that its solubility in water-insoluble and/or poorly water-soluble acidic pharmaceutically active ingredients is superior to water in a solvent acceptable for the pharmaceutical field, preferably organically miscible with water. a solvent, such as a water-soluble alcohol solvent commonly used in the pharmaceutical field, such as ethanol, propylene glycol, glycerol, acetone, isopropanol or tert-butanol, preferably one or more of ethanol, acetone, propylene glycol and glycerol. Particularly preferred is ethanol. In the mixture of water and an organic solvent, the concentration of the organic solvent can be arbitrarily selected. The amount of the solvent in the alkaline solution is such that at least the drug is soluble, at least the minimum amount of granulating liquid required for wet granulation, generally 5 to 100% by mass of the dry granulated dry material, preferably 10 ~50%.

In the preparation of the medicated alkaline solution, some excipients such as a binder, a surfactant, a solubilizing agent, and a water-soluble carrier of the solid dispersion may be added. Preferably, the water-insoluble and/or water-insoluble acidic pharmaceutically active ingredient is dissolved in the alkaline solution containing the alkalizing agent while and/or after, the water-soluble solution of the surfactant, the solubilizing agent and the solid dispersion is further added. One or more of the carrier materials are then subjected to a subsequent step of uniformly mixing the excipients with the excipients for wet granulation. Wherein, when the water-soluble carrier of the solid dispersion and the water-insoluble and/or poorly water-soluble acidic pharmaceutically active ingredient are simultaneously added to the alkaline solution containing the alkalizing agent, the amount of the water-soluble carrier of the solid dispersion to be added at this time is required. Controlled to ensure that the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredients are completely dissolved in the alkaline agent-containing alkaline The amount in the solution is below; after that, a water-soluble carrier of the solid dispersion may be further added to the solution, and when the amount added is large, the obtained drug-containing acidic liquid may be in the form of a suspension or a viscous liquid. Particularly preferred in the present invention are the addition of povidone, polyethylene glycol (preferably polyethylene glycol 400-8000), sodium dodecyl sulfate, poloxamer, polyoxyethylene castor oil, Tween (preferably Tween 80). And one or more of polyoxyl 40 stearate, lactose, mannitol, sucrose, hydroxypropyl-β-cyclodextrin, β-cyclodextrin and maltitol. The surfactant and/or solubilizer is preferably added in an amount of 0.05 to 5 times, more preferably 0.05 to 2 times, the mass of the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient. The water-soluble carrier of the solid dispersion is preferably added in an amount of from 0.5 to 20 times, more preferably from 0.5 to 2 times, the mass of the water-insoluble and/or water-insoluble acidic pharmaceutical active ingredient. By adding a surfactant and/or a solubilizing agent as described above, the solubility of the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient in an alkaline solution can be increased, the amount of the solvent can be reduced, and the operation of the subsequent granulation step can be facilitated. It is further worth mentioning that one or more of the water-soluble carriers of the surfactant, the solubilizer and the solid dispersion are added as described above, in particular, the water-soluble carrier of the solid dispersion can make the dissolution characteristics of the obtained solid preparation. Better.

Preferably, in the preparation of the medicated alkaline solution, the preparation temperature of the medicated alkaline solution may be appropriately raised by a conventional heating method such as a hot water bath to facilitate dissolution of the pharmaceutically active ingredient. When water is used as the solvent, it is preferably raised to 40 to 80 °C. When a mixed solution of water and an organic solvent is used as a solvent, the preferred increase is 40 to 70 °C. When ethanol is used as the solvent, the preferred increase is 30 to 50 °C.

In the present invention, the excipient may be selected from any of the excipients known and widely used in the art, such as fillers, binders, disintegrants, adsorbents, lubricants and the like. The amount of the excipients can be selected according to routine or prior knowledge in the art. Wherein the filler is preferably one or more of lactose, microcrystalline cellulose, starch, pregelatinized starch, mannitol, sucrose and maltitol. The binder is preferably one or more of hypromellose, povidone, methylcellulose and hydroxypropylcellulose. The disintegrant is preferably one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and croscarmellose sodium. The lubricant is preferably magnesium stearate, micronized silica gel (colloidal silica), talc or sodium stearate.

When the auxiliary material and the medicated alkaline liquid are uniformly mixed and subjected to the wet granulation step, The acidifying agent is added to lower the alkalinity of the mixture of the acidifying agent and the medicated alkaline solution with respect to the alkalinity of the medicated alkaline solution.

According to common knowledge in the art, the acidulant should be a pharmaceutically acceptable agent compatible with water insoluble and/or poorly water soluble acidic pharmaceutical active ingredients. Preferably, the present invention is preferably a combination of an alkalizing agent and an acidifying agent of the following type: the alkalizing agent is an inorganic strong base, an organic strong base or an inorganic medium strong base, and the acidifying agent is an inorganic strong acid (such as hydrochloric acid).

The amount of the acidifying agent is such an amount that at least the alkalinity of the mixture of the acidifying agent and the medicated alkaline liquid is lowered relative to the alkalinity of the medicated alkaline liquid. Preferably, the amount of the alkalizing agent and the acidifying agent satisfies the following relationship: The value obtained by the formula 1 is 0.01 to 1.5, preferably 0.2 to 1.1, more preferably 0.9 to 1.1.

(Number of moles of acidifying agent xA) I (molar number of alkalizing agent xB) Formula 1 wherein A is the number of hydrogen ions in the acidifying agent molecule, and B is the total number of valence states of the alkalizing agent molecule anion.

The present invention particularly preferably has a combination of the following alkalizing agent and acidifying agent of the formula 1 having a value of 0.9 to 1.1: sodium hydroxide and hydrochloric acid, potassium hydroxide and hydrochloric acid, sodium ethoxide and hydrochloric acid, sodium carbonate and hydrochloric acid, and potassium carbonate and hydrochloric acid. .

For certain water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredients, the addition of an acidifying agent is more advantageous for the stability of the solid preparation. For certain water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredients, the solid preparation can still have better stability without adding an acidifying agent or an acidifying agent in the formulation, but does not affect the preparation. Under the premise of stability, appropriately increasing the amount of acidifier to reduce alkalinity can help to alleviate the pH of solid preparations.

In the present invention, the wet granulation can be carried out according to the conventional steps and conditions of various granulation methods in the field of wet granulation in the art, such as extrusion granulation (such as swinging machine extrusion, spiral extrusion or rotary extrusion). Pressing, etc., stirring granulation, fluidized spray granulation or centrifugal spray granulation. For larger doses in solid preparations (generally greater than 10%) or less soluble in alkaline solutions containing alkalizing agents, larger amounts of alkaline solution are required to dissolve complete water insolubility and/or poor water solubility. The acidic pharmaceutically active ingredient may be selected from a wet granulation process in which the amount of the granulation solution is limited, such as fluidized spray granulation or centrifugal spray granulation.

When an acidulant is used, it is preferred to carry out the specific operation in any of the following ways: mode (1) The acidifying agent or the acidifying agent-containing solution and the auxiliary material are uniformly mixed, and then uniformly mixed with the medicated alkaline liquid, and subjected to extrusion granulation or stirring granulation; and (2) the medicated alkaline liquid and the acidifying agent or The solution of the acidifying agent is uniformly mixed to obtain a granulating liquid, and then the granulating liquid and the auxiliary material are subjected to extrusion granulation, agitation granulation, fluidized spray granulation or centrifugal spray granulation; and the method (3) will contain The alkaline solution of the drug is uniformly mixed with the auxiliary material, and then uniformly mixed with the solution containing the acidifying agent, and subjected to extrusion granulation or stirring granulation; and (4) the medicated alkaline liquid and the auxiliary material of 1/3 or less And the acidifying agent or the acidifying agent-containing solution is uniformly mixed (the specific operation may be: firstly mixing 1/3 or less of the auxiliary material with the acidifying agent or the acidifying agent-containing solution, and then mixing the obtained mixture with the medicated alkaline liquid; Or, firstly mix 1/3 or less of the auxiliary material and the medicated alkaline liquid, and then uniformly mix with the acidifying agent or the acidifying agent-containing solution, and then mix with the remaining auxiliary materials for extrusion granulation or stirring granulation. The excipients in the 1/3 or less of the excipients are preferably water-soluble excipients. The 1/3 or less of the above may be usually 1/4 to 1/10 or less. The acidifier-containing solution refers to a solution obtained by dissolving an acidifying agent with a small amount of solvent according to a routine operation in the art to facilitate the mixing step; the solvent may be water, an organic solvent or water and an organic solvent. Mixture. The organic solvent is the same as described above.

After the wet granulation is completed, the solid granule preparation can be directly obtained, or can be used as a preparation intermediate, and further solid preparations such as tablets or capsules can be obtained through further conventional steps.

Further, the present invention also relates to a solid preparation prepared by the above method.

In the present invention, each of the above preferred conditions can be arbitrarily combined on the basis of common knowledge in the art, and preferred embodiments of the present invention can be obtained.

In the present invention, the reagents and starting materials used are commercially available.

The positive progress of the invention is that the preparation method of the invention avoids the defects of serious pollution, large loss and serious safety hazard caused by mechanical pulverization treatment, and achieves reduction of water insolubility and/or poor water solubility during granulation. The effect of the particle size of the acidic pharmaceutical active ingredient. The method is easy to operate, has a high safety factor, and is easy to be applied to industrial production. The solid active preparation of the present invention has a small particle size, excellent dissolution characteristics, high bioavailability, small individual difference, and also good stability and content uniformity. detailed description

The invention is further illustrated by the following examples, but the invention is not limited thereto.

The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer. The dosage form specification is based on the content of the active ingredient of the drug, such as 2 mg/tablet, which means that each tablet contains 2 mg of the active ingredient of the drug.

The unit of use is gram and the percentage is the mass percentage.

The mass percentage of the pharmaceutically active ingredient and the solvent is the mass percentage of the wet granulated dry material. Wherein the amount of the solvent includes water in an aqueous solution of an acidifying agent and an alkalizing agent.

The coating material is a premix of the gastric coating material - Opadry. Comparative Example 1 and Example 1 Indapamide particle formulation and preparation method (Indapamide molecular weight: 365.83)

Example 2~3 Indapamide granule formula and preparation method

Example 4 Indapamide granule formula and preparation method

Example 5 Indapamide Tablets (2.5 mg/tablet) Formulation and Preparation Method

Comparative Example 2 and Example 6 Indapamide Tablets (2.5 mg/tablet) Formulation and Preparation Method

The indapamide is passed through an 80 mesh sieve, and the indapamide, povidone K30, ethanol, sugar, and microcrystalline cellulose are uniformly mixed with the milk, and the polybasic aqueous solution containing 10% sodium hydroxide is added to prepare a drug-containing alkaline dimension. The ketone K30 aqueous solution of ethanol is stirred, added with 10% hydrochloric acid aqueous solution while stirring, and then made into a soft material, extruded and granulated, and the wet granule is dried and added to the mixed powder of lactose and microcrystalline cellulose to prepare a mixture.

After the whole granules, magnesium stearate and talc powder are added to form a soft material, which is extruded and granulated, and the wet granules are dried.

Tableting. The mixture was added to the Opadry in the water while stirring, and magnesium stearate and talc powder were added and then compressed. Powder, continue to stir for 45 minutes after the addition, add Opadry powder in water while stirring, add the coating solution of 19% concentration, continue to stir for 45 minutes after the core, and prepare the film with 19wt% concentration. Coating. The coating liquid is film coated on the core.

Example 7 Indapamide Tablets (2.5 mg/tablet) Formulation and Preparation Method

Example 8 Indapamide Tablets (2.5 mg/tablet) Formulation and Preparation Method

Example 10 Indapamide Capsule (2.5 mg/granule) Formulation and Preparation Method The particles before the tableting of Example 6 were passed through a 30 mesh sieve, uniformly mixed, and then filled. Comparative Example 3 Glipizide granule formulation and preparation method (glipizide molecular weight 445.54)

Example 11~12 glipizide granule formula and preparation method thereof

Comparative Example 14 and Example 13 Glipizide Tablets (2.5 mg/tablet) Formulation and Preparation Method

Comparative Example 4 Example 13 Drug glipizide 2.5 (2.3%, micronized treatment) Glipizide 2.5 (2.2%, no pretreatment) Lactose 100, povidone K30 2, lactose lactose 100, polydimensional Ketone Κ30 2, magnesium stearate 0.5, accessories

Magnesium 0.5, talc 1, sodium carboxymethyl starch 5 talc 1, sodium carboxymethyl starch 5 Solvent water 8.5 (7.7%) water 3.75 (6.8%)

10% sodium hydroxide solution 2.25 alkalizing agent

(Molecular ratio with glipizide: 1.00) Acidifier \ 10% aqueous hydrochloric acid 2.05 (Formula 1 value: 1.00) Glipizide, Povidone 30 and 10% Hydrogen Oxygen Glipizide over 80 mesh Sieve, with milk

The sodium sulphate solution is formulated into a medicated alkaline solution, and 25% of the sugar is added and uniformly mixed, and the povidone Κ30 is added.

The amount of lactose is stirred evenly, and 10% salt is added with stirring to prepare an aqueous solution for stirring to form a soft material.

The aqueous acid solution is added to the 75% amount of lactose and stirred to process the granules. The wet granules are dried and then granulated.

Made of soft material, extruded granulated, wet granules dried, magnesium stearate, talc and sodium carboxymethyl starch

grain. Add magnesium stearate, talc and carboxymethyl starch and compress.

Tablet after sodium.

Example 14 Glipizide Tablets (2.5 mg/tablet) Formulation and Preparation Method

Example 15 glipizide tablets (5 mg / tablet) formula and preparation method

Example 16 glipizide capsule (2.5 mg / granule) formula and preparation method The granules before the tableting of Example 14 were passed through a 30 mesh sieve, and the mixture was uniformly mixed and then filled. Example 17 Folic acid granule formula and preparation method (folic acid molecular weight 441.4) )

Comparative Example 5 and Example 18 Folic acid granule formulation and preparation method (folic acid molecular weight 441.4)

Example 19 Folic acid granule formula and preparation method

Comparative Example 6 Folic Acid Tablets (5 mg/tablet) Formulation and Preparation Method

Example 21 Folic acid tablet (5 mg / tablet) formula and preparation method

Example 23 Folic acid capsule (5 mg / granule) formula and preparation method

The granules before the tableting of Example 21 were passed through a 30-mesh sieve, uniformly mixed, and then filled. Example 24 Folic acid tablet (5 mg / tablet) formula and preparation method

Example 26 Methotrexate particle formula and preparation method

Example 28 Methotrexate tablets (2.5 mg / tablet) formula and preparation method

Example 30 Indapamide Tablets (2.5 mg/tablet) Formulation and Preparation Method

Example 32 Glipizide Tablets (5 mg/tablet) Formulation and Preparation Method

Example 34 Folic acid tablet (5 mg / tablet) formula and preparation method

Example 36 Methotrexate tablet formulation and preparation method

Example 37 Benzyl fluorothiazide tablets (2.5 mg / tablet) formulation and preparation method

Example 38 Benzyl fluorothiazide particle formulation and preparation method

Example 39 Benzyl fluorothiazide tablets (5 mg / tablet) formulation and preparation method

Example 40 Indapamide Tablets (2.5 mg/tablet) Formulation and Preparation Method

Effect Example 1 Particle size comparison test

Test equipment: BT-9300S laser particle size distribution instrument; BT-800 automatic cycle injection system. Test conditions: The medium in the circulating injection system is water, the volume is about 570ml, and the centrifugal pump has a rotation speed of 1600rpm.

Test method: Take about 2g of particles, add to the circulating injection system, make the absorbance of the system reach about 15%, turn on the ultrasonic dispersion for 3 minutes, and test the sample for 6 consecutive times to obtain the average particle size. D10, D50 and D90 are the corresponding particle sizes when the cumulative particle size distribution percentage reaches 10%, 50% and 90%, respectively. 1) Indapamide particle size comparison:

From the above data, it can be seen that the intrinsic average particle size of indapamide in the indapamide particles obtained by the method of the present invention is reduced to 8.5 to 21.8% of the particle diameter of the drug substance, reaching 4.78 to 12.25 μm.

2) Glipizide particle size comparison:

It can be seen from the above data that the volume average particle diameter of glipizide in the glipizide particles prepared by the method of the invention is reduced to 8.8 to 8.5% of the particle size of the raw material treated by the micropowder, and reaches 0.62 to 0.60 micron. . 3) Folic acid particle size comparison:

From the above data, it can be seen that the average volume fraction of folic acid in the folic acid granules obtained by the method of the present invention is reduced to 15.9 to 34.6% of the particle size of the raw material treated with the fine powder, and is 0.89 to 1.94 μm.

4) Methotrexate particle size:

From the above data, it can be seen that the volume average particle diameter of methotrexate in the methotrexate particles obtained by the method of the present invention is reduced to 5.2 to 10.9% of the particle diameter of the drug substance, which is 4.43 to 9.37 μm.

4) Benzyl fluorothiazide particle size:

From the above data, it is seen that the volume average particle diameter of benzyl fluorothiazide in the benzfluorothiazine particles obtained by the method of the present invention is reduced to 8.9% of the particle diameter of the drug substance to 6.43 μm. Effect Example 2 Dissolution comparison test

1) Indapamide tablets dissolution test

Dissolution method: Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), the dissolution solution 900 ml, take 0.2mol / l potassium dihydrogen phosphate solution 250ml, add 0.2mol / KOH The sodium solution was diluted with water to 1000 ml of 118 m, the pH was adjusted to 6.8, the rotation speed was 100 rpm, and the control solution was prepared according to the law. According to the spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance was measured at a wavelength of 240 nm, and the amount of dissolution per tablet was calculated.

2) Glipizide tablet dissolution test

Dissolution method (1): Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), the eluate is phosphate buffer (pH 7.4) 500ml, the rotation speed is 100 rpm , operate according to law, and prepare a control solution. According to the spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance was measured at a wavelength of 222 nm, and the amount of dissolution per tablet was calculated.

Dissolution method (2): Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), the eluate is water 500ml, the rotation speed is 100 rpm, operate according to the law, and prepare the control solution . According to the spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance was measured at a wavelength of 222 nm, and the amount of dissolution per tablet was calculated.

3) Folic acid tablet dissolution test

Dissolution method (1): Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), the eluate is phosphate buffer (pH 6.8) buffer 900ml, the rotation speed is every minute 100 rpm, operate according to law, and prepare a control solution. According to the spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance is measured at a wavelength of 281 nm, and the dissolution of each tablet is calculated.

Dissolution method (2): Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), the eluate is 900ml of water, the rotation speed is 100 rpm, operate according to the law, and prepare the control solution . According to the spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance was measured at a wavelength of 281 nm, and the amount of dissolution per tablet was calculated. Dissolution (%)

Example

5min 15min 30min 45min comparison 6 32.18 42.70 46.26 49.51

20 42.85 55.69 61.88 63.74

21 57.40 62.81 65.29 66.37

22 60.30 66.41 69.76 71.04

35 59.78 65.34 68.33 69.49

Effect Example 3 Stability Comparison Test

1) indapamide

The test samples were placed in high-density polyethylene plastic bottles, sealed, placed in an accelerated inspection box, and subjected to an accelerated test for 3 months at a temperature of 40 ° C ± 2 ° C and a relative humidity of 75% ± 5%. Stability determination of related items.

Method for determining the substance: Protect from light. Take the appropriate amount of fine powder, add appropriate amount of mobile phase, shake in a hot water bath for 5 minutes, dissolve indapamide, dilute with mobile phase to make a solution containing about 0.5 mg of indapamide per 1 ml, filter After that, the filtrate was taken as the test sample. According to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix V D), octadecyl silicon germanium bonded silica was used as a filler and determined separately. Calculated according to the area normalization method.

The dissolution test method was the same as in the effect example 2.

Effect Example 4 Comparison of the content of the hooks

1) Indapamide tablets

Determination of content uniformity: Take 1 tablet of this product, place it in the milk, add appropriate amount of ethanol, grind, and transfer it to 100ml volumetric flask with ethanol, shake it, dissolve indapamide, dilute with ethanol to scale Shake well, filter, and accurately measure 10ml of the filtrate. Place in a 50ml volumetric flask, dilute to the mark with ethanol, shake well, take the reference solution under the solution and the content determination, and observe the UV-visible spectrophotometry. Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance is measured at a wavelength of 242 nm, calculated.

2) Glipizide tablets

Determination of content uniformity: Take 1 piece of this product, grind it, add phosphate buffer (pH 7.4), grind it in an appropriate amount, and transfer it to a 200ml volumetric flask with phosphate buffer (pH 7.4). Shake well. , filtered, take the filtrate as the test solution; take the appropriate amount of glipizide reference substance, the same method to make a solution containing about 25 per 1ml, as a reference solution. The above two solutions were taken, and the absorbance was measured at a wavelength of 275 nm, and calculated.

3) Folic acid tablets

Determination of content uniformity: Take 1 piece of this product, place it in a 25ml volumetric flask, add about 15ml of 0.5% ammonia solution, heat in a hot water bath for 20 minutes, shake it to dissolve the folic acid, let cool, dilute with water to the scale Shake, filter, and take the filtrate as the test solution, according to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix VD), using 18 垸垸 silicon germanium bonded silica as a filler, record the chromatogram Another folic acid reference substance, determined by the same method, according to the external standard method to calculate the content of the peak area, should be consistent with (Chinese Pharmacopoeia 2010 edition two appendix XE).

4) Benzyl fluorothiazide tablets

Determination of content uniformity: Take 1 tablet of this product, place it in a mortar, grind it, add 0.4% sodium hydroxide solution, grind it, and transfer it to a 25ml volumetric flask with 0.4% sodium hydroxide solution, shake it thoroughly. Dissolve the benzyl fluorothiazide, dilute to the mark with 0.4% sodium hydroxide solution, shake well, filter, accurately measure the 2ml of the filtrate, place in a 25ml volumetric flask, dilute with water to the mark, shake well, according to spectrophotometry ( Chinese Pharmacopoeia 2010 edition two appendix IV A), absorbance at 274nm wavelength; another precision weighed benzyl fluorothiazide reference substance, add 0.01mol / L sodium hydroxide solution dissolved and quantitatively diluted to make each lml 15 g of solution, the same method of measuring absorbance, calculated.

Claims

Rights request

A method for preparing a pharmaceutical solid preparation, which comprises the steps of: dissolving a water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient in an alkaline solution containing an alkalizing agent to obtain a drug-containing alkaline After the solution, the excipient and the medicated alkaline solution are uniformly mixed and subjected to wet granulation.

2. The method according to claim 1, wherein: the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is 20% or less, preferably 10% or less, more preferably in the solid preparation. The water-insoluble or poorly water-soluble acidic pharmaceutical active ingredient is 5% or less; the percentage is the mass percentage.

3. The method according to claim 1, wherein: the water-insoluble and/or poorly water-soluble basic pharmaceutically active ingredient is glipizide, folic acid, bumetanide, diclofenac, Isocyanol, benzfluorothiazide, p-fluorothiazide, methotrexate, vitamin H, hexaerythritol, indapamide, furosemide, thioguanine, allopurinol, gliclazone , simvastatin, leflunomide, hydrochlorothiazide or phenobarbital.

The method according to any one of claims 1 to 3, wherein the alkalizing agent is an inorganic base and/or an organic base, or a strong base and/or a weak base, preferably selected from hydrogen. One or more of sodium oxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, meglumine, diethanolamine, and triethanolamine.

5. The method of claim 1 wherein:

When the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is indapamide, the alkalizing agent is sodium hydroxide, potassium hydroxide or sodium ethoxide;

When the water-insoluble and/or water-insoluble acidic pharmaceutical active ingredient is glipizide, the alkalizing agent is sodium hydroxide or potassium hydroxide;

When the water-insoluble and/or water-insoluble acidic pharmaceutical active ingredient is folic acid, the alkalizing agent is sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium carbonate or potassium carbonate;

When the water-insoluble and/or water-insoluble acidic pharmaceutical active ingredient is methotrexate, the alkalizing agent is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; When the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is benzfluorothiazide, the alkalizing agent is sodium hydroxide or potassium hydroxide.

6. The method according to claim 1, 4 or 5, wherein: the alkalizing agent is used in an amount such that the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is completely dissolved. 1.5 times, more preferably 1 to 1.05 times.

The method according to claim 1, 4 or 5, wherein the molar ratio of the alkalizing agent to the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is from 0.1 to 2.5, more preferably 0·9~1·5.

8. The method of claim 1 wherein:

When the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is indapamide, the alkalizing agent is sodium hydroxide or sodium ethoxide in an amount of 0.7 to 1.1 times the molar amount of indapamide;

When the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is glipizide, the alkalizing agent is sodium hydroxide having a molar amount of glipizide of 0.95 to 1.1 times;

The water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is folic acid, and the alkalizing agent is sodium hydroxide having a molar amount of folic acid of 1.8 to 2.1 times or a molar amount of 0.95 to 1.1 times of sodium carbonate or potassium carbonate. ;

The water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is methotrexate, and the alkalizing agent is a molar amount of methotrexate of 1.4 to 1.6 times sodium hydroxide or a molar amount of 0.85 to 1.1 times. Sodium carbonate; the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is benzfluorothiazide, and the alkalizing agent is sodium hydroxide having a molar amount of benzyl fluorothiazide of 0.9 to 1.6 times.

9. The method according to claim 1, wherein: the solvent in the alkaline agent-containing alkaline solution is water, an organic solvent or a mixture of water and an organic solvent, and the ions in the alkalizing agent are Dissociation in the solvent;

The organic solvent is a solvent acceptable for the field of the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient which is superior to water, preferably a water-soluble alcohol or a ketone solvent, more preferably One or more of ethanol, acetone, propylene glycol, and glycerol.

The method according to claim 1 or 9, wherein the amount of the solvent in the alkaline solution is from 5 to 100% by mass, preferably from 10 to 50% by mass based on the dry granulated dry material.

11. The method according to claim 1, wherein: while and/or after the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is dissolved in the alkaline solution containing the alkalizing agent, Further adding one or more of a surfactant, a solubilizing agent and a water-soluble carrier of the solid dispersion, and then subjecting the obtained medicated alkaline liquid to a subsequent step, that is, uniformly mixing with the auxiliary material, performing wet granulation; When the insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is dissolved in the alkaline solution containing the alkalizing agent, and the water-soluble carrier of the solid dispersion is also added, the amount of the water-soluble carrier of the solid dispersion is controlled at It can ensure that the water-insoluble and/or water-insoluble acidic pharmaceutical active ingredient is completely dissolved in the alkaline solution containing the alkalizing agent;

One or more of the water-soluble carrier of the surfactant, solubilizer and solid dispersion are preferably povidone, polyethylene glycol 400-8000, sodium dodecyl sulfate, and poloxa a kind of polyoxyethylene castor oil, Tween 80, polyoxyl 40 stearate, lactose, mannitol, sucrose, hydroxypropyl-β-cyclodextrin, β-cyclodextrin and maltitol Or a variety;

The surfactant and/or the solubilizing agent are preferably added in an amount of 0.05 to 5 times, more preferably 0.05 to 2 times, the mass of the water-insoluble and/or water-insoluble acidic pharmaceutical active ingredient;

The water-soluble carrier of the solid dispersion is preferably added in an amount of from 0.5 to 20 times, more preferably from 0.5 to 2 times, the mass of the water-insoluble and/or water-insoluble acidic pharmaceutical active ingredient.

12. The method according to claim 1, wherein: in preparing the medicated alkaline solution, the solution is prepared according to the following operation: when water is used as a solvent, the temperature is raised to 40 to 80 ° C _; When a mixed solution of water and an organic solvent is used as a solvent, the temperature is raised to 40 to 70 ° C _; when ethanol is used as a solvent, the temperature is raised to 30 to 50 ° C.

The method according to any one of claims 1 to 12, wherein: in the step of uniformly mixing the auxiliary material and the medicated alkaline liquid to perform wet granulation, acidification is further added. The agent lowers the alkalinity of the mixture of the acidifying agent and the medicated alkaline solution with respect to the alkalinity of the medicated alkaline solution.

14. The method according to claim 13, wherein: the alkalizing agent is an inorganic strong base, An organic strong base or an inorganic medium strong base, wherein the acidifying agent is an inorganic strong acid;

More preferably, the alkalizing agent and acidifying agent are the combination of sodium hydroxide and hydrochloric acid, potassium hydroxide and hydrochloric acid, sodium ethoxide and hydrochloric acid, sodium carbonate and hydrochloric acid, and potassium carbonate and hydrochloric acid.

The method according to claim 13 or 14, wherein the amount of the alkalizing agent and the acidifying agent satisfies the following relationship: The value obtained by the formula 1 is 0.01 to 1.5, preferably 0.2 to 1.1. More preferably 0.9-1.1;

(number of moles of acidifier xA) I (number of moles of alkalizing agent xB)

Wherein A is the number of hydrogen ions in the acidifier molecule, and B is the total number of valence states of the alkalinizer molecular anion.

16. The method of claim 13 wherein: the specific operation is performed in any of the following ways:

Mode (1) uniformly mixing the acidifying agent or the acidifying agent-containing solution and the auxiliary material, and uniformly mixing with the medicated alkaline liquid, and performing extrusion granulation or stirring granulation;

Mode (2) uniformly mixing the medicated alkaline solution with an acidifying agent or a solution containing an acidifying agent to obtain a granulating liquid, and then pulverizing, agitating, granulating, and fluidizing the granulating liquid and the auxiliary material. Spray granulation or centrifugal spray granulation, etc.;

Mode (3) uniformly mixing the medicated alkaline solution with the auxiliary material, and then uniformly mixing with the acidifying agent-containing solution, and performing extrusion granulation or stirring granulation;

(4) uniformly mixing the medicated alkaline liquid with 1/3 or less of the auxiliary material, and the acidifying agent or the acidifying agent-containing solution, and then mixing with the remaining auxiliary materials for extrusion granulation or stirring granulation; The excipients in the excipients of 1/3 or less are preferably water-soluble excipients.

17. The method of claim 1 wherein: the solid granules obtained by the process of claim 1 are subjected to further conventional procedures to produce tablets or capsules.

18. A pharmaceutical solid preparation prepared by the method according to any one of claims 1 to 17.