Pharmaceutical composition containing trihexylamine hydrochloride and preparation method of pharmaceutical composition

Abstract

The invention belongs to the field of medicines, and particularly relates to a pharmaceutical composition containing tribenthol hydrochloride and a preparation method of the pharmaceutical composition. The preparation method mainly comprises the following steps: pre-treating, pre-mixing for the first time, pre-mixing for the second time, pre-mixing for the third time, totally mixing, tabletting and packaging. According to the present invention, the trihexylalcohol hydrochloride tablet is prepared by using the direct powder compression method, such that the mixing uniformity is good by using the premixing manner of the equal-amount gradually-increasing mixing, and the microcrystalline cellulose and the lactose are adopted as the filler to ensure the good compressibility of the total mixing particles so as to prepare the trihexylalcohol hydrochloride tablet; calcium hydrogen phosphate dihydrate or anhydrous calcium hydrogen phosphate is adopted as a filling agent to guarantee good fluidity of the total mixed particles, the layering risk of the total mixed particles is reduced through model screening of lactose and particle size screening of the calcium hydrogen phosphate dihydrate or anhydrous calcium hydrogen phosphate, and the content and content uniformity of finished products are guaranteed to meet the requirements.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a pharmaceutical composition containing trihexyphenidyl hydrochloride and a preparation method thereof. BACKGROUND

[0002] Trihexyphenidyl hydrochloride is a central anticholinergic anti-Parkinson's disease (PD) drug, which is easily absorbed by oral administration, and reduces the effect of acetylcholine (Ach) in the nigrostriatal pathway by selectively blocking the cholinergic nerve pathway of the striatum, and has a smaller effect on peripheral nerve pathways, thus helping to balance the neurotransmitter levels in the brain of patients to a certain extent. The drug has good antitremor effect, and can also improve dyskinesia and muscle rigidity. It can be used to treat a small number of PD patients who cannot accept levodopa (L-DOPA) or dopamine receptor agonists, and is mainly used in clinical practice for early mild PD patients, PD patients who cannot tolerate levodopa or are prohibited from using levodopa, and Parkinson's syndrome caused by antipsychotic drugs.

[0003] The original research company of trihexyphenidyl hydrochloride tablets is LEDERLE company, which was approved by the Food and Drug Administration (FDA) in May 1949, and the trade name is "ARTANE (ARTANE)", and the specifications include 2mg and 5mg. The generic drug trihexyphenidyl hydrochloride tablets of Watson Labs company was approved by the FDA in November 1974, and is listed as a reference preparation by the FDA. In the "Directory of Generic Reference Preparations (Seventh Batch)" issued by the National Medical Products Administration (NMPA), the product of the company is also confirmed as the reference preparation of trihexyphenidyl hydrochloride tablets.

[0004] The original preparation process of trihexyphenidyl hydrochloride tablets is to mix trihexyphenidyl hydrochloride and other excipients by wet granulation, then dry the wet granules in an oven, and then granulate, add total mixing, and press and package to form. The wet granulation process has the following problems:

[0005] (1) The wet granulation process has many procedures, complex operation, and long production cycle;

[0006] (2) The dried wet granules have a long drying time, and consume time and energy, and there is a risk of increasing related substances;

[0007] (3) The prepared granules have small particle size and poor flowability, which affects the filling during tabletting and causes large tablet weight differences. SUMMARY

[0008] To solve the above problems, the present application provides a pharmaceutical composition containing benztropine hydrochloride, which comprises the following components by weight fraction:

[0009] benztropine hydrochloride 1-10 parts, first filler 30-100 parts, second filler 30-80 parts, third filler 30-70 parts, disintegrant 1-10 parts, glidant 0.1-1 part and lubricant 1.5-3 parts;

[0010] The first filler is microcrystalline cellulose, the second filler is lactose, and the third filler is calcium hydrogen phosphate dihydrate or anhydrous calcium hydrogen phosphate.

[0011] Further, it comprises the following components by weight fraction: benztropine hydrochloride 2 parts, first filler 50-80 parts, second filler 45-65 parts, third filler 40-60 parts, disintegrant 2-6 parts, glidant 0.1-0.5 parts and lubricant 1.6-2.8 parts;

[0012] The proportion of the first filler microcrystalline cellulose is 30%-70%wt, and the proportion of the second filler lactose is 20%-40%wt.

[0013] The present application also provides a preparation method of the above-mentioned pharmaceutical composition, comprising the following steps:

[0014] (1) Mix the glidant and part of the first filler and sieve to obtain a mixture a;

[0015] (2) Mix benztropine hydrochloride and part of the first filler in a mixer to obtain a mixture b;

[0016] (3) Add part of the first filler to the mixer in step (2) and continue mixing to obtain a mixture c;

[0017] (4) Add the remaining first filler, second filler, third filler, disintegrant and mixture a to the mixer in step (3) and continue mixing to obtain a mixture d;

[0018] (5) Add the lubricant to the mixer in step (4) and mix to obtain a mixture e;

[0019] (6) Tablet and package.

[0020] Further, the mixing in step (2) is carried out at a rotation speed of 5-20 rpm for 1-5 min.

[0021] Further, the mixing in step (3) is carried out at a rotation speed of 5-20 rpm for 1-5 min.

[0022] Furthermore, in step (4), the mixing speed is 5-20 rpm, the time is 10-25 min, and the loading coefficient of the mixer is 30%-80%.

[0023] Furthermore, in step (5), the total mixing speed is 5-20 rpm, the time is 1-15 min, and the loading coefficient of the mixer is 30%-80%.

[0024] Furthermore, the tableting in step (6) is performed using a rotary tablet press with a die diameter of 6 to 12 mm. During the tableting process, the tablet weight difference is controlled within ±6.5%, and the average hardness is between 30 and 100 N.

[0025] The present invention has the following beneficial effects:

[0026] (1) By using different preparation processes, the present invention greatly simplifies the process and improves production efficiency.

[0027] (2) The process of the present invention does not require a drying step, which avoids the risk of the increase of related substances under humid and hot conditions and increases the stability of the product.

[0028] (3) By screening excipients from different manufacturers and models, this invention obtains particles with suitable particle size and good flowability, which makes the tableting process smooth, the tablet weight difference small, and improves the uniformity of the product. Detailed Implementation

[0029] This document details various exemplary embodiments of the present invention. Unless otherwise specified, the methods used in these embodiments employ conventional methods, and the reagents used are commercially available or prepared using conventional methods. This detailed description should not be construed as a limitation of the invention, but rather as a more detailed description of certain aspects, characteristics, and embodiments of the invention. It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, regarding numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as any smaller range between any other stated value or intermediate value within said range, are also included within the scope of this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0030] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0031] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0032] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0033] The basic principle of this invention:

[0034] The technical solution provided by this invention fully leverages the advantages of the direct powder compression method. By pulverizing the active ingredient of trihexyphenidyl hydrochloride to a suitable particle size, and premixing it using an equal-volume incremental mixing method, good mixing uniformity is ensured. Microcrystalline cellulose and lactose are used as fillers to ensure good compressibility of the total mixed particles. Calcium dicalcium phosphate dihydrate or anhydrous calcium dicalcium phosphate is used as a filler to ensure good flowability of the total mixed particles. Furthermore, by screening the type of lactose and the particle size of calcium dicalcium phosphate dihydrate or anhydrous calcium dicalcium phosphate, the risk of stratification of the total mixed particles is reduced, ensuring that the content and content uniformity of the finished product meet the requirements.

[0035] The microcrystalline cellulose mentioned in the following examples is manufactured by Microcellulose Weissenborn GmbH+Co.KG (model: 102); the lactose is manufactured by GranuLac140 (Germany); the dicalcium phosphate dihydrate or anhydrous dicalcium phosphate is manufactured by Huzhou Zhanwang Pharmaceutical Co., Ltd.; the sodium carboxymethyl starch is manufactured by Anhui Shanhe Pharmaceutical Excipients Co., Ltd. (model: SH-H); the silica is manufactured by Anhui Shanhe Pharmaceutical Excipients Co., Ltd. (model: SH-QX1); and the magnesium stearate is manufactured by Liaoning Aoda Pharmaceutical Co., Ltd.

[0036] In this invention, the particle size of the active pharmaceutical ingredient, filler, etc., is determined according to the particle size and particle size distribution determination method (General Rule 0982, Method 3, Dry Method) in Part IV of the Chinese Pharmacopoeia 2020.

[0037] Example 1

[0038] The preparation method of benztropine hydrochloride tablets includes the following steps:

[0039] (1) Crushing and weighing: The active pharmaceutical ingredient of trihexyphenidyl hydrochloride was mechanically crushed, and the particle size D90 after crushing was ≤100μm. According to the weight ratio, each active pharmaceutical ingredient and excipient was weighed, including 2 parts of trihexyphenidyl hydrochloride, 65.6 parts of microcrystalline cellulose, 56 parts of lactose, 50 parts of calcium hydrogen phosphate dihydrate, 4 parts of sodium carboxymethyl starch, 0.2 parts of silicon dioxide, and 2.2 parts of magnesium stearate, for later use;

[0040] (2) Pretreatment: The silica obtained in step (1) is mixed with 5 parts of microcrystalline cellulose and then passed through a 40-mesh sieve to obtain mixture a;

[0041] (3) Premix 1: Add the benzyl hydrochloride obtained in step (1) and 8 parts of microcrystalline cellulose into a mixer and mix for 4 minutes to obtain mixture b;

[0042] (4) Premix 2: Add 30 parts of microcrystalline cellulose from step (1) to the mixer from step (3) and mix for 4 minutes to obtain mixture c;

[0043] (5) Premix 3: Add the remaining microcrystalline cellulose, lactose, calcium hydrogen phosphate dihydrate, sodium carboxymethyl starch and mixture a from step (1) to the mixer from step (4) and mix for 16 min to obtain mixture d;

[0044] (6) Total mixing: Add the magnesium stearate obtained in step (1) to the mixer obtained in step (5) and mix for 8 minutes to obtain mixture e;

[0045] (7) Tableting: The mixture e described in step (6) is tableted using a rotary tablet press with a die diameter of 8 mm. During the tableting process, the weight difference of the tablets is controlled within ±6.5%, and the average hardness is between 30 and 100 N to obtain raw tablets.

[0046] (8) Packaging: The raw film described in step (7) is packaged in a plastic bottle to obtain the product.

[0047] Example 2

[0048] This embodiment is basically the same as that of embodiment 1, except that the 65.6 parts of microcrystalline cellulose and 56 parts of lactose in step (1) of embodiment 1 are changed to 70.6 parts of microcrystalline cellulose and 51 parts of lactose.

[0049] Example 3

[0050] This embodiment is basically the same as that of embodiment 1, except that the 65.6 parts of microcrystalline cellulose and 4 parts of sodium carboxymethyl starch in step (1) of embodiment 1 are changed to 63.6 parts of microcrystalline cellulose and 6 parts of sodium carboxymethyl starch.

[0051] Example 4

[0052] This embodiment is basically the same as that of embodiment 1, except that the 8 parts of microcrystalline cellulose in step (3) of embodiment 1 are changed to 4 parts of microcrystalline cellulose; and the 30 parts of microcrystalline cellulose in step (4) are changed to 8 parts of microcrystalline cellulose.

[0053] Example 5

[0054] This embodiment is basically the same as embodiment 1, except that the mixing time of 16 minutes in step (5) of embodiment 1 is changed to 20 minutes.

[0055] Example 6

[0056] This embodiment is basically the same as embodiment 1, except that the mixing time of step (6) in embodiment 1 is changed from 8 minutes to 11 minutes.

[0057] Comparative Example 1

[0058] This comparative example is basically the same as Example 1, except that the lactose type GranuLac140 in the example is replaced with FlowLac100.

[0059] Comparative Example 2

[0060] This comparative example is basically the same as Example 1, except that the 65.6 parts of microcrystalline cellulose and 2.2 parts of magnesium stearate in step (1) of Example 1 are changed to 66.36 parts of microcrystalline cellulose and 1.44 parts of magnesium stearate.

[0061] Effect evaluation experiment

[0062] Dissolution determination, dissolution curve method: basket method; dissolution medium: pH 6.8 phosphate buffer medium; dissolution volume: 900 ml; rotation speed: 100 rpm; sampling time: 5 min, 10 min, 15 min, 30 min, 45 min.

[0063] The uniformity of particle mixing and the uniformity of finished product content were determined according to the high performance liquid chromatography method of the Chinese Pharmacopoeia 2020 edition.

[0064] Table 1. Comparison of the effects of trihexyphenidyl hydrochloride tablets prepared in Examples 1-6 and Comparative Examples 1-2.

[0065]

[0066] Note: " / " in the table indicates that the item was not detected.

[0067] As shown in Table 1, Examples 1 to 6 adopted the direct powder compression method. Through the study of the proportion of filler, the amount of other excipients, the mixing time, etc., the process was smooth, and the obtained particle mixing uniformity, finished product content uniformity and dissolution curve met the requirements.

[0068] Comparative Example 1 used FlowLac100 lactose from Germany and employed a suitable mixing process, resulting in good particle uniformity. However, particle stratification occurred in subsequent processes, and the uniformity of the finished product content exceeded the limit.

[0069] Comparative Example 2 used magnesium stearate as a lubricant, with an amount of 1.44 parts. The lubrication effect was insufficient, and sticking occurred during the tableting process.

[0070] In summary, this invention uses suitable excipients and adopts a direct powder compression preparation method. The process is stable, and the particle mixing uniformity, finished product content uniformity, and dissolution curve test results meet the requirements, representing a significant improvement over the original wet granulation process.

[0071] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A pharmaceutical composition containing trihexyphenidyl hydrochloride, characterized in that, The following components are included by weight: 1-10 parts of trihexyphenidyl hydrochloride, 30-100 parts of the first filler, 30-80 parts of the second filler, 30-70 parts of the third filler, 1-10 parts of disintegrant, 0.1-1 parts of flow aid, and 1.5-3 parts of lubricant; The first filler is microcrystalline cellulose, the second filler is lactose, and the third filler is calcium hydrogen phosphate dihydrate or anhydrous calcium hydrogen phosphate.

2. The pharmaceutical composition according to claim 1, characterized in that, The product comprises the following components by weight: 2 parts of trihexyphenidyl hydrochloride, 50-80 parts of the first filler, 45-65 parts of the second filler, 40-60 parts of the third filler, 2-6 parts of disintegrant, 0.1-0.5 parts of flow aid, and 1.6-2.8 parts of lubricant; The first filler, microcrystalline cellulose, accounts for 30% to 70% wt, and the second filler, lactose, accounts for 20% to 40% wt.

3. The method for preparing the pharmaceutical composition according to claim 1, characterized in that, Includes the following steps: (1) The gliding agent and part of the first filler are mixed and sieved to obtain mixture a; (2) Benzyl hydrochloride and part of the first filler were mixed in a mixer to obtain mixture b; (3) Add a portion of the first filler to the mixer in step (2) and continue mixing to obtain mixture c; (4) Add the remaining first filler, second filler, third filler, disintegrant and mixture a to the mixer in step (3) and continue mixing to obtain mixture d; (5) Add lubricant to the mixer in step (4) and mix thoroughly to obtain mixture e; (6) Tableting and packaging.

4. The preparation method according to claim 3, characterized in that, The mixing process described in step (2) involves mixing in a mixer at a speed of 5-20 rpm for 1-5 minutes.

5. The preparation method according to claim 3, characterized in that, The mixing speed in step (3) is 5-20 rpm, and the time is 1-5 min.

6. The preparation method according to claim 3, characterized in that, The mixing speed in step (4) is 5-20 rpm, the time is 10-25 min, and the loading coefficient of the mixer is 30%-80%.

7. The preparation method according to claim 3, characterized in that, The total mixing speed in step (5) is 5-20 rpm, the time is 1-15 min, and the loading coefficient of the mixer is 30%-80%.

8. The preparation method according to claim 3, characterized in that, The tableting process described in step (6) is performed using a rotary tablet press with a die diameter of 6 to 12 mm. During the tableting process, the tablet weight difference is controlled within ±6.5%, and the average hardness is between 30 and 100 N.

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