Difenidol composition as well as preparation method and application thereof

Abstract

The invention discloses a difenidol composition as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The technical problem to be solved is to improve the drug stability and improve the dissolution similarity with the original drug. According to the technical scheme, the difenidol composition is characterized by comprising the following raw materials: difenidol, lactose, starch, potassium hydrogen tartrate, a disintegrating agent, a lubricating agent and a film coating premix. The lactose comprises crushed lactose and uncrushed lactose; the D90 of the difenidol and the crushed lactose is equal to 120 to 150 microns; the mass ratio of the difenidol to the crushed lactose is 1: (2-3); a film forming material in the film coating premix is polyvinyl alcohol.

Description

Technical Field

[0001] This invention provides a difenidol hydrochloride composition, its preparation method, and its application, belonging to the field of pharmaceutical preparations. Background Technology

[0002] For understanding the technical content of this invention: Diphenidol hydrochloride can improve vertebrobasilar artery blood supply, regulate vestibular system function, inhibit the vomiting center, and has anti-vertigo and antiemetic effects. Diphenidol hydrochloride tablets are a drug preparation used to treat dizziness, nausea, and vomiting caused by various reasons, such as motion sickness, seasickness, and airsickness. The original manufacturer of the formulation is NIPPON SHINYAKU Co., Ltd. of Japan. The formulation specification is 25mg, and the brand name is "Cephadol".

[0003] To ensure the efficacy and quality of the drug, the developed formulation must be consistent with the original drug in terms of dissolution rate, and its subsequent stability must also be guaranteed to ensure good quality.

[0004] Relevant patent documents retrieved: This document, published in China (CN110251471A) on September 20, 2019, discloses a difenidol hydrochloride tablet and its preparation method. The difenidol hydrochloride tablet comprises the following components by weight percentage: 15-25% difenidol hydrochloride and 85-75% excipients. The Dv90 particle size of the difenidol hydrochloride is 10-50 μm. The pH of the difenidol hydrochloride tablet is controlled between 3.55 and 5.54. By controlling the pH value and the Dv90 particle size of the difenidol hydrochloride raw material within the range of 10-50 μm, the prepared difenidol hydrochloride tablet achieves the same dissolution rate as the original drug in water, pH 1.2, pH 4.0, and pH 6.8 media, while simultaneously improving the dissolution rate (dissolution rate greater than 90% at 15 min). However, in order to improve the dissolution similarity of drugs, the D90 particle size is in the range of 10-50μm. If the fine particle size is too small, the specific surface area of ​​the material will increase, and it will come into contact with air and moisture, resulting in poor stability.

[0005] Relevant non-patent literature retrieved: The journal or book title is *China Pharmaceutical Industry*, the article title is "Optimization of Formulation and Preparation Process of Difenidol Hydrochloride Single-Layer Osmotic Pump Controlled-Release Tablets", Volume 30, Issue 9, Publication Date: May 5, 2021. This article discloses a study on the coating amount, keeping the tablet core formulation, coating solution formulation, and process parameters unchanged, investigating the effect of coating weight increase of 3%, 5%, and 7% on the release rate. Results showed that with a 3% coating weight increase, the controlled-release tablet coating ruptured at 5-6 hours, causing a burst drug release; when the coating weight increase was 7%, the drug release was slower than with a 5% increase. The optimal combination was: NaCl 90 mg, PEO-N 20 mg, PEG1500 mixed with coating solution in a ratio of 8 g:1000 ml, with a coating weight increase of 4.50%. The experiment yielded an average cumulative release rate of 66.93% after 14 hours.

[0006] The prior art represented by the aforementioned documents has at least the following unresolved technical problems or defects: Improving stability and achieving dissolution similar to the original drug cannot be achieved simultaneously. The relevant evidence is that the fine particle size of the pulverized material in patent CN110251471A is too small, which increases the specific surface area of ​​the material, leading to contact with air and moisture and causing poor stability.

[0007] In solving the above problems or overcoming the above defects, the present invention encountered the following difficulties and obstacles: To improve the dissolution of self-made formulations, when difenidol raw material is pulverized to below D90 to 50 μm as required by CN110251471A, the pressure of the compressed gas flow needs to reach above 0.8 MPa, which not only places high demands on the equipment but also consumes a lot of energy. When difenidol raw material is pulverized to below D90 to 50 μm, the sample stability is relatively poor.

[0008] In this study, when researching the raw materials of diphenhydramine and lactose pulverization, if the ratio exceeds 1:3 (i.e. 1:3.5), the prepared particles have poor flowability, which easily leads to large differences in tablet weight. Summary of the Invention

[0009] The purpose of this invention is to provide: A difenidol hydrochloride composition, and related technologies thereof, to solve technical problems such as improving drug stability, improving dissolution similarity with the original drug, or combinations thereof.

[0010] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0011] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0012] The definitions of standard chemical terms can be found in the reference "Pharmacopoeia of the People's Republic of China (2020 Edition), China Medical Science and Technology Press: May 2020: 1st Edition."

[0013] Unless otherwise stated, conventional methods within the scope of the art, such as liquid chromatography detection, shall be used.

[0014] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0015] The term "difenidol" as used herein refers to difenidol and its pharmaceutically acceptable salts, including difenidol benzenesulfonate, difenidol hydrochloride, etc. This invention uses difenidol hydrochloride.

[0016] In a first aspect, the present invention provides: a diphenhydramine composition comprising the following raw materials: diphenhydramine, lactose, starch, potassium bitartrate, disintegrant, lubricant, and film coating premix; wherein the lactose comprises pulverized lactose and uncrushed lactose; the D90 of the diphenhydramine and pulverized lactose is 120-150 μm; the mass ratio of the diphenhydramine to pulverized lactose is 1:(2-3); and the film-forming material in the film coating premix is ​​polyvinyl alcohol.

[0017] The technical feature of the difenidol composition, by weight, is selected from: 200-300 parts difenidol, 600-800 parts lactose, 50-150 parts starch, 100-300 parts potassium hydrogen tartrate, 30-60 parts disintegrant, 5-15 parts lubricant, and 50-90 parts film coating premix.

[0018] The raw materials of the technical feature difenidol composition, by weight, are preferably: 250-300 parts difenidol, 650-800 parts lactose, 100-150 parts starch, 200-300 parts potassium hydrogen tartrate, 50-60 parts disintegrant, 10-15 parts lubricant, and 55-83 parts film coating premix.

[0019] The mass ratio of fenido and pulverized lactose, which are technically characterized, is selected from: 1:(2-3).

[0020] The preferred mass ratio of fenidotoluene to pulverized lactose is 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4; 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, or any combination thereof.

[0021] The technical feature of the disintegrant is selected from at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and croscarmellose.

[0022] The preferred technical feature of the disintegrant is at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium.

[0023] The technical characteristic disintegrant is further preferably at least one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

[0024] The preferred disintegrant is sodium carboxymethyl starch.

[0025] The technical feature lubricant is selected from at least one of magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, and talc.

[0026] The preferred technical lubricant is at least one of magnesium stearate, calcium stearate, stearic acid, and hydrogenated vegetable oil.

[0027] The technically characteristic lubricant is further preferably selected from at least one of magnesium stearate, calcium stearate, and stearic acid.

[0028] Among them, the preferred technical lubricant is magnesium stearate.

[0029] Based on further solutions to the technical problems of the present invention, or simultaneous solutions to multiple technical problems, the preferred solution in the technical solution provided in the first aspect of the present invention includes: The first preferred option is the mass ratio of difenidol to pulverized lactose. This technical solution, based on solving the technical problems of "improving drug stability and increasing dissolution similarity with the original drug", further solves the technical problems of "further improving drug stability and increasing dissolution similarity with the original drug".

[0030] Secondly, the present invention provides a method for preparing a diphenhydramine composition, comprising the following steps: (1) Mix diphenhydramine and some lactose and grind them to D90=120-150μm to obtain a mixture of active ingredients; (2) Granulate the mixture of active ingredients, the remaining unpulverized lactose, starch, potassium hydrogen tartrate and binder, and dry them after granulation to obtain dry granules; (4) Mix the dried granules, disintegrant and lubricant together and compress into tablets; (5) Coating is performed using a film coating premix.

[0031] The technical feature adhesive is selected from an aqueous solution of ethanol.

[0032] Among them, the volume fraction of ethanol in the aqueous solution of ethanol is 40-60%.

[0033] The technical feature is that the volume fraction of ethanol in the aqueous solution of ethanol is 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, or any combination thereof.

[0034] The moisture content of the dried particles, as described in the technical feature, is selected from 1-2 wt%.

[0035] The moisture content of the dried particles is preferably 1 wt%, 1.2 wt%, 1.4 wt%, 1.6 wt%, 1.8 wt%, 2 wt%, or any combination thereof.

[0036] The weight gain of the technical feature coating is selected from 4-6 wt%.

[0037] The preferred weight gain of the coating is 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, or any combination thereof.

[0038] Thirdly, the present invention provides: a difenidol medicament comprising the above-described difenidol composition.

[0039] The technically characteristic drug is selected from at least one of the following: tablets, injections, capsules, granules, suppositories, pills, softgels, emulsions, inhaled preparations, sprays, aerosols, gels, powders, syrups, oral solutions, oral suspensions, and oral emulsions.

[0040] Fourthly, the present invention provides the use of difenidol compositions in improving the stability and dissolution properties of difenidol.

[0041] Among them, the technical characteristic of dissolution performance is: similar to the dissolution of the original drug.

[0042] The beneficial effects of this invention are as follows: The present invention has at least the following beneficial effects: Compared with existing technologies, the present invention has better technical effects in improving drug stability and dissolution similarity with the original drug.

[0043] According to experimental tests, the present invention reduces the drug stability from 0.46% impurity I and 1.15% total impurities after 6 months of storage in the prior art to less than 0.33% impurity I and 0.55% total impurities after 6 months of storage, while ensuring similar dissolution as the reference formulation.

[0044] Furthermore, based on the present invention: 1. Based on the comparison of Example 1 and Comparative Examples 1-5, the present invention employs a combination of specific technical means, including the particle size of the pulverized material, the ratio of difenidol hydrochloride to lactose in the pulverized material, and the type of film-forming material, to achieve new technical effects with better stability and dissolution similar to the reference formulation. The combined technical effect is superior to the sum of the effects of each individual technical means. Attached Figure Description

[0045] Figure 1 This is a dissolution curve of the example in phosphate medium at pH 6.8.

[0046] Figure 2 This is a comparative dissolution curve in phosphate medium at pH 6.8. Detailed Implementation

[0047] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0048] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0049] Film coating premix: a mixture of polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc, with polyvinyl alcohol as the main film-forming material. Model: WYA01YS. Manufacturer: Lianyungang Kanglite Pharmaceutical Co., Ltd.

[0050] Lactose: Model: G200, Manufacturer: Metformin GmbH, Germany.

[0051] Corn starch: Model: Maize Starch B, Manufacturer: Roquette Freres.

[0052] The prescription composition of Examples 1-4 is shown in Table 1.

[0053] Table 1. Prescription composition (total of 10,000 tablets, unit: g)

[0054] The prescription compositions of Comparative Examples 1-5 are shown in Table 2.

[0055] Table 2. Prescription composition (total of 10,000 tablets, unit: g)

[0056] #: Add the completely pulverized lactose from Comparative Example 4 as the first step; *: The film-forming material is polyvinyl chloride. Model: WYA01YS, Manufacturer: Lianyungang Kanglite Pharmaceutical Co., Ltd.

[0057] Preparation methods of Examples 1-4, Comparative Examples 1-3 and Comparative Example 5: (1) Use a common mechanical pulverizer to mix diphenidol hydrochloride and lactose and pulverize to the target particle size.

[0058] (2) The above-mentioned pulverized mixture, the remaining unpulverized lactose, corn starch, and potassium bitartrate are placed in a fluidized bed for one-step granulation. The inlet air temperature is 85℃, the material temperature is 70℃, and the air volume is 1500m³. 3 / h, adhesive supply pump speed 4rpm, atomization pressure 0.30Mpa, after the adhesive is used up, fluidize and dry for 13 minutes, and control the particle moisture content at 1%.

[0059] (4) Add the dried granules, sodium carboxymethyl starch, and magnesium stearate to the mixer in sequence and mix for 5 minutes at 10 rpm. Remove the material and compress it into tablets using a 7mm round punch.

[0060] (5) Coating is performed using a film coating premix. The coating solution concentration is 8%. Diphenhydramine hydrochloride tablets are added to the coating machine and preheated to 40°C. The heating temperature is set to 60°C and the air volume is 1000 m³ / h. 3 / h, coating pan speed 8rpm.

[0061] Preparation method of Comparative Example 4: (1) Use a common mechanical pulverizer to mix diphenidol hydrochloride and lactose and pulverize to the target particle size.

[0062] (2) The above-mentioned pulverized mixture, corn starch, and potassium bitartrate are placed in a fluidized bed for one-step granulation. The inlet air temperature is 85℃, the material temperature is 70℃, and the air volume is 1500 m³ / h. 3 / h, adhesive supply pump speed 4rpm, atomization pressure 0.30Mpa, after the adhesive is used up, fluidize and dry for 13 minutes, and control the particle moisture content at 1%.

[0063] (4) Add the dried granules, sodium carboxymethyl starch, and magnesium stearate to the mixer in sequence and mix for 5 minutes at 10 rpm. Remove the material and compress it into tablets using a 7mm round punch.

[0064] (5) Coating is performed using a film coating premix. The coating solution concentration is 8%. Diphenhydramine hydrochloride tablets are added to the coating machine and preheated to 40°C. The heating temperature is set to 60°C and the air volume is 1000 m³ / h. 3 / h, coating pan speed 5-8rpm.

[0065] Example 1: Dissolution curve detection According to the Dissolution and Release Determination Method in General Chapter 0931 of the Chinese Pharmacopoeia, the drug dissolution in phosphate medium at pH 6.8 was determined. The dissolution method was the paddle method, with a medium volume of 900 mL, a water bath temperature of 37 ± 0.5 °C, and a paddle speed of 50 r / min. The dissolution curves of the original drug Cephadol® and Examples 1-4 and Comparative Examples 1-3 were measured according to the procedure. The results are shown in Table 3. Figure 1 and Figure 2 .

[0066] Table 3: Dissolution curves of different formulations

[0067] In this invention, the dissolution curves of Examples 1-2 in pH 6.8 phosphate buffer medium are similar to those of the control example - the original drug Cephadol® (dissolution greater than 85% at 15 min), while the dissolution of Comparative Example 1 is less than 85% at 15 min. It can be seen that the difenidol hydrochloride tablets of this invention can significantly improve the dissolution rate of the drug formulation when using difenidol hydrochloride and lactose with a particle size D90 of less than 150 μm.

[0068] Test Example 2: Stability Comparison Test Examples 1-3, Comparative Example 5, and Control Example - the original drug Cephadol® were placed continuously for 6 months under accelerated testing conditions (i.e., temperature 40℃±2℃, relative humidity 75%±5%) to examine the changes in related substances of each sample. The results are shown in Table 4.

[0069] Impurity I, CAS: 89410-63-9.

[0070] Methods for detecting impurity I and total impurities: Determined by high performance liquid chromatography (General Chapter 0512, Chinese Pharmacopoeia 2020 Edition).

[0071] Test solution: Take 20 tablets of this product, remove the coating and weigh accurately, grind finely, accurately weigh an appropriate amount of fine powder (equivalent to 25 mg of difenidol hydrochloride), place it in a 50 ml volumetric flask, add an appropriate amount of mobile phase, shake to dissolve difenidol hydrochloride, dilute to the mark with mobile phase, shake well, filter, and collect the filtrate.

[0072] Impurity I reference solution: Weigh 25 mg of impurity I reference standard accurately, place it in a 50 ml volumetric flask, add mobile phase to dissolve and dilute to the mark, and shake well.

[0073] Reference solution: Accurately measure 1 ml of the test solution and 1 ml of impurity I reference solution, place them in the same 100 ml volumetric flask, dilute to the mark with the mobile phase, and shake well.

[0074] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; 0.5% triethylamine solution (pH adjusted to 4.0 with phosphoric acid)-methanol (44:56) was used as the mobile phase; detection wavelength was 210 nm; injection volume was 20 μL.

[0075] System applicability requirements: The theoretical plate number, calculated based on the difenido peak, should be no less than 1500, and the separation between the difenido peak and adjacent impurity peaks should meet the requirements.

[0076] Determination method: Accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, and record the chromatograms up to 4 times the retention time of the main component peak.

[0077] Limits: If there is a chromatographic peak in the chromatogram of the test solution that has the same retention time as impurity I, the peak area calculated by the external standard method shall not exceed 0.5% of the labeled amount of difenidol hydrochloride, and the sum of the peak areas of other impurities shall not exceed the peak area of ​​difenidol hydrochloride in the control solution (1.0%).

[0078] Table 4: Stability Results

[0079] The results showed that, under accelerated testing conditions for 6 months, the related substances in Examples 1, 3, and 4 of this invention and Comparative Example 3 were all below the limit requirements, while the related substances in Comparative Examples 2, 4, and 5 increased significantly and exceeded the limit requirements.

[0080] Test Example 3: Flowability and Tableting Differences Methods for testing fluidity (angle of repose): Angle of repose: An excess of the test particles is added to a container with a base plate of fixed diameter. When the powder flows out from the central hole at the bottom of the container, a sliding inclined plane (the vertical shear plane is triangular) is formed at the opening of the base plate inside the container. The angle formed by this sliding inclined plane and the horizontal base plate is the angle of repose. The evaluation criteria are shown in Table 5.

[0081] Table 5 Evaluation Criteria

[0082] Tablet compression difference detection method: Take 20 tablets of the test sample, accurately weigh the total weight, calculate the average tablet weight, and then accurately weigh each tablet separately. Compare the weight of each tablet with the average tablet weight.

[0083] The experimental results are shown in Table 6.

[0084] Table 6. Results of tablet compression differences

[0085] The results showed that when the mass ratio of difenidol hydrochloride to lactose was 1:(2-3), the resulting granules had good flowability (angle of repose less than 35°), which in turn promoted small tablet weight differences after compression (tablet weight difference less than ±2.0%). However, when the ratio of difenidol hydrochloride to lactose exceeded the range, reaching 1:3.5, the excessive amount of fine powder resulted in poor flowability of the granulated granules (angle of repose greater than 45°), thus causing large tablet weight differences after compression (tablet weight difference greater than ±7.5%). Therefore, the preferred mass ratio of difenidol hydrochloride to lactose was 1:(2-3).

[0086] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A diphenhydramine composition, characterized in that, The product comprises the following raw materials: diphenidol, lactose, starch, potassium bitartrate, disintegrant, lubricant, and film coating premix; the lactose includes pulverized lactose and uncrushed lactose; the D90 of the diphenidol and pulverized lactose is 120-150 μm; the mass ratio of diphenidol to pulverized lactose is 1:(2-3); and the film-forming material in the film coating premix is ​​polyvinyl alcohol.

2. The diphenhydramine composition according to claim 1, characterized in that, By weight, it includes 200-300 parts diphenhydramine, 600-800 parts lactose, 50-150 parts starch, 100-300 parts potassium bitartrate, 30-60 parts disintegrant, 5-15 parts lubricant, and 50-90 parts film coating premix.

3. The diphenhydramine composition according to claim 1, characterized in that, The disintegrant is at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium.

4. The diphenhydramine composition according to claim 1, characterized in that, The lubricant is at least one of magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, and talc.

5. A method for preparing the difenidol composition according to any one of claims 1-4, characterized in that, Includes the following steps: (1) Mix diphenhydramine and some lactose and grind them to D90=120-150μm to obtain a mixture of active ingredients; (2) Granulate the mixture of active ingredients, the remaining unpulverized lactose, starch, potassium hydrogen tartrate and binder, and dry them after granulation to obtain dry granules; (4) Mix the dried granules, disintegrant and lubricant together and compress into tablets; (5) Coating is performed using a film coating premix.

6. The preparation method according to claim 5, characterized in that, The adhesive is an aqueous solution of ethanol.

7. The preparation method according to claim 6, characterized in that, The volume fraction of ethanol in the aqueous solution is 40-60%.

8. The preparation method according to claim 5, characterized in that, The moisture content of the dried particles is selected from 1-2 wt%.

9. A difenidol medicament comprising the difenidol composition according to any one of claims 1-4.

10. The use of the difenidol composition according to any one of claims 1-4 in improving the stability and dissolution properties of difenidol.

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