A kind of pyritinol hydrochloride dry suspension and preparation method thereof

Abstract

The present invention belongs to the technical field of drug preparation, and discloses a pyritinol hydrochloride dry suspension and a preparation method thereof. The pyritinol hydrochloride dry suspension comprises the following components: pyritinol hydrochloride, cross-linked carboxymethyl cellulose salt, adhesive, filler and suspending agent; the filler is lactose and mannitol; the suspending agent is xanthan gum and / or gum arabic; the adhesive is hydroxypropyl methylcellulose E5. The pyritinol hydrochloride dry suspension provided by the present invention uses cross-linked carboxymethyl cellulose salt as a disintegrant, and through the selection of adhesive, filler and suspending agent, the pyritinol hydrochloride dry suspension has good particle properties and appearance, excellent sedimentation ratio, accurate dosage, high solubility, and can reach the blood drug concentration required for treatment faster and facilitate the treatment of young patients. The pyritinol hydrochloride dry suspension provided by the present invention has good taste and strong compliance through the adjustment of the prescription.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and particularly relates to a pyritinol hydrochloride dry suspension and a preparation method thereof. Background Art

[0002] Pyritinol hydrochloride, also known as Brain Renew, is a vitamin B6 derivative that can promote glucose and amino acid metabolism in the brain, improve systemic assimilation, increase carotid blood flow, promote brain function, and also stimulate the limbic system and reticular structure. It is clinically used for dizziness, swelling and pain, insomnia, memory loss, inattention, and mood changes caused by sequelae of brain trauma, encephalitis, and meningitis; it is also used for cerebral arteriosclerosis and Alzheimer's mental symptoms. It can also be used to treat some organic dementia and brain dysfunction, such as consciousness disorders after craniocerebral injury, children's learning ability and sequelae of craniocerebral injury. Studies have shown that most children with autism have low intelligence and poor self-care ability. Such children can choose to use intelligence-enhancing drugs that promote brain function development, including pyritinol, to promote the development of central nervous system functions, increase cognitive functions, and improve intelligence levels. Studies have shown that the double-blind method was used to statistically analyze the effects of this product on children with poor learning ability. After oral administration for 6-15 weeks, the reading and calculation abilities of the treatment group were significantly improved, which was statistically significant.

[0003] At present, pyritinol hydrochloride preparations are mostly tablets, capsules, and injections, and there is no dry mixed suspension. Since pyritinol hydrochloride capsules and pyritinol hydrochloride tablets cannot be used accurately when used for children, it is extremely inconvenient for children to take them, and their compliance is poor; and due to the dissolution rate of the drug, the drug cannot be released quickly to the target; at the same time, pyritinol hydrochloride tastes bitter, and it is difficult for children to accept the medication. Therefore, developing a pyritinol hydrochloride drug with a dosage form and taste that is convenient for children to take can facilitate the treatment of young patients. Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention provides a pyritinol hydrochloride dry suspension and a preparation method thereof. The pyritinol hydrochloride dry suspension provided by the present invention has good mouthfeel, strong compliance, high solubility, can reach the blood drug concentration required for treatment more quickly, and is convenient for the treatment of young patients.

[0005] The invention provides a pyritinol hydrochloride dry suspension.

[0006] Specifically, a pyritinol hydrochloride dry suspension comprises the following components: pyritinol hydrochloride, cross-linked carboxymethyl cellulose salt, a binder, a filler and a suspending agent;

[0007] The fillers are lactose and mannitol;

[0008] The suspending agent is xanthan gum and / or gum arabic;

[0009] The binder is hypromellose (hydroxypropyl methylcellulose) E5.

[0010] Preferably, the pyritinol hydrochloride dry suspension comprises the following components in parts by weight: 50 parts of pyritinol hydrochloride, 10-30 parts of cross-linked carboxymethyl cellulose salt, 3-25 parts of binder, 800-1200 parts of filler and 40-100 parts of suspending agent.

[0011] Further preferably, the pyritinol hydrochloride dry suspension comprises the following components in parts by weight: 50 parts of pyritinol hydrochloride, 10-25 parts of cross-linked carboxymethyl cellulose salt, 10-25 parts of binder, 900-1100 parts of filler and 50-80 parts of suspending agent.

[0012] Preferably, the mass ratio of the lactose to the mannitol is 1:(1.5-3.0); further preferably, the mass ratio of the lactose to the mannitol is 1:(1.5-2.0).

[0013] Preferably, the cross-linked carboxymethyl cellulose salt is cross-linked carboxymethyl cellulose sodium.

[0014] Preferably, the pyritinol hydrochloride dry suspension further comprises at least one of a taste masking agent, a sweetener, and a flavor corrective.

[0015] Further preferably, the pyritinol hydrochloride dry suspension comprises 1.2-5 parts of taste masking agent, 6-10 parts of sweetener and 2-6 parts of flavor corrective agent by weight.

[0016] Preferably, the taste masking agent is carbam.

[0017] Preferably, the sweetener is selected from at least one of sucrose, xylitol or sucralose; more preferably, the sweetener is sucralose.

[0018] Preferably, the flavoring agent includes sweet orange powder and / or cyclodextrin; further preferably, the flavoring agent is sweet orange powder.

[0019] Preferably, the pyritinol hydrochloride dry suspension further comprises a colorant; preferably, the colorant is sunset yellow.

[0020] Preferably, the pyritinol hydrochloride dry suspension comprises the following components in parts by weight: 50 parts of pyritinol hydrochloride, 10-30 parts of cross-linked carboxymethyl cellulose salt, 3-25 parts of hydroxypropyl methylcellulose E5, 300-400 parts of lactose, 600-800 parts of mannitol, 40-100 parts of xanthan gum, 1.2-5 parts of carbam, 6-10 parts of sucralose and 2-6 parts of sweet orange powder.

[0021] Further preferably, the pyritinol hydrochloride dry suspension comprises the following components, by weight: 50 parts of pyritinol hydrochloride, 10-25 parts of cross-linked carboxymethyl cellulose salt, 10-25 parts of hydroxypropyl methylcellulose E5, 300-400 parts of lactose, 600-750 parts of mannitol, 50-80 parts of xanthan gum, 1.2-5 parts of carbam, 6-10 parts of sucralose and 2-6 parts of sweet orange powder.

[0022] The invention also provides a method for preparing the pyritinol hydrochloride dry suspension.

[0023] Specifically, a method for preparing a pyritinol hydrochloride dry suspension comprises the following steps:

[0024] (1) sieving pyritinol hydrochloride to obtain material A; mixing a filler, a cross-linked carboxymethyl cellulose salt, and a suspending agent, and sieving to obtain material B; and mixing the material A with the material B to obtain material C; and preparing an adhesive to prepare an adhesive solution;

[0025] (2) preparing wet granules from the material C and the binder solution, and then granulating the granules to obtain a pyritinol hydrochloride dry suspension.

[0026] Preferably, the screening process is through a 80-120 mesh sieve.

[0027] Preferably, the mass percentage of the binder in the binder solution is 3.0%-5.0%.

[0028] More specifically, a method for preparing a pyritinol hydrochloride dry suspension comprises the following steps:

[0029] (1) Pyritinol hydrochloride is mixed with a taste masking agent and a sweetener, and crushed, and the mixture is passed through a 80-120 mesh sieve, and then anhydrous ethanol is added to obtain a paste, which is dried at 50±2° C., crushed, and passed through a 80-120 mesh sieve to obtain material A; a filler is mixed and crushed, and the mixture is passed through a 80-120 mesh sieve, and then a cross-linked carboxymethyl cellulose salt and a suspending agent are added to the mixture to obtain material B; the material A and the material B are mixed, and the mixture is passed through a 80-120 mesh sieve to obtain material C; and a binder solution having a mass percentage of 3.0% to 5.0% is prepared;

[0030] (2) preparing wet granules with the material C and the binder solution, and then granulating the granules, and finally drying and granulating the granules at 55±5° C. to obtain a pyritinol hydrochloride dry suspension.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] (1) The pyritinol hydrochloride dry suspension provided by the present invention uses cross-linked carboxymethyl cellulose salt as a disintegrant, and through the selection of a binder, a filler and a suspending agent, the pyritinol hydrochloride dry suspension has good particle properties and appearance, an excellent sedimentation ratio, an accurate dosage, a high solubility, can reach the blood drug concentration required for treatment more quickly, and is convenient for the treatment of young patients.

[0033] (2) The pyritinol hydrochloride dry suspension provided by the present invention has good taste and strong compliance through adjustment of the prescription, and is particularly suitable for children's medication. DETAILED DESCRIPTION

[0034] In order to make the technical scheme of the present invention more clearly understood by those skilled in the art, the following embodiments are listed for illustration. It should be pointed out that the following embodiments do not limit the protection scope of the present invention.

[0035] The pyritinol hydrochloride used in the following examples and comparative examples was purchased from Zhejiang Ruixin Pharmaceutical Co., Ltd. (230209), sucralose was purchased from Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd. (20221101), xanthan gum was purchased from Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd. (F201C230202), sucrose was purchased from Lingli Sugar Factory of Nanning Sugar Co., Ltd. (211902), and sunset yellow was purchased from DYECHEM PVT.LTD.(100000140094), Hydroxypropyl methylcellulose was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd. (201026), Mannitol was purchased from Guangxi Nanning Chemical Pharmaceutical Co., Ltd. (F313D), Lactose was purchased from Zhenjiang Kangfu Bioengineering Co., Ltd. (20200109), Carbomer Type B was purchased from Gu'an Xixing Pharmaceutical Co., Ltd. (20210206), Cross-linked carboxymethyl cellulose sodium was purchased from Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd. (20181201), and Orange powder was purchased from Shaanxi Xintianyu Biotechnology Co., Ltd. (20190506). Unless otherwise specified, other raw materials, reagents or devices can be obtained from conventional commercial channels or can be obtained by existing known methods.

[0036] Example

[0037] Prescription 1: A pyritinol hydrochloride dry suspension, the prescription filling volume is 1.2g, the specific ratio is: pyritinol hydrochloride 50mg, carbam B 2.4mg, sucralose 8.4mg, lactose 372mg, mannitol 684mg, xanthan gum 60mg, cross-linked sodium carboxymethyl cellulose 18mg, sunset yellow 0.36mg, sweet orange powder 4.8mg, and hypromellose E5 20mg.

[0038] A method for preparing a pyritinol hydrochloride dry suspension comprises the following steps:

[0039] 1) Pyritinol hydrochloride, carbomer and sucralose were mixed and crushed, passed through a 100-mesh sieve, and anhydrous ethanol was slowly added while stirring, and the properties of the material were observed until a paste was obtained, dried at 50° C., crushed again, and passed through a 100-mesh sieve to obtain material A;

[0040] 2) mixing lactose and mannitol, crushing them, passing through a 100-mesh sieve, transferring them to a mixer, adding xanthan gum and cross-linked sodium carboxymethyl cellulose, and mixing them thoroughly to obtain material B;

[0041] 3) Add materials A and B and mix. After mixing for 10 minutes, 5 minutes and 10 minutes, take samples from the upper, middle and lower layers to measure the content respectively. After mixing evenly, pass through a 100-mesh sieve to obtain material C.

[0042] 4) Pretreatment process parameter control: add anhydrous ethanol while observing until a paste is formed; drying temperature 50±2°C; mixing time of material B ≥10min; mixing time of material C ≥10min.

[0043] 5) Preparation of binder solution: add purified water at room temperature to the pulping barrel, slowly add hypromellose to the pulping barrel, stir until evenly dispersed, and prepare a 4% concentration of hypromellose E5 solution; take half of the binder solution, add sunset yellow, stir evenly, and place it in a separate barrel with the remaining binder solution for standby use;

[0044] 6) Preparation of wet granules: Place the weighed material C in a whole granulation wet mixing granulator, open the loading cover, first add the adhesive containing sunset yellow in batches, then add the adhesive without sunset yellow as appropriate. The adhesive should be evenly added on the surface of the material. The wet mixing time after each addition of the adhesive is 2 minutes. After the granulation is completed, transfer the wet granules to a stainless steel barrel.

[0045] 7) Granulation: Install a 20-mesh screen and add the wet granules into a swing granulator for granulation.

[0046] 8) Drying: Set the oven temperature to 55±5℃, and evenly place the prepared wet granules on the drying cloth on the tray. The thickness should be ≤3cm, and the amount placed on each tray should be consistent. Start timing after the equipment displays the temperature reaches 55℃, record the drying temperature every 10 minutes, turn the material over once after 1 hour, and check the drying condition at any time. The drying time is 2.5 hours, and the moisture is tested regularly. After the moisture is finally controlled to <2%, stop heating, and discharge the material after cooling to below 40℃. Add sweet orange essence to each tray in proportion, and then discharge the material into a stainless steel sealed barrel.

[0047] 9) Granulation: Install a 18-mesh screen to granulate the dried granules. The granulated granules are packed and sealed in low-density polyethylene bags.

[0048] 10) Total mixing: Add the granules into the mixer, set the mixing speed, mix for 5 minutes, and after mixing, transfer the materials into a stainless steel sealed barrel. Take samples for testing.

[0049] 11) Repackaging: Repack the qualified materials according to the packing quantity.

[0050] In terms of oral solid preparations, compared with pyritinol hydrochloride tablets and pyritinol hydrochloride capsules, the pyritinol hydrochloride dry suspension provided by the embodiment of the present invention has obvious clinical advantages, especially for children. The dosage form of this specification is accurate in dosage, good in taste, strong in compliance, and fast in absorption, and can reach the blood drug concentration required for treatment more quickly.

[0051] The above raw and auxiliary materials were mixed in a certain proportion for compatibility test. The specific process is as follows: Take appropriate amount of samples, place them under strong light irradiation (4500±500Lx) for 10 days, high temperature (60℃) for 30 days, and high humidity (relative humidity 92.5%, 25℃) for 10 days for inspection, and detect the appearance and related substances. The results are shown in Table 1.

[0052] Table 1

[0053]

[0054]

[0055] The excipients with good solubility were selected, and the pyritinol hydrochloride dry suspension (231001, 231002, 231003) was prepared according to the proposed prescription 1, and the influencing factors were investigated for the stability of the samples. The results of the stability test are shown in Table 2.

[0056] Table 2 Stability test results

[0057]

[0058] Through the investigation of influencing factors, it was found that the stability of the sample was good, but under strong light and high temperature conditions, impurity 1 and the single largest impurity increased rapidly, and there was one new impurity above the quantitative limit. Therefore, light and heat should be avoided during production, transportation and storage.

[0059] Comparative Example:

[0060] Using excipients with good compatibility with pyritinol hydrochloride, different prescriptions were designed, and the prescriptions were screened from the aspects of filler dosage, binder concentration, flavoring agent dosage, suspending agent dosage, disintegrant dosage, etc., and the prescriptions were compared and studied through the particle properties, appearance, sedimentation ratio, dissolution behavior and taste of the samples. The specific formulas are shown in Tables 3 and 4.

[0061] Table 3 Research and comparison of different prescriptions

[0062]

[0063]

[0064] From the analysis of Table 3, it can be seen that the sedimentation ratio of comparative prescription 1 is less than 0.9, which is unqualified, with more fine powder and a slightly bitter taste. It can be seen that controlling the amount of suspending agent xanthan gum is the key to making the sedimentation ratio qualified; and increasing the amount of hydroxypropyl methylcellulose E5 improves the particle properties. From comparative prescription 2, it can be seen that the sedimentation ratio is slightly improved after increasing the amount of xanthan gum, but it is still unqualified; the particles are better after increasing the amount of hydroxypropyl methylcellulose. From the analysis of prescription 1 and comparative prescription 3, it can be seen that after replacing hydroxypropyl methylcellulose with a 4% mass percentage of hydroxypropyl methylcellulose E50 dilute alcohol solution (the volume ratio of water to ethanol in the solvent is 1:1, that is, 50% dilute alcohol solution), although hydroxypropyl methylcellulose-E50 can improve the particle properties, it will affect the solubility of the drug, even if the disintegrant cross-linked carboxymethyl cellulose sodium is added, its solubility is still low. From the analysis of prescription 1 and comparative prescription 4, it can be seen that cross-linked carboxymethyl cellulose sodium is the key to promoting drug dissolution, and the amount of cross-linked carboxymethyl cellulose sodium needs to be controlled. Analysis of Prescription 1 and Comparative Prescription 5 shows that when the amount of filler is the same, but the ratio of lactose to mannitol is 1:1, its dissolution is affected to a certain extent. Analysis of Prescription 1 and Comparative Prescription 6 shows that after xanthan gum is replaced with gum arabic, the integrity of the particles is good, the sedimentation ratio is qualified, and the taste is good, but its dissolution is affected to a certain extent. Compared with Comparative Prescriptions 1-6, Prescription 1 has a good taste, high dissolution, and complete and uniform particles.

[0065] Table 4 Research and comparison of different prescriptions

[0066]

[0067]

[0068]

[0069] As can be seen from Table 4, in Comparative Prescription 7, aspartame is used to replace sucralose as a sweetener, and the taste is too sweet. In addition, it is reported that aspartame has certain risks as a sweetener and is not recommended to be added. In Comparative Prescription 8, starch is used as a filler to replace lactose, and the particles have more powder, the solution is turbid, and the taste is average. In Comparative Prescription 9, after replacing xanthan gum with gum arabic, it does not affect the integrity of the particles, the sedimentation ratio is qualified, and the taste is good. In Comparative Prescription 10, sucrose is used to replace sucralose as a sweetener, and its taste is average, which may be due to insufficient sweetness. In Comparative Prescription 11, cyclodextrin is used as a flavoring agent to replace sweet orange essence. The taste is slightly worse than sweet orange powder, and the taste is average. After the additional addition of cyclodextrin in Comparative Prescription 12, the taste has hardly changed.

[0070] Comparing Prescription 1 in Table 3 and Prescription 2 in Table 4, after replacing sucralose with an equal amount of xylitol, the taste is slightly worse than sucralose, but it does not affect other properties.

[0071] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A pyritinol hydrochloride dry suspension, characterized in that, The composition comprises the following components by weight: 50 parts of pyritinol hydrochloride, 10-30 parts of cross-linked carboxymethyl cellulose salt, 3-25 parts of binder, 800-1200 parts of filler and 40-100 parts of suspending agent; The filler is lactose and mannitol, and the mass ratio of the lactose to the mannitol is 1:(1.5-3.0); The suspending agent is xanthan gum and / or gum arabic; The binder is hypromellose E5.

2. Pyritinol hydrochloride dry suspension according to claim 1, characterized in that, The pyritinol hydrochloride dry suspension comprises the following components by weight: 50 parts of pyritinol hydrochloride, 10-25 parts of cross-linked carboxymethyl cellulose salt, 10-25 parts of binder, 900-1100 parts of filler and 50-80 parts of suspending agent.

3. The pyritinol hydrochloride dry suspension according to claim 1 or 2, characterized in that, The mass ratio of the lactose to the mannitol is 1:(1.5-2.0).

4. The pyritinol hydrochloride dry suspension according to claim 1 or 2, characterized in that, The pyritinol hydrochloride dry suspension further comprises at least one of a taste masking agent, a sweetener and a flavor corrective.

5. Pyritinol hydrochloride dry suspension according to claim 4, characterized in that, The pyritinol hydrochloride dry suspension comprises 1.2-5 parts of taste masking agent, 6-10 parts of sweetener and 2-6 parts of flavor corrective agent by weight.

6. Pyritinol hydrochloride dry suspension according to claim 5, characterized in that, The masking agent is carbam; the sweetener is selected from at least one of sucrose, xylitol or sucralose; and the flavor corrector includes sweet orange powder and / or cyclodextrin.

7. The pyritinol hydrochloride dry suspension according to claim 6, wherein The pyritinol hydrochloride dry suspension comprises the following components by weight: 50 parts of pyritinol hydrochloride, 10-30 parts of cross-linked carboxymethyl cellulose salt, 3-25 parts of hydroxypropyl methylcellulose E5, 300-400 parts of lactose, 600-800 parts of mannitol, 40-100 parts of xanthan gum, 1.2-5 parts of carbam, 6-10 parts of sucralose and 2-6 parts of sweet orange powder.

8. The preparation method of the pyritinol hydrochloride dry suspension according to claim 1, characterized in that, The following steps are involved: (1) sieving pyritinol hydrochloride to obtain material A; mixing a filler, a cross-linked carboxymethyl cellulose salt, and a suspending agent, and sieving to obtain material B; and mixing the material A with the material B to obtain material C; and preparing an adhesive to prepare an adhesive solution; (2) preparing wet granules from the material C and the binder solution, and then granulating the granules to obtain a pyritinol hydrochloride dry suspension.

Images