阅读说明：本技术 一种复方地氯雷他定伪麻黄碱缓释口崩片及其制备方法 (Compound desloratadine and pseudoephedrine sustained-release orally disintegrating tablet and preparation method thereof ) 是由 马建洋 王宇杰 于 2020-04-17 设计创作，主要内容包括：本发明提供了一种复方地氯雷他定伪麻黄碱缓释口崩片及其制备方法。本发明主要包括采用流化床制粒法制备复方地氯雷他定伪麻黄碱缓释颗粒,再经粉末直压法制成口崩片。本发明将两种剂量悬殊的活性物质通过流化床制粒法制备成复方缓释颗粒,再经粉末直压制备成口崩剂。其特点是在在不需要饮水的条件下,该口崩片遇唾液迅速崩解缓释颗粒、吞咽服用,服用方便,尤其适合老人、儿童以及昏迷病人等吞咽困难的特殊病人；且该缓释口崩片解决了地氯雷他定需要速释而伪麻黄碱需要缓释的问题,能够使两种药物同时作用,提高治疗效果,方法简便,易于质量控制,适合工业化生产。(The invention provides a compound desloratadine pseudoephedrine sustained-release orally disintegrating tablet and a preparation method thereof. The invention mainly comprises preparing compound desloratadine and pseudoephedrine sustained-release granules by adopting a fluidized bed granulation method, and preparing the orally disintegrating tablets by a powder direct compression method. The invention prepares two active substances with different dosages into compound sustained-release granules by a fluidized bed granulation method, and then prepares the oral disintegrating agent by directly pressing the powder. The orally disintegrating tablet is characterized in that the orally disintegrating tablet rapidly disintegrates and slowly releases granules when meeting saliva and is convenient to take when being swallowed without drinking water, and is particularly suitable for special patients with dysphagia, such as the old, children, coma patients and the like; the sustained-release orally disintegrating tablet solves the problems that the desloratadine needs to be quickly released and the pseudoephedrine needs to be slowly released, can ensure that two medicaments simultaneously act, improves the treatment effect, has simple and convenient method, is easy to control the quality and is suitable for industrial production.)

1. A compound desloratadine pseudoephedrine sustained-release orally disintegrating tablet is characterized by consisting of sustained-release particles and auxiliary materials, wherein the sustained-release particles consist of compound desloratadine pseudoephedrine and sustained-release matrix materials.

2. The sustained-release orally disintegrating tablet according to claim 1, wherein the sustained-release granules are composed of pharmacologically effective amounts of desloratadine and pseudoephedrine with a sustained-release matrix material.

3. The sustained-release orally disintegrating tablet according to any of claims 1 to 2, wherein the pseudoephedrine is used in an amount not exceeding a pharmacologically effective dose.

4. The sustained-release orally disintegrating tablet according to any of claims 1 to 2, wherein the sustained-release matrix material is one or a combination of more than one of acrylic resin (e.g., Eudragit RS-30D, RS, RL-30D, RL), hypromellose, ethylcellulose, microcrystalline cellulose, crospovidone, starch, dextrin, sucrose, stearyl alcohol, and glyceryl monostearate.

5. The compound desloratadine and pseudoephedrine sustained-release orally disintegrating tablet according to claim 1, wherein the sustained-release particles have a particle size of less than or equal to 10% passing through a 200-mesh sieve, less than or equal to 80% passing through an 80-mesh sieve, and 100% passing through a 20-mesh sieve; the dosage is 50-80% of the weight of the tablet.

6. The sustained-release orally disintegrating tablet according to claim 1, wherein the disintegrant is crospovidone (PVPP), low-substituted hydroxypropylcellulose (L-HPC), carboxymethyl starch sodium (CMS-Na), croscarmellose sodium (CCNa), or the like, and is used in an amount of 0.5 to 25% based on the sustained-release orally disintegrating tablet.

7. The sustained-release orally disintegrating tablet according to claim 1, wherein the filler is microcrystalline cellulose, sucrose, lactose or the like in an amount of 5 to 20% by weight of the sustained-release orally disintegrating tablet.

8. The sustained-release orally disintegrating tablet according to claim 1, wherein the lubricant is magnesium stearate, talc, aerosil, sodium lauryl sulfate, and the amount of the lubricant is 0.1-5% of the weight of the sustained-release orally disintegrating tablet.

Technical Field

The invention relates to the technical field of medicines, in particular to a compound desloratadine and pseudoephedrine sustained-release orally disintegrating tablet and a preparation method thereof.

Background

Desloratadine (Desloratadine) having the chemical name 8-chloro-6, 11-dihydro-11 (4-piperidylidene) -5H-benzo-5, 6-heptane 1, 2-b-pyridine. Desloratadine is a non-sedating long-acting tricyclic antihistamine, is an active metabolite of loratadine, and can relieve symptoms related to allergic rhinitis or chronic idiopathic urticaria by selectively antagonizing peripheral H1 receptors. The traditional Chinese medicine composition is clinically used for seasonal and perennial allergic rhinitis, allergic conjunctivitis and urticaria. Desloratadine is a new generation of antihistamine medicine, has quick response and long action duration, not only has the antihistaminic effect, but also has the anti-inflammatory activity, has obvious effects of removing congestion and eliminating wheal, has no side effect of a central nervous system, has no cardiotoxicity and has no interaction among medicines. Almost insoluble in water, soluble in chloroform and methanol, has long elimination half-life (about 27h), and is administered 1 time per day, and its hydrochloride and sulfate are soluble in water, ethanol and diethyl ether, and have short half-life (about 7h), and are administered 3 times per day.

Pseudoephedrine (Pseudoephedrine), the chemical name is S- (R, R) ] -a-1[1- (methylamino) ethyl ] -benzyl alcohol hydrochloride, is an adrenergic receptor agonist, can selectively shrink nasal mucosa blood vessels, relieve nasal obstruction and clear nasal discharge, and the hydrochloride and sulfate thereof are easily soluble in water, ethanol and ether and have half-life of about 7 h.

Clinical studies have shown that pseudoephedrine, whether used alone or in combination with antihistamines, is safe and effective for treating nasal mucosal congestion. The two components can synergistically relieve the symptoms of allergic rhinitis, namely pseudoephedrine salt which is easy to dissolve in water needs to be slowly released, desloratadine which is slightly soluble in water needs to be quickly released, and the difference of physicochemical property and pharmacokinetic property of the pseudoephedrine salt and the desloratadine causes that the pseudoephedrine salt and the desloratadine cannot be simply and compositely administered. The desloratadine and pseudoephedrine sustained-release orally disintegrating tablet is invented for coordinating the administration frequency, obtaining stable blood concentration and improving the administration compliance.

Disclosure of Invention

The invention provides a compound desloratadine and pseudoephedrine orally disintegrating tablet with a slow release effect, which can be rapidly disintegrated in saliva, swallowed and conveniently administered, and simultaneously solves the problems that desloratadine needs to be rapidly released and pseudoephedrine needs to be slowly released, so that two medicines can simultaneously act, the treatment effect is improved, the method is simple and convenient, the quality control is easy, and the compound desloratadine and pseudoephedrine orally disintegrating tablet is suitable for industrial production.

The invention relates to a compound desloratadine and pseudoephedrine sustained-release orally disintegrating tablet and a preparation method thereof. The compound desloratadine pseudoephedrine sustained-release granules are prepared by applying a fluidized bed granulation method and materials with sustained-release effect, and then directly applying a direct tabletting material to carry out tabletting to obtain the orally disintegrating tablet.

The invention provides a preparation method of the compound desloratadine pseudoephedrine sustained-release orally disintegrating tablet, which comprises

The method comprises the following steps:

sustained-release granule part:

the sustained-release granules contained in the invention are composed of compound desloratadine pseudoephedrine and sustained-release matrix material, wherein:

(1) a pharmacologically effective amount of pseudoephedrine is 120mg (12 hours extended release) or 240mg (24 hours extended release);

(2) the sustained-release matrix material is one or a composition of more than one of acrylic resin (such as Eudragit RS-30D, RS, RL-30D, RL), hydroxypropyl methylcellulose, ethyl cellulose, microcrystalline cellulose, crospovidone, starch, dextrin, sucrose, octadecanol and glycerin monostearate, and the dosage of the sustained-release matrix material is 5-50% of the weight of the tablet;

(3) the particle size of the sustained-release particles is less than or equal to 10 percent, the sustained-release particles pass through a 200-mesh sieve, less than or equal to 80 percent pass through a 80-mesh sieve, 100 percent pass through a 20-mesh sieve, and the dosage is 50-80 percent of the weight of the tablet;

the preparation process method of the sustained-release granules is fluidized bed granulation, and the specific method comprises the following steps: after the loratadine, the pseudoephedrine and the sustained-release matrix material are uniformly mixed, a hydroxypropyl methylcellulose water solution or an ethanol/water solution is used as a bonding agent to prepare a soft material, and after granulation, the soft material is prepared by granulation through a fluidized bed.

Sustained release orally disintegrating tablet

(1) The dosage of the sustained-release orally disintegrating tablet provided by the invention is 50-80% of the weight of the tablet.

(2) The disintegrating agent is crospovidone (PVPP), low-substituted hydroxypropyl cellulose (L-HPC), carboxymethyl starch sodium (CMS-Na), cross-linked carboxymethyl starch sodium (CCNa) and the like, and the dosage of the disintegrating agent is 0.5-20% of the weight of the tablet.

(3) The filler is microcrystalline cellulose, sucrose, lactose and the like, and the dosage of the filler is 5-20% of the weight of the tablet.

(4) The lubricant is magnesium stearate, talcum powder, superfine silica gel powder and sodium dodecyl sulfate, and the dosage of the lubricant is 0.1-5% of the weight of the tablet.

The invention provides a compound desloratadine pseudoephedrine sustained-release orally disintegrating tablet which is prepared by a direct powder tabletting method, and the specific method comprises the following steps: the sustained-release granules are uniformly mixed with a disintegrating agent, a filling agent and a lubricating agent, and then a tablet machine is used for direct tabletting.

Detailed Description

Unless otherwise specified, the reagents used in the following examples are all common commercial reagents, and the methods used are all conventional in the art.

Example 1

Preparation: the desloratadine and the pseudoephedrine are sieved by a sieve of 80 meshes, and the other auxiliary materials are sieved by a sieve of 60 meshes. After the raw materials and the auxiliary materials are uniformly mixed, 5% hydroxypropyl methylcellulose solution is used as an adhesive to prepare a soft material, granulation is carried out by a 24-mesh sieve, granulation is carried out by a fluidized bed, and granulation is carried out by the 24-mesh sieve to obtain the slow-release granules. Adding crospovidone, silicon dioxide and talcum powder, mixing, and directly tabletting.

The orally disintegrating tablet can be completely disintegrated within 60 s.

Example 2:

preparation: the desloratadine and the pseudoephedrine are sieved by a sieve of 80 meshes, and the other auxiliary materials are sieved by a sieve of 60 meshes. After the raw materials and the auxiliary materials are uniformly mixed, 5% hydroxypropyl methylcellulose solution is used as an adhesive to prepare a soft material, granulation is carried out by a 24-mesh sieve, granulation is carried out by a fluidized bed, and granulation is carried out by the 24-mesh sieve to obtain the slow-release granules. Adding crospovidone, silicon dioxide and talcum powder, mixing, and directly tabletting.

The orally disintegrating tablet can be completely disintegrated within 60 s.

Example 3:

preparation: the desloratadine and the pseudoephedrine are sieved by a sieve of 80 meshes, and the other auxiliary materials are sieved by a sieve of 60 meshes. After the raw materials and the auxiliary materials are uniformly mixed, 75% ethanol/water solution of hydroxypropyl methylcellulose is used as an adhesive to prepare a soft material, granulation is carried out by a 24-mesh sieve, granulation is carried out by a fluidized bed, and granulation is carried out by the 24-mesh sieve to obtain the slow-release granules. Adding crospovidone, silicon dioxide and talcum powder, mixing, and directly tabletting.

The orally disintegrating tablet can be completely disintegrated within 60 s.

Comparative example 1:

preparation: the desloratadine and the pseudoephedrine are sieved by a sieve of 80 meshes, and the other auxiliary materials are sieved by a sieve of 60 meshes. After the raw materials and the auxiliary materials are uniformly mixed, 5% hydroxypropyl methylcellulose solution is used as an adhesive to prepare a soft material, the soft material is granulated by a 24-mesh sieve, the granulation is carried out at the temperature of 50 +/-5 ℃, and the granulation is carried out by the 24-mesh sieve to obtain the sustained-release granules. Adding crospovidone, silicon dioxide and talcum powder, mixing, and directly tabletting.

The orally disintegrating tablet can be completely disintegrated within 60 s.

Comparative example 2:

preparation: the desloratadine and the pseudoephedrine are sieved by a sieve of 80 meshes, and the other auxiliary materials are sieved by a sieve of 60 meshes. After the raw materials and the auxiliary materials are uniformly mixed, 5% hydroxypropyl methylcellulose solution is used as an adhesive to prepare a soft material, granulation is carried out by a 24-mesh sieve, granulation is carried out by a fluidized bed, and granulation is carried out by the 24-mesh sieve to obtain the slow-release granules. Adding crospovidone, silicon dioxide and talcum powder, mixing, and directly tabletting.

The orally disintegrating tablet can be completely disintegrated within 60 s.

Table 1 the experimental values of disintegration time, friability, tablet hardness, dissolution rate of each example are as follows:

TABLE 2 influencing factor test results (0 day sample is bare chip, 10 day sample is double aluminum package sample)

Experimental results and conclusions:

(1) from examples 1-3, it can be seen that by adopting the preparation method of the compound desloratadine and pseudoephedrine sustained-release orally disintegrating tablet provided by the invention, the disintegration time of the orally disintegrating tablet is less than 45s, the friability and the content uniformity are both qualified, and the sample stability is better in 0 day and 10 days.

(2) As can be seen from comparative example 1, the direct heat drying method adopted for granulation resulted in unqualified sample content uniformity, and the factors affecting the samples in 0 day and 10 days resulted in higher single impurity and total impurity levels, and probably because the fluidized bed granulation was more direct heat drying granulation, the particles were uniform in particle size, good in fluidity and compression formability, and less or almost no migration of soluble components between particles, the fluidized bed granulation was adopted.

As can be seen from comparative example 2, when the amount of lactose as a filler in the formula is greater than 20%, the friability of the sample is not acceptable, and therefore, the amount of the filler is reasonably controlled to be 5-20%.