CN111714463B

CN111714463B - Mirtazapine oral preparation and preparation method thereof

Info

Publication number: CN111714463B
Application number: CN202010815918.7A
Authority: CN
Inventors: 刘晓琳; 董楠; 杨小云
Original assignee: Zhaoqing Institute Of Biotechnology Co ltd
Current assignee: Zhaoqing Institute Of Biotechnology Co ltd
Priority date: 2020-08-14
Filing date: 2020-08-14
Publication date: 2022-06-17
Anticipated expiration: 2040-08-14
Also published as: CN111714463A

Abstract

The invention relates to a mirtazapine oral preparation and a preparation method thereof. The preparation raw materials of the mirtazapine oral preparation comprise the following components in percentage by mass: 2-6% of mirtazapine, 75-85% of diluent, 3-10% of disintegrant, 3-8% of adhesive and 0.3-2% of glidant. The beneficial effects of the invention include: the invention forms a specific raw material formula of the mirtazapine oral preparation by comprehensively adjusting the dosage of auxiliary materials such as a diluent, a disintegrant adhesive and a glidant. Meanwhile, the inventor also unexpectedly finds that the raw material formula is suitable for tabletting by a dry pressing method, the forming effect is good, and the obtained tablet has uniform mirtazapine distribution. In addition, the oral preparation prepared by the raw material formula of the invention has better disintegration and dissolution.

Description

Mirtazapine oral preparation and preparation method thereof

Technical Field

The invention relates to the technical field of veterinary medicines, and in particular relates to a mirtazapine oral preparation and a preparation method thereof.

Background

In 2016 to 2019, the market scale of pets in China shows high-speed growth, for example, the number of dogs and cats as pets and the number of pet raising people continuously rise, and the growth trend of about 10 percent is kept. According to data of '2019 consumption white paper in pet industry', the number of dogs and cats in cities and towns nationwide in 2019 reaches 9915 thousands, the consumption market scale of dogs and cats is 2024 million yuan, and the overall increase is 18.5%. The consumption market scale of the pet dog is 1244 million yuan, which is increased by 17.8 percent than the last year; the consumption market of the pet cat is 780 billion yuan, which is increased by 19.6 percent compared with the last year.

With the economic explosion of pets, diseases of many pets are also valued, and common pet diseases such as appetite disturbance, anorexia and the like often secondary to a plurality of chronic diseases and aggravate the catabolism induced by the diseases. Anorexia varies in degree when acute and chronic diseases occur in dogs and cats, when surgical pain occurs, or when problems such as dental dysfunction and chronic renal failure occur. In addition, elderly pets often experience loss of appetite and weight for unknown reasons. Such as dogs, cats and the like, have a reduced appetite and are ineffectual to be enticed with the foods they prefer to eat, requiring pharmacotherapy to increase the appetite and even further medical measures to supplement adequate nutrition. Therefore, there is a need to develop a drug for promoting appetite, increasing food intake, and controlling weight loss in pets.

Mirtazapine, a norrenaturent specific 5-hydroxytryptamine antidepressant, is a drug approved by many countries for the treatment of human depression, has a sedative effect, has good tolerance, almost no anticholinergic effect, and has no influence on the cardiovascular system in therapeutic dose. In pet medicine, mirtazapine can be used for improving appetite of pets such as dogs and cats, and treating inappetence and nausea-complicated disorders, such as gastrointestinal diseases, liver and kidney diseases, and other cases in which inappetence and nausea are accompanied.

At present, no specific mirtazapine medicine developed for pets is mainly a traditional mirtazapine medicine for human use in pet medicine, such as an orally disintegrating composition containing mirtazapine, a disintegrating agent, a filling agent and a stabilizing agent, wherein the weight percentages of the components are as follows: 9-15% of mirtazapine, 45-70% of filling agent, 15-40% of disintegrating agent and 0-15% of stabilizing agent, wherein the disintegrating agent is a mixture of sodium carboxymethyl starch, konjac powder and sodium bentonite. The orally disintegrating composition may further comprise taste enhancers, binders, and the like. For another example, the internal disintegrating composition comprises mirtazapine, a disintegrant, a filler and other auxiliary materials, and the weight percentages of the components are as follows: 1-10% of mirtazapine, 10-50% of disintegrating agent and 35-80% of filling agent. In the medical practice of pets, the traditional mirtazapine medicament for human use generally has the problems of poor palatability, refusal of medication for pets and difficulty in feeding.

Disclosure of Invention

Based on the above, the main object of the present invention is to provide an oral mirtazapine preparation and a method for preparing the same. The mirtazapine oral preparation disclosed by the invention is good in palatability and can be actively eaten by pets.

The purpose of the invention is realized by the following technical scheme:

the invention provides a mirtazapine oral preparation, which is prepared from the following raw materials in percentage by mass:

in one embodiment, the raw materials for preparing the mirtazapine oral dosage further comprise a flavor enhancer.

In one embodiment, the flavor enhancer is a mixture of (0.5-1.5): (4.5-5.5): (0.008-0.012) a mixture of citric acid, a pet phagostimulant, and sucralose.

In one embodiment, the pet food attractant is selected from at least one of chicken liver powder, beef powder and yeast hydrolysate.

In one embodiment, the mass percentage of the flavor enhancer in the preparation raw material is 4-8%.

In one embodiment, the diluent is selected from at least one of lactose, microcrystalline cellulose, and mannitol.

In one embodiment, the disintegrant is selected from at least one of sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, and cross-linked polyvinyl pyrrolidone.

In one embodiment, the binder is selected from at least one of beta-cyclodextrin, maltodextrin, sodium carboxymethylcellulose, and polyvinyl pyrrolidone.

In one embodiment, the glidant is selected from at least one of aerosil, magnesium stearate and talc.

It is another object of the present invention to provide a process for the preparation of mirtazapine oral dosage as described above, said process comprising the steps of:

preparing the mirtazapine, the binder, the disintegrant, the diluent, and the glidant into a mixture;

preparing an oral dosage form from said mixture.

In one embodiment, the oral dosage form is an oral tablet.

In one embodiment, the mirtazapine is sieved through an 80-120 mesh sieve.

In one embodiment, the binder, the disintegrant, the diluent, and the glidant are sieved through a 30-50 mesh sieve.

In one embodiment, the flavor enhancer is further added to the mixture.

The invention has the following beneficial effects:

according to the invention, the specific mirtazapine oral preparation raw material formula is formed by comprehensively adjusting the dosages of the auxiliary materials such as the diluent, the disintegrating agent, the adhesive and the flow aid, the oral preparation prepared by the formula has the advantage of good palatability, and pets can actively feed. Meanwhile, the inventor also unexpectedly finds that the raw material formula is suitable for tabletting by a dry pressing method, the forming effect is good, and the obtained tablet has uniform mirtazapine distribution. In addition, the oral preparation prepared by the raw material formula of the invention has better disintegration and dissolution.

Detailed Description

In order that the invention may be more fully understood, reference will now be made to the following description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The embodiment of the invention provides a mirtazapine oral preparation, which is prepared from the following raw materials in percentage by mass:

according to the embodiment of the invention, the specific raw material formula of the mirtazapine oral preparation is formed by comprehensively adjusting the dosage of the auxiliary materials such as the diluent, the disintegrating agent, the adhesive and the glidant.

The dry tabletting process is relatively simple, low in cost and favorable for large-scale production. However, dry tabletting has high material requirements, and the selection of the material types, particularly the proportion of the materials, has a significant influence on the tabletting effect. The inventor finds that when the mirtazapine tablet material is prepared by adopting the diluent, the disintegrant, the binder and the glidant with proper dosage in the embodiment of the invention, the obtained material can be used for dry tabletting, and has good forming effect, such as smooth surface, good hardness and friability, stable tablet weight, no phenomena of fracture, cracking, crushing and the like, and good disintegration and dissolution effects.

According to the embodiment of the invention, when a proper amount of diluent is selected, the smell of each auxiliary material and the smell of the combined product are fully considered, and the auxiliary material with the taste similar to sucrose or sweet taste is selected, so that the instant desorption heat in the oral cavity is fast and the taste is better, and the pleasant smell and taste to pets are increased; the mirtazapine raw material forms certain static electricity after being screened, the dispersion degree of the material is poor, and a proper amount of lubricant, flow aid and the like are added to be attached to the surface of the material, so that the surface net charge of the raw material is reduced, the friction force between the materials is reduced, and the fluidity of the material is increased. Meanwhile, the materials with similar bulk density to the main components are mixed and sieved, and then the low-content raw materials can be uniformly distributed by adopting an increasing dilution method.

The mirtazapine tablet provided by the embodiment of the invention is used for pets, the mirtazapine content of the medicinal component is relatively low, and when the content of the medicinal component is low, the problem that the medicinal component is not easy to distribute uniformly is often caused. According to the embodiment of the invention, by comprehensively adjusting the dosage of the auxiliary materials such as the diluent, the disintegrant adhesive and the glidant, when the obtained auxiliary material is mixed with the mirtazapine to form a tabletting material, the uniform distribution of the medicinal components in the mirtazapine tablets can be ensured.

Preferably, the raw materials for preparing the mirtazapine oral preparation also comprise a flavor enhancer. The "flavor enhancer" according to the embodiment of the present invention is a general term for substances that stimulate taste or smell receptors, and is generally classified into sweeteners, souring agents, bittering agents, salty agents, umami agents, and other flavoring agents. It is understood that the type and content of the added flavor enhancer are not limited in order to further induce the pet to take the mirtazapine tablets, and when the mirtazapine oral preparation is provided for pets of different species, the type of the corresponding flavor enhancer can be selected as appropriate according to the specific situation of the pet of the species, a single type of flavor enhancer can be selected, or different flavor enhancers can be selected to be used in combination.

Preferably, the flavor enhancer is prepared from the following components in a mass ratio of (0.5-1.5): (4.5-5.5): (0.008-0.012) a mixture of citric acid, a pet phagostimulant, and sucralose. For pets with severe food preferences, such as cats, the flavor enhancer can achieve a good food calling effect even when the appetite of the pet is particularly poor.

It is understood that the kind of the pet food attractant is not particularly limited in the embodiments of the present invention, and includes but is not limited to: chicken liver powder, beef powder, yeast hydrolysate and the like.

Preferably, the flavor enhancer accounts for 4-8% of the preparation raw material by mass.

It is understood that the embodiments of the present invention are not particularly limited to the types of diluents, including but not limited to the following types: lactose, microcrystalline cellulose, mannitol, and the like.

It is to be understood that the examples of the present invention do not specifically limit the kinds of the disintegrants, and include, but are not limited to, the following kinds: the disintegrating agent is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyethylene pyrrolidone and the like.

It is to be understood that the examples of the present invention do not specifically limit the types of adhesives, including but not limited to the following types: beta-cyclodextrin, maltodextrin, sodium carboxymethylcellulose, polyvinylpyrrolidone K30, and the like. Polyvinylpyrrolidone is for example polyvinylpyrrolidone K30.

It is understood that the glidants of the embodiments of the present invention are not particularly limited in kind, including but not limited to the following kinds: silica gel micropowder, magnesium stearate, talc powder, etc.

The embodiment of the invention also provides a preparation method of the mirtazapine oral preparation, which comprises the following steps:

preparing an oral dosage form from said mixture.

It is understood that in the preparation of the above mixture, different kinds of the preparation raw materials may be mixed at the same time or may be mixed step by step, and the same kind of the preparation raw materials may be added at once or may be added in portions. Specific ways include, but are not limited to, the following: mirtazapine, a binder and a disintegrant may be mixed to prepare a mixture, to which a diluent and a glidant are added.

Preferably, the oral dosage form is an oral tablet. The oral tablet is prepared by means of compression, preferably under a pressure in the range of 20-30N.

Preferably, the mirtazapine is sieved through a sieve of 80-120 mesh.

Preferably, the binder, the disintegrant, the diluent, and the glidant are sieved through a 30-50 mesh sieve.

Example 1

The embodiment provides a Miazepini tablet and a preparation method thereof.

The preparation raw materials of the mirtazapine tablet are shown in the following table:

TABLE 1

The preparation method of the mirtazapine tablet adopts dry method direct tabletting and comprises the following steps:

1. weighing: weighing the materials according to the prescription, sieving mirtazapine with a 100-mesh sieve, and sieving other raw materials with a 40-mesh sieve for later use;

2. mixing: 1) uniformly mixing mirtazapine, beta-cyclodextrin (adhesive) and sodium carboxymethyl starch (disintegrant) for later use; 2) premixing citric acid, sucralose and a small amount of chicken liver powder, adding the rest chicken liver powder, and uniformly mixing; 3) adding mannitol and a small amount of lactose (diluent) into the materials prepared in the steps 1) and 2), mixing, adding the rest of lactose (diluent), microcrystalline cellulose and superfine silica gel powder (glidant), and uniformly mixing.

3. Tabletting: the tablets were compressed under a pressure of 25N with a tablet weight of 140 mg/tablet.

Example 2

The embodiment provides a Mizengping and a preparation method thereof.

TABLE 2

The preparation method of the mirtazapine tablet adopts dry method direct compression and comprises the following steps:

1. weighing: weighing the materials according to the prescription, sieving mirtazapine with a 80-mesh sieve, and sieving other raw materials with a 30-mesh sieve for later use;

2. mixing: 1) uniformly mixing mirtazapine, beta-cyclodextrin (adhesive) and sodium carboxymethyl starch (disintegrant) for later use; 2) premixing citric acid, sucralose and a small amount of hydrolyzed chicken liver powder, adding the rest hydrolyzed chicken liver powder, and uniformly mixing; 3) adding a small amount of lactose (diluent) into the materials prepared in the steps 1) and 2), mixing, adding the rest of lactose (diluent), microcrystalline cellulose and superfine silica gel powder (glidant), and uniformly mixing.

3. Tabletting: tabletting was carried out under a pressure of 20N and with a tablet weight of 140 mg/tablet.

Example 3

The embodiment provides a Miazepini tablet and a preparation method thereof.

TABLE 3

1. weighing: weighing the materials according to the prescription, sieving mirtazapine with a 120-mesh sieve, and sieving other raw materials with a 50-mesh sieve for later use;

2. mixing: 1) uniformly mixing mirtazapine, beta-cyclodextrin (adhesive) and sodium carboxymethyl starch (disintegrant) for later use; 2) premixing citric acid, sucralose and a small amount of chicken liver powder, adding the rest chicken liver powder, and uniformly mixing; 3) adding mannitol into the materials prepared in the steps 1) and 2), mixing, adding microcrystalline cellulose and micro-powder silica gel (flow aid), and uniformly mixing.

3. Tabletting: the tablets were compressed under a pressure of 30N with a tablet weight of 140 mg/tablet.

Example 4

The embodiment provides a Mizengping and a preparation method thereof.

TABLE 4

2. mixing: 1) uniformly mixing mirtazapine, beta-cyclodextrin (adhesive) and sodium carboxymethyl starch (disintegrant) for later use; 2) premixing citric acid, sucralose and a small amount of chicken liver powder, adding the rest chicken liver powder, and uniformly mixing; 3) adding mannitol and a small amount of lactose (diluent) into the materials prepared in the steps 1) and 2), mixing, adding the rest of lactose (diluent) and microcrystalline cellulose (diluent), mixing, adding superfine silica gel powder (glidant), and uniformly mixing.

3. Tabletting: tabletting was carried out under a pressure of 25N and with a tablet weight of 140 mg/tablet.

Example 5

This example is a modification of example 1, and is modified from example 1 in that no flavor enhancer is contained.

The preparation of mirtazapine tablets for this example is shown in the following table:

TABLE 5

2. mixing: 1) uniformly mixing mirtazapine, beta-cyclodextrin (adhesive) and sodium carboxymethyl starch (disintegrant) for later use; 2) adding mannitol and a small amount of lactose (diluent) into the material obtained in the step 1), mixing, adding the rest of lactose (diluent), microcrystalline cellulose and silica gel micropowder (glidant), and uniformly mixing.

Example 6

This example is a modification of example 1, and the modification to example 1 is that the type of flavor enhancer is different.

TABLE 6

Preparation method referring to example 1, the mirtazapine tablet is prepared by a dry direct compression method, which comprises the following steps:

2. mixing: 1) uniformly mixing mirtazapine, beta-cyclodextrin (adhesive) and sodium carboxymethyl starch (disintegrant) for later use; 2) adding mannitol and a small amount of lactose (diluent) into the material prepared by the step 1) and the hydrolyzed chicken liver powder, mixing, adding the rest of lactose (diluent), microcrystalline cellulose and superfine silica gel powder (glidant), and uniformly mixing.

Comparative example 1

This comparative example is that of example 5, the main difference with respect to example 5 being the amount of starting material used. The method comprises the following specific steps:

TABLE 7

Comparative example 2

This comparative example is a comparative example to example 5, the difference with respect to example 5 being the amount of starting material used for the preparation. The method comprises the following specific steps:

the mirtazapine tablets of this comparative example were prepared from the following raw materials as shown in the table:

TABLE 8

2. mixing: 1) uniformly mixing mirtazapine, beta-cyclodextrin (adhesive) and sodium carboxymethyl starch (disintegrant) for later use; 2) adding mannitol and a small amount of lactose (diluent) into the material obtained in the step 1), mixing, adding the rest of lactose (diluent), microcrystalline cellulose and superfine silica gel powder (glidant), and uniformly mixing.

Comparative example 3

TABLE 9

Performance test

Palatability test

Dogs were selected for the trial and divided into 9 groups of 6 dogs each. Separately feeding mirtazapine tablets provided in the above examples and comparative examples, observing whether the dogs are actively fed within 2 minutes, recording the number of dogs fed, and calculating the feed intake rate according to the following formula: the palatability was evaluated by taking dogs/test dogs at a (%) feed rate of 100%.

TABLE 10

	Test dog	Feeding dog	Feed intake (%)
				Example 1	6 are	6	100％
Example 2	6 are	5	83.33％
				Example 3	6 are	5	83.33％
Example 4	6 are	5	83.33％
				Example 5	6 are	5	83.33％
Example 6	6 are	4	66.67％
				Comparative example 1	6 are	2	33.33％
Comparative example 2	6 are	2	33.33％
				Comparative example 3	6 are	1	16.67％

(II) moldability

1. Measurement of hardness

The test method comprises the following steps: 10 samples were taken and placed on a tablet hardness tester, and the average value was taken.

And (3) testing results:

TABLE 11

2. Friability measurement

Several samples, weighing about 6.5g total, were blown off the powder falling off the tablets by a blower, precisely weighed, placed in a jar with a friability apparatus and rotated 100 times.

Taking out, removing powder by the same method, precisely weighing, and measuring weight loss and fragmentation.

TABLE 12

	Before measurement/g	Measured in/g	Weight reduction/g	Fragmentation event
					Example 1	6.5317	6.5241	0.12％	Without fragmentation
Example 2	6.5307	6.5202	0.16％	Without fragmentation
					Example 3	6.5402	6.5332	0.10％	Without chipping
Example 4	6.5426	6.4961	0.71％	Without fragmentation

Example 5	6.2238	6.2146	0.15％	Without fragmentation
					Example 6	6.3752	6.3682	0.11％	Without fragmentation
Comparative example 1	6.5432	6.4021	2.16％	With chipping
					Comparative example 2	6.6891	6.6792	0.15％	Without fragmentation
Comparative example 3	6.3392	6.3243	0.24％	Without chipping

3. Check for difference in slice weight

Taking 20 samples to be tested, precisely weighing the total weight, obtaining the average weight of the samples, and precisely weighing the weight of each sample. The weight of each tablet is not more than 2 tablets exceeding the weight difference limit, and not more than 1 time exceeding the limit of the tablet when compared with the average tablet weight. Less than 0.3g, and a weight variation limit of. + -. 7.5%.

Watch 13

	The difference of tablet weight%	Excess number of sheets	Whether it is qualified or not
				Example 1	1.12％	0	Qualified
Example 2	2.08％	0	Qualified
				Example 3	3.86％	1	Qualified
Example 4	3.57％	1	Qualified
				Example 5	0.68％	0	Qualified
Example 6	1.57％	0	Qualified
				Comparative example 1	2.35％	0	Qualified
Comparative example 2	5.35％	1	Qualified
				Comparative example 3	1.86％	0	Qualified

4. Dissolution determination

Measuring by adopting a slurry method, after the temperature of a dissolution medium (0.9% hydrochloric acid solution) in a dissolution instrument is constant at 37 +/-0.5 ℃, taking 6 test samples, respectively putting the test samples into dissolution cups, rotating at 50 r/min, taking a proper amount of solution after 15 minutes, filtering, diluting the solution to obtain a test sample solution, and measuring the absorbance at the wavelength of 315 nm;

and (4) taking a mirtazapine reference substance to be diluted to the same concentration to be used as a reference substance solution, measuring by the same method, and calculating the dissolution amount of each tablet. The limit is 80% of the indicated amount and should be in accordance with the specification.

TABLE 14

Numbering	Determination of the light absorption value	Amount of CX eluted	Dissolution rate	Whether it is qualified or not
					Example 1	0.31	7.05	93.37％	Qualified
Example 2	0.30	6.82	90.33％	Qualified
					Example 3	0.32	7.27	96.29％	Qualified
Example 4	0.29	6.59	87.28％	Qualified
					Example 5	0.32	7.27	96.29％	Qualified
Example 6	0.31	7.05	93.37％	Qualified
					Comparative example 1	0.30	6.82	90.33％	Qualified
Comparative example 2	0.26	5.984	78.78％	Fail to be qualified
					Comparative example 3	0.25	5.71	75.75％	Fail to be qualified

In conclusion, the specific mirtazapine tablet raw material formula is formed by comprehensively adjusting the dosage of the auxiliary materials of the diluent, the disintegrant adhesive and the glidant, and the tablet prepared by the formula has the effect of good palatability and can be taken by pets positively. Meanwhile, the inventor also unexpectedly finds that the raw material formula is suitable for tabletting by a dry pressing method, the forming effect is good, and the mirtazapine in the obtained tablets is uniformly distributed. In addition, the tablets prepared by the raw material formula have better disintegration and dissolution.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. The mirtazapine oral preparation is characterized by comprising the following raw materials in percentage by mass:

the diluent consists of lactose, microcrystalline cellulose and mannitol, wherein the lactose, the microcrystalline cellulose and the mannitol respectively account for 42%, 36.01% and 5.99% of the raw materials in percentage by mass;

the disintegrating agent is sodium carboxymethyl starch;

the adhesive is beta-cyclodextrin;

the glidant is micro-powder silica gel;

the mirtazapine oral dosage is an oral tablet.

2. A process for the preparation of mirtazapine oral dosage form according to claim 1, comprising the steps of:

preparing an oral dosage form from said mixture.

3. The method of preparing mirtazapine oral dosage form of claim 2, wherein mirtazapine is passed through a sieve of 80-120 mesh.

4. The process for preparing an oral dosage form of mirtazapine as claimed in claim 2, wherein the binding agent is sieved through a 30-50 mesh sieve.

5. The process for preparing mirtazapine oral dosage form of claim 2, wherein the disintegrant is passed through a 30-50 mesh sieve.

6. The method of preparing mirtazapine oral dosage form of claim 2, wherein the diluent is passed through a 30-50 mesh screen.

7. The process for preparing mirtazapine oral dosage form of claim 2, wherein the glidant is passed through a 30-50 mesh screen.