CN106822051A

CN106822051A - A kind of Oxiracetam pelliculae pro cavo oris and preparation method thereof

Info

Publication number: CN106822051A
Application number: CN201510900581.9A
Authority: CN
Inventors: 叶雷
Original assignee: Chongqing Runze Pharmaceutical Co Ltd
Current assignee: Chongqing Runze Pharmaceutical Co Ltd
Priority date: 2015-12-07
Filing date: 2015-12-07
Publication date: 2017-06-13

Abstract

A kind of Oxiracetam pelliculae pro cavo oris, it is obtained by including the raw material including Oxiracetam, filmogen and filler and plasticizer, with a small amount of saliva is that can dissolve in oral cavity, medication by being not required to water delivery service, medication is convenient, it is difficult to spue after being adhered on tongue, is adapted to the old man of dysphagia, and by mucosal absorption, avoid head and cross elimination effect, bioavilability is improve, pharmaceutical dosage is reduced, so as to reduce drug side-effect.Preparation method of the present invention is simple, and process costs are low, is adapted to large-scale production.

Description

Oxiracetam oral film agent and preparation method thereof

Technical Field

The invention relates to oxiracetam, and in particular relates to an oxiracetam oral film agent and a preparation method thereof.

Background

Oxiracetam (Oxiracetam), chemically known as 4-hydroxy-2-oxo-1-pyrrolidineacetamide, is a nootropic drug first synthesized in 1974 by the company starchy, italy, and is a derivative of hydroxyamino butyric acid (GABOB), which can promote learning, enhance memory, and protect the central nervous system of damaged nerve cells. The structure is as follows:

since the medicine is put on the market, the medicine is always the leading product in the medicine for treating dementia due to the characteristics of good effect, high safety, wide range of indications, little drug interaction, low toxicity and the like, and dosage forms such as injection, capsule, tablet and the like are developed and marketed successively.

CN104069074A discloses an oxiracetam injection freeze-drying preparation, which is prepared by firstly forming oxiracetam into aqueous solution with a certain concentration, and then adding ethanol for freeze-drying; the freeze-dried preparation basically does not contain auxiliary materials, and has the advantages of quick redissolution, good quality and stable storage. The preparation is directly injected into tissues or blood vessels, and has no absorption process or short absorption process, so that the blood concentration can quickly reach the peak to play a role; however, the preparation and production process is complicated, the injection is sterile and pyrogen-free, the production process is strict, more steps require higher equipment conditions, and the drugs in the injection are generally dispersed in water in micron-sized solid small particles in molecular state, so that the dispersion degree is very high, and the stability problems of drug hydrolysis, oxidation, large solid particle coalescence and the like are often caused by high-temperature sterilization. Meanwhile, because the injection directly and rapidly enters the human body without the protection of the normal physiological barrier of the human body, if the dosage is improper or the injection is too fast or the quality of the medicine has problems, the injection can bring harm to the patient and even cause irrecoverable consequences. In addition, pain from injection, inability to self-administer by the patient, local induration from injection, and vascular inflammation from intravenous injection are problems in clinical use.

CN101732251A discloses an oxiracetam liposome, which is prepared from oxiracetam, phospholipid, cholesterol, Tween 80 and a proper amount of osmotic pressure regulator and buffer solution; the liposome has good stability, high encapsulation rate, and small toxic and side effects; however, the liposome preparation process is complex and is not suitable for large-scale production; more importantly, the curative effect of the liposome in a human body is still to be further researched, and at present, a liposome preparation is rarely used clinically in China.

CN103494790A discloses an oxiracetam capsule, which is prepared from xylitol, a lubricant and oxiracetam in a crystalline form; the prepared oxiracetam capsule has the advantages of obviously improved quality stability, simple preparation process and reduced production cost. CN104739796A discloses an oxiracetam tablet, which is prepared from a certain amount of oxiracetam, a filler, a disintegrating agent, an adhesive and a lubricant; the tablet is convenient for administration, carrying, transportation and storage. However, in actual clinical practice, capsules and tablets often cause cough and patients with mental retardation are mostly old people, and the patients often have difficulty in swallowing the medicine and are inconvenient to take oxiracetam capsules and tablets.

CN1555794A discloses an oxiracetam dispersible tablet, which is prepared from oxiracetam, a disintegrating agent, a lubricant, a flow aid and an adhesive, and the oxiracetam dispersible tablet can be rapidly disintegrated into uniformly dispersed fine particles after oral administration, thereby being beneficial to the dissolution and absorption of the medicament; it is convenient for administration, and can be dispersed in water and administered orally, or be administered orally by sucking or swallowing. Oral dispersible tablets also have the problem of choking cough, while sucking dispersible tablets has slow effect, gritty and bitter taste and is not easy to take.

The oral film agent is an oral solid quick-release new dosage form which is increasingly widely applied abroad in recent years, and has the unique characteristic of quick dissolution in the oral cavity without drinking water, so that the oral film agent has multiple advantages and is particularly suitable for old patients. Although the oral film has many advantages, the problems of low drug loading, difficult control of disintegration time and tensile vertical strength, taste masking and the like caused by the limitations of film forming materials and preparation technologies of the oral film restrict the development and application of the oral film.

Disclosure of Invention

The invention aims to provide an oxiracetam oral film agent which has stable chemical and physical properties, moderate hardness, higher drug-loading rate and short disintegration time.

The invention also aims to provide the preparation method of the oxiracetam oral film agent, which is simple to operate, does not need special equipment and is suitable for industrial production.

The parts are parts by weight unless otherwise specified.

The purpose of the invention is realized as follows:

an oxiracetam oral film agent is prepared from oxiracetam, a film forming material, a filler and a plasticizer according to the following mixture ratio:

the parts are parts by weight.

The film-forming material is selected from one or more of hydroxypropyl cellulose, sodium alginate, hydroxypropyl methylcellulose, pullulan, pectin, maltodextrin, sodium carboxymethylcellulose, polyvidone-vinyl acetate, polyoxyethylene or amylopectin.

The plasticizer is one or more selected from propylene glycol, glycerol, dibutyl phthalate, triethyl citrate, triacetin, PEG400 and PEG 600.

The filler is one or more selected from microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pregelatinized starch, and croscarmellose sodium.

The inventor finds that the selection of a film-forming material is important for the successful preparation of the oxiracetam oral film agent in the research and development process, and improper selection can cause various problems of poor film-forming property, poor appearance, long disintegration time and the like. Research shows that by using the film forming material with specific type and dosage, the oxiracetam oral film agent with moderate thickness, good mechanical property and short disintegration time can be prepared.

Preference is given to

An oxiracetam oral film agent is prepared from 1-20 parts of oxiracetam, 35-70 parts of film forming material, 5-30 parts of plasticizer and 5-30 parts of filler; the film forming material is one or the combination of two of hydroxypropyl cellulose and pullulan.

In further research, the inventor also finds that in the process of preparing the oxiracetam oral film by using hydroxypropyl cellulose or pullulan as a film forming material, the film agents are still adhered to each other and are soft. Based on a large number of experiments, the inventors found that the above problems can be solved by using appropriate types and amounts of plasticizers.

Preference is given to

An oxiracetam oral film agent is prepared from raw materials including 1-20 parts of oxiracetam, 35-65 parts of film forming materials, 5-25 parts of plasticizers and 5-30 parts of fillers; the film forming material is one or the combination of two of hydroxypropyl cellulose and pullulan; the plasticizer is glycerol or propylene glycol.

More preferably:

an oxiracetam oral film agent is prepared from raw materials including 1-20 parts of oxiracetam, 40-65 parts of hydroxypropyl cellulose, 10-25 parts of glycerol and 5-30 parts of a filling agent.

In order to increase the dissolution rate of the oxiracetam oral film agent, the dosage of the glycerol and the hydroxypropyl cellulose is preferably glycerol: and (3) hydroxypropyl cellulose is 1: 3-4.

Or

An oxiracetam oral film agent is prepared from raw materials including 1-20 parts of oxiracetam, 35-60 parts of pullulan, 15-30 parts of propylene glycol and 5-30 parts of a filling agent.

In order to increase the dissolution rate of the oxiracetam oral film agent, the dosage of the propylene glycol and the pullulan is preferably the ratio of propylene glycol: the pullulan is 1: 2-2.5.

1-5 parts of flavoring agent can be added into the oxiracetam oral film agent in the preparation process; the flavoring agent is selected from one or more of xylitol, aspartame, acesulfame potassium, sucralose and essence.

The thickness of the oxiracetam oral film agent is preferably 80-120 mu m, and more preferably 100-110 mu m, considering both the adaptability of patients and the disintegration time of the oral film agent.

The preparation method of the oxiracetam oral film agent comprises the following steps:

1) dissolving a film forming material in absolute ethyl alcohol to form homogeneous viscous liquid, then adding a plasticizer and uniformly mixing to form a material I;

2) mixing oxiracetam and a filler uniformly, and dispersing with absolute ethyl alcohol to form a material II;

3) mixing the material II with the material I, and stirring for 30-180min to form oxiracetam bubble-free suspension viscous liquid;

4) and (3) casting the oxiracetam bubble-free suspension viscous liquid prepared in the step 3) on a mold, drying at 45-95 ℃, cooling at room temperature, forming a film, and cutting to obtain the oxiracetam oral film agent.

In particular, the present invention relates to a method for producing,

a preparation method of an oxiracetam oral film agent comprises the following steps:

dissolving 35-70 parts of film forming material in absolute ethyl alcohol to form homogeneous viscous liquid, then adding 5-30 parts of plasticizer and uniformly mixing to form a material I;

uniformly mixing 1-20 parts of oxiracetam, 5-30 parts of filler and 2-5 parts of flavoring agent, and dispersing with absolute ethyl alcohol to form a material II;

Wherein,

the amount of the absolute ethyl alcohol in the step 1) and the step 2) is determined by a person skilled in the art according to actual needs.

The stirring speed in the step 3) is 400 r/min-800 r/min, and the stirring time is preferably 60 min-120 min.

The film forming material is one or two of hydroxypropyl cellulose or pullulan.

The correctant is selected from one or more of xylitol, aspartame, acesulfame potassium, and sucralose.

The cutting in the step 4) is performed according to the required shape and size.

The invention has the following beneficial effects:

1. the oxiracetam oral film agent can be dissolved by a small amount of saliva in the oral cavity, and can be taken without water, so that the oxiracetam oral film agent is convenient to take.

2. The oxiracetam oral film agent has the advantages of uniform and complete appearance, uniform color, consistent thickness, stable physical and chemical properties, short disintegration time, high dissolution speed and quick response.

3. The oxiracetam oral film agent is not easy to spit out after being adhered on the tongue, is suitable for the old with dysphagia, is absorbed through mucous membrane, avoids first-pass elimination effect, improves bioavailability, reduces medicinal dosage, and reduces side effect of the medicament.

4. The invention takes the film forming property, the appearance and the disintegration time of the oral film agent into consideration, and carefully selects the hydroxypropyl cellulose, the hydroxypropyl cellulose or the pullulan with specific dosage as the film forming material, so that the prepared oxiracetam oral film agent has moderate thickness, good mechanical property and shorter disintegration time.

5. The invention combines the specific film forming material with the specific type and dosage of plasticizer, thereby effectively solving the technical problems of mutual adhesion, soft quality and the like of the films, and realizing that the prepared oxiracetam oral film has good demoulding performance, moderate hardness, high mechanical property and short disintegration time, and does not have the defects of easy fracture or increase of disintegration time due to too high hardness or inaccurate dosage due to extension of the oral film.

6. The preparation method is simple, low in process cost and suitable for large-scale production.

Examples

In order to make the objects and technical solutions of the present invention clearer, preferred embodiments of the present invention are described in detail below. It is to be noted that: the following examples are intended to illustrate the invention further and are not to be construed as limiting the scope of the invention. The invention is not limited to the embodiments described above, but rather, many modifications and variations may be made by one skilled in the art without departing from the scope of the invention.

The raw materials and reagents used in the invention are all commercial products. Wherein the oxiracetam raw material (the content is 99.8 percent, provided by Chongqing Dongze medicine science and technology development Co., Ltd., the batch number is 20140917); hypromellose (HPMC, dow chemical, usa, specification E5); hydroxypropylcellulose (HPC, Ashland corporation, usa, specification LF); pullulan (Shandong Furuida Biotech Co., Ltd.); maltodextrin (Deqing Sanfu food Co., Ltd., glucose (DE) value 15% -20%); polyethylene glycol (PEG)400 (pharmaceutical limited Huari, Hunan); glycerol, absolute ethanol (lake nan Er kang pharmaceuticals GmbH); triethyl citrate (TEC, bexad yobo primary medicine science and technology development ltd); low-substituted hydroxypropylcellulose (L-HPC), pregelatinized starch (anshui mountain river pharmaceutic adjuvant, ltd); microcrystalline cellulose (MCC, JRS, germany, specification VIVAPUR 101); acesulfame k (vedo corporation); xylitol (limited by Shandong Futian science and technology group); acetonitrile and methanol are chromatographically pure, and other reagents are analytically pure. In example n is the number of oxiracetam oral films measured.

Example 1

1) dissolving 40-65 parts of hydroxypropyl cellulose in absolute ethyl alcohol to form homogeneous viscous liquid, then adding 10-25 parts of glycerol and uniformly mixing to form a material I;

2) uniformly mixing 1-20 parts of oxiracetam, 5-30 parts of filler and 3-5 parts of flavoring agent, and dispersing with absolute ethyl alcohol to form a material II;

3) mixing the material II with the material I, and stirring at a stirring speed of 500 r/min-800 r/min for 60 min-120 min to form oxiracetam bubble-free suspension viscous liquid;

4) and (3) casting the oxiracetam bubble-free suspension viscous liquid prepared in the step 3) on a mold, drying at 55-90 ℃, cooling at room temperature, forming a film, and cutting to obtain the oxiracetam oral film agent.

Example 2

1) dissolving 35-60 parts of pullulan polysaccharide in absolute ethyl alcohol to form homogeneous viscous liquid, then adding 15-30 parts of propylene glycol, and uniformly mixing to form a material I;

3) mixing the material II with the material I, and stirring at a stirring speed of 500 r/min-700 r/min for 70-130min to form oxiracetam bubble-free suspension viscous liquid;

4) and (3) casting the oxiracetam bubble-free suspension viscous liquid prepared in the step 3) on a mold, drying at 45-85 ℃, cooling at room temperature, forming a film, and cutting to obtain the oxiracetam oral film agent.

Example 3

1) Dissolving hydroxypropyl cellulose in absolute ethyl alcohol to form homogeneous viscous liquid, then adding glycerol and uniformly mixing to form a material I;

2) mixing oxiracetam and microcrystalline cellulose uniformly, and dispersing with absolute ethyl alcohol to form a material II;

3) mixing the material II and the material I, and stirring at the stirring speed of 500-600 r/min for 80-90 min to form oxiracetam bubble-free suspension viscous liquid;

4) and (3) casting the oxiracetam bubble-free suspension viscous liquid prepared in the step 3) on a mold, drying at 72-75 ℃, cooling at room temperature, forming a film, and cutting to obtain the oxiracetam oral film agent.

Example 4

1) Dissolving hydroxypropyl cellulose in 50ml of absolute ethyl alcohol to form homogeneous viscous liquid, then adding glycerol and uniformly mixing to form a material I;

2) mixing oxiracetam, microcrystalline cellulose and aspartame uniformly, and dispersing with 20ml of absolute ethyl alcohol to form a material II;

3) mixing the material II and the material I, and stirring at the stirring speed of 500-600 r/min for 90-100 min to form oxiracetam bubble-free suspension viscous liquid;

4) and (3) casting the oxiracetam bubble-free suspension viscous liquid prepared in the step 3) on a mold, drying at 75-90 ℃, cooling at room temperature, forming a film, and cutting to obtain the oxiracetam oral film agent.

Example 5

1) Dissolving pullulan in 50mL absolute ethyl alcohol to form homogeneous viscous liquid, then adding propylene glycol and uniformly mixing to form a material I;

2) mixing oxiracetam and pregelatinized starch uniformly, and dispersing with 35mL of absolute ethyl alcohol to form a material II;

3) mixing the material II and the material I, and stirring at the stirring speed of 500-600 r/min for 70-80 min to form oxiracetam bubble-free suspension viscous liquid;

4) and (3) casting the oxiracetam bubble-free suspension viscous liquid prepared in the step 3) on a mold, drying at 72-85 ℃, cooling at room temperature, forming a film, and cutting to obtain the oxiracetam oral film agent.

Example 6

1) Dissolving pullulan in 50 parts of absolute ethyl alcohol to form homogeneous viscous liquid, adding propylene glycol, and uniformly mixing to form a material I;

2) mixing oxiracetam, low-substituted hydroxypropyl cellulose and xylitol uniformly, and dispersing by using 30 parts of absolute ethyl alcohol to form a material II;

Comparative example 1

1) Dissolving 50 parts of sodium alginate in 50 parts of absolute ethyl alcohol to form homogeneous viscous liquid, then adding 20 parts of propylene glycol, and uniformly mixing to form a material I;

2) uniformly mixing 15 parts of oxiracetam, 20 parts of low-substituted hydroxypropyl cellulose and 5 parts of xylitol, and dispersing with 30 parts of absolute ethyl alcohol to form a material II;

Comparative example 2

1) Dissolving 50 parts of sodium alginate in 50 parts of absolute ethyl alcohol to form homogeneous viscous liquid, then adding 20 parts of dibutyl phthalate, and uniformly mixing to form a material I;

Comparative example 3

1) Dissolving 50 parts of pullulan polysaccharide in 50 parts of absolute ethyl alcohol to form homogeneous viscous liquid, then adding 20 parts of glyceryl triacetate, and uniformly mixing to form a material I;

Oral film property determination

Measurement method

Thickness and mass

Thickness measurement (4 angles and centers) is carried out on different positions of the film agent by using a thickness gauge, the mass of each film agent is precisely weighed, and the mean value and the standard deviation are calculated.

Mechanical Properties

The mechanical properties of the film agent are measured by 3 indexes: tensile strength, elongation and folding endurance. Cutting the film into 2.0cm multiplied by 3.0cm, longitudinally stretching each film by a tensile testing machine (the stretching speed is 25mm/min) until the film is broken, recording the reading, and calculating the tensile strength and the elongation. The folding resistance of the film was measured by repeating folding until the film was broken at the same site, and the folding resistance was expressed by the logarithm of the number of times of double folding before breaking.

Content (wt.)

The content of the oxiracetam oral film agent is determined by an HPLC method, the chromatographic conditions comprise a chromatographic column InertSustain C18 column (4.6mm × 250mm, 5 mu m), 0.02mol/L sodium dihydrogen phosphate solution as a mobile phase, the detection wavelength of 210nm, the column temperature of 30 ℃, the flow rate of 0.6ml/min, the sample injection amount of 20 mu L, the linear relation between the concentration C of oxiracetam and the peak area A in the range of 0.5-100 mu g/ml is good, and the linear equation is that A is 3.7381 × 10⁴c+3.7513×10³And R2 ═ 0.9998. The RSD in the method is 0.60% (n is 6), the average recovery rate is 100.4% (n is 9), and the method can be directly used for analyzing and measuring oxiracetam oral films.

The test results of examples 3-6 and comparative examples 1-3 are specifically shown in the following table:

note:¹⁾n-6 for thickness, quality and mechanical properties, n-10 for content and content uniformity

The prepared oxiracetam film agent has good thickness uniformity, proper flexibility and tensile property, and the weight difference and the content uniformity accord with the regulations of the second part of the Chinese pharmacopoeia 2010 edition. The films A +1.80 XS prepared in examples 3-6 were all less than 4, and the oxiracetam oral films A +1.80 XS prepared in comparative examples 1-3 were above 5.

Disintegration time

The film was placed in a beaker containing 50ml of purified water at 37 ℃ and vortexed. Visually, the disintegration time of the film was recorded and 3 films were taken for each example.

Results the average disintegration times of examples 3-6 and comparative examples 1-3 were:

the disintegration time of the films prepared in examples 3-6 is less than 30s, and the disintegration time of the oxiracetam oral film prepared in comparative examples 1-3 is more than 35 s.

In vitro dissolution test

Dissolution rate is measured by adopting a slurry method, the dissolution rates of the oxiracetam oral film agents of the examples 3-6 and the comparative examples 1-3 are measured, the dissolution medium is water, the dissolution volume is 1000mL, the temperature is 37 ℃, and the rotating speed is 100 rpm.

The results are specified in the following table.

The test shows that: the oxiracetam oral film agent of the embodiments 3 to 6 starts to disintegrate within 10s, the drug release is rapid, the dissolution exceeds 85% within 5min, and the dissolution is basically complete within 10 min; the oxiracetam oral film agent prepared in the comparative examples 1-3 starts to disintegrate within 10s, releases the drug rapidly, and dissolves out more than 70% within 5min, 90% within 10min and basically completely dissolves out within 20 min;

comparative example 1 the effect of the film-forming material on the oxiracetam oral film was examined (see reference example 6), and experiments showed that the prepared oxiracetam oral film had a disintegration time of more than 30s and a slightly slower dissolution rate than the oxiracetam oral film with hydroxypropyl cellulose or prussian polysaccharide as the film-forming material when sodium alginate was used as the film-forming material. The inventor also uses other film forming materials (pectin, maltodextrin, sodium carboxymethyl cellulose, amylopectin, povidone-vinyl acetate and polyoxyethylene) to perform experiments with reference to comparative example 1, and the results show that the oxiracetam oral film agent prepared by taking the maltodextrin, the sodium carboxymethyl cellulose and the amylopectin as the film forming materials has better film forming property and appearance, but has longer disintegration time; the oxiracetam oral film prepared from pectin, povidone-vinyl acetate and polyoxyethylene has poorer mechanical property, and the demolding property of the oxiracetam oral film is lower than that of the oxiracetam oral film prepared from prussian polysaccharide and/or hydroxypropyl cellulose.

Examples 7 to 14

Examples 7-14 were run according to the procedure of examples 4-6 with the following parameters:

the properties of the oral films prepared in examples 7-14 were measured as described above.

The thickness, quality, mechanical properties, content and content uniformity measurements are as follows:

The prepared oxiracetam film agent has good thickness uniformity, proper flexibility and tensile property, and the weight difference and the content uniformity accord with the regulations of the second part of the Chinese pharmacopoeia 2010 edition.

The disintegration times are specified in the following table:

the oxiracetam oral films prepared in examples 7-14 have good disintegration properties.

In vitro dissolution test, see table below

Tests show that the oxiracetam oral film has good solubility.

Generally speaking, the oxiracetam oral film agent has the advantages of uniform and complete appearance, uniform color and luster, consistent thickness, stable physical and chemical properties, short disintegration time, high dissolution speed and quick response.

Claims

1. An oxiracetam oral film agent is prepared from the following raw materials including oxiracetam, a film forming material, a filler and a plasticizer in parts by weight:

1-20 parts of oxiracetam

30-80 parts of film forming material

5-30 parts of plasticizer

5-30 parts of a filling agent.

2. The oral film of claim 1, wherein: the film forming material is selected from one or more of hydroxypropyl cellulose, sodium alginate, hydroxypropyl cellulose, pullulan, pectin, maltodextrin, sodium carboxymethylcellulose, povidone-vinyl acetate, polyoxyethylene or amylopectin.

3. The oral film of claim 1, wherein: the plasticizer is selected from one or more of propylene glycol, glycerol, dibutyl phthalate, triethyl citrate, triacetin, PEG400 and PEG 600.

4. The oral film of claim 1, wherein: the filler is selected from one or more of microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pregelatinized starch and croscarmellose sodium.

5. The oral film of claim 1 or 4, wherein: is prepared from raw materials including 1-20 parts of oxiracetam, 35-65 parts of film-forming material, 5-25 parts of plasticizer and 5-30 parts of filler; the film forming material is one or the combination of two of hydroxypropyl cellulose and pullulan; the plasticizer is glycerol or propylene glycol.

6. The oral film of claim 5, wherein: is prepared from raw materials including 1-20 parts of oxiracetam, 40-65 parts of hydroxypropyl cellulose, 10-25 parts of glycerol and 5-30 parts of filler.

7. The oral film of claim 5, wherein: is prepared from oxiracetam (1-20 portions), pullulan (35-60 portions), propylene glycol (15-30 portions) and filler (5-30 portions).

8. The oral film of claim 1, 2, 3, 4, 6 or 7, wherein: the thickness of the oxiracetam oral film agent is 80-120 mu m.

9. The oral film of claim 5, wherein: the thickness of the oxiracetam oral film agent is 80-120 mu m.

10. The process for preparing an oxiracetam oral film of any of claims 1-9, comprising the steps of: