TWI623326B - An oral instant soluble film former of olanzapine - Google Patents

Abstract

The present invention relates to an olanzapine oral fast-dissolving film agent, its preparation method and medical application. The film agent includes the following components by weight percentage: olanzapine 1 to 30 wt%, polymer film-forming material: 40 to 90 wt%, increasing Plasticizer: 0 to 40wt%, flavoring agent 0 to 30wt%, other accessories: 0 to 5wt%. The administration of this dosage form does not need to be taken with water, it can quickly melt in the oral cavity, avoid the phenomenon of schizophrenia patients storing and vomiting drugs in the oral cavity, and help to improve the compliance of patients with medication. The main form of the dosage form obtained by the preparation method of the present invention has a good dispersion effect in the hydrophilic matrix glue and a good appearance of the finished product. The main form dissolves quickly and has good stability, and the product dosage is accurate. There is almost no dust flying in the production process. Solve labor protection and environmental pollution problems.

Description

Olanzapine Oral Instant Film

The invention belongs to the field of chemical pharmacy, and specifically relates to an olanzapine oral instant film agent and a preparation method thereof.

Due to the rapid development of society and development, while people are under increasing pressure from work and life, mental illnesses are gradually increasing. According to statistics, mental illness has already ranked first in the ranking of the total burden of disease in China, surpassing diseases such as the cardiovascular, cerebrovascular, respiratory and malignant tumors. The number of people with various mental illnesses in China is over 100 million.

Schizophrenia is a persistent and usually chronic major mental illness, and it is the most serious type of mental illness. The WHO estimates that the lifetime prevalence of schizophrenia is 3.8 ‰ to 8.4 ‰, the research lifetime prevalence in the United States is as high as 1.3%, and the epidemiological survey of 12 regions in China: the lifetime prevalence of schizophrenia is 5.6 ‰. The disease is a chronic disease, and its high recurrence rate and high disability rate are the direct causes of the poverty of the patients and their families returning to poverty due to the disease, and are the key mental illnesses for prevention and treatment by the state. At present, in the selection of drugs for the treatment of schizophrenia, it should vary from person to person and from symptom. From the perspective of the development of clinical psychiatry, whether it is positive or negative symptoms, the second generation of antipsychotic drugs should be preferred. The World Mental Health Association's treatment rules system recommends that the second-generation antipsychotic drugs are generally used as first-line drugs. While in positive and negative symptoms In terms of control, olanzapine is the most effective of the second-generation antipsychotic drugs.

Schizophrenia is also a common unexplained spirit Diseases, according to epidemiological calculations, there are currently about 10 million schizophrenic patients in China. At present, the preferred method of treatment for schizophrenia is drug therapy, and atypical antipsychotic drugs have become the first choice for the treatment of schizophrenia. Olanzapine, risperidone, quetiapine, aripiprazole, and ziprasidone are the most commonly used atypical antipsychotic drugs in China, and are called schizophrenia by psychiatrists in China "Five Golden Flowers" for treatment. Among them, olanzapine has been widely recognized by clinicians for its remarkable clinical efficacy, excellent TTD (continuous medication time before withdrawal), and extremely low adverse reactions, and its market share of 48% is far ahead of other atypical anti-cancer drugs. Psychotropic drugs.

Traditional psychiatric drugs are represented by chlorpromazine and fluoropyridoxine, Although it has a certain curative effect on positive symptoms, it has a poor curative effect on negative symptoms such as indifference, loneliness, few words and poor thinking. Moreover, extrapyramidal reactions such as restlessness, salivation, tremor, and bradykinesia are more common, and a few patients will also have delayed dyskinesia and malignant symptoms.

Clozapine is the first atypical antipsychotic drug discovered, which is diazoxide Zhuo compound is a new type of antipsychotic drug, widely used in clinical, mainly used for various schizophrenia and a variety of psychosis and agitation symptoms, because of the risk of agranulocytosis, mainly used for traditional antipsychotic drugs ineffective or Patients with severe reactions in the extrapyramidal system. Olanzapine has a chemical structure close to clozapine, which maintains the therapeutic effect of clozapine, especially for refractory schizophrenia. After clinical observations of 1.7 million patients abroad, no agranulocytosis was found, and epilepsy, salivation, and orthostatic hypotension rarely occurred.

Olanzapine is a marketed second-generation antipsychotic drug, suitable for Used in the treatment of schizophrenia, bipolar disorder, anxiety and depression. The drug was first developed by Eli Lilly and was marketed in the United States and Europe after being approved by the US FDA and EU EMEA in September 1996.

When patients with schizophrenia are in the acute phase and bipolar affective mania, Patients often refuse to take medication, oral medicine and Tibetan medicine are the most common, and medication compliance problems are common in schizophrenic patients. Therefore, the bulky dosage forms such as tablets and capsules are often unable to play a role in this type of patients. For patients with schizophrenia, the use of easy-to-use dosage forms should be considered.

Oral instant film is an agent that can better improve patient compliance type. But generally speaking, oral instant film preparation is made of hydrophilic matrix material, but olanzapine is almost insoluble in water, it is difficult to disperse in hydrophilic glue, and in the process of drying The hydrophobicity of azapine, during the drying process, the olanzapine main drug will agglomerate, which affects the content uniformity of the main drug. Therefore, the preparation of olanzapine fast-dissolving film agent with good efficacy, to solve the problems of even dispersion of olanzapine in the aqueous matrix of the preparation, as well as the problems of dispersion and agglomeration of the main drug in the process of blade coating and drying are urgently needed for this type of dosage form Solve technical problems.

The present invention aims to provide a dosage form that can solve the above problems, achieve rapid disintegration and absorption, facilitate taking, improve the patient's medication compliance, and have higher bioavailability, thereby indirectly improving the disease control rate. Specifically, it is to provide a pharmaceutical dosage form that can be quickly dissolved in the oral cavity to overcome the problems of inconvenient administration of olanzapine as a tablet.

The olanzapine film agent of the present invention comprises the following components: Olanzapine

Polymer film-forming materials

excipient

Flavoring agent.

Further, the olanzapine oral fast-dissolving film agent of the present invention includes the following components in weight percentage:

The polymer film-forming materials include hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), sodium alginate, and polyoxyethylene (PEO) ), One or more of corn starch.

The plasticizer includes one or more of polyethylene glycol (PEG), glycerin, or Tween 80.

The flavoring agent includes one or more sweeteners and fragrances; the sweetener is selected from sucrose, mannitol, dextran, sucralose, and aspartame; and the fragrance is selected from tree oil and sweet orange oil , Menthol oil, menthol oil, menthol; the olanzapine oral instant film preparation, also includes other auxiliary materials, the other auxiliary materials include more than one of pigments, antioxidants or preservatives.

Preferably, the olanzapine oral instant film preparation includes the following components by weight:

The olanzapine oral fast-dissolving film agent can quickly dissolve and disperse in water, specifically, it can completely dissolve in water at 25 ° C for 60 seconds, and disperse the olanzapine main drug.

The olanzapine oral plastic solution film can have a certain toughness, and its 2 × 10cm ² film agent has a breaking force greater than 10 Newtons.

In the olanzapine oral instant film preparation, the average particle diameter of the olanzapine main drug is below 10 μm.

Another object of the present invention is to provide a method for preparing a olanzapine film agent with a uniform drug load, so that olanzapine is dispersed in a hydrophilic matrix glue to prepare a film agent with a uniform content. The method includes the following steps: (1) Grinding, sieving or jet milling to crush olanzapine with an average particle size of less than 10 μm; (2) Dispersing the olanzapine main drug in an aqueous ethanol solution and stirring After homogenization, add polymer film-forming material aqueous solution, then mix evenly to obtain polymer glue for scraping coating; (3) Add flavoring agent, disperse, if bubbles are generated in the solution, place it under vacuum to defoam; (4) Scrape the above polymer glue onto the plastic film, dry it, peel the film from the plastic film, cut it to a certain size, and seal it.

Another object of the present invention is to provide a flat port for the olanzapine Cavity instant film agent is used to treat schizophrenia, bi-directional affective disorder, anxiety disorder, depression and other diseases.

The olanzapine oral fast-dissolving film agent provided by the present invention has the following characteristics: (1) It is instant and easy to take, and the polymer skeleton can be dissolved in water at 25 ° C in about 60 seconds to disperse the main drug of olanzapine; Appropriate strength, discomfort in the mouth when the strength is too strong, and inconvenience when the preparation is too thin, so it is necessary to prepare a suitable strength preparation for easy consumption; (3) has a certain drug load, and the drug load is uniform , Can reach the unit dose of olanzapine.

The non-mucoadhesive olanzapine oral disintegrating film dosage form provided by the present invention can be rapidly dissolved in the oral cavity when it is exposed to saliva; the main drug of olanzapine is mainly absorbed through the gastrointestinal tract. The film product has a bioavailability similar to that of olanzapine collapsible tablets.

Relative to those individuals who have difficulty swallowing tablets or pills, olanzapine oral film can greatly improve the compliance of administration. Olanzapine oral film is not required to be taken after oral administration. It can be dissolved in a few seconds under the action of saliva, and then enters the stomach with the saliva. At the same time, the situation of Tibetan medicine and vomiting in the oral cavity of schizophrenic patients is avoided. Pills and tablets can be contained in the mouth of the user without swallowing, and then taken out later. And quickly dissolve, thereby limiting or completely preventing users from taking it out.

The following examples will be used to further explain and explain the invention. Olanzapine oral instant film, its preparation method and use. However, the following examples should not be seen as limiting the invention in any way.

Example 1

The prescription amount is 2000 tablets (specification 5mg) or 1000 tablets (specification 10mg)

Steps: Weigh 20g of mannitol, put it in a suitable container, and add 200g of ethanol / water solution (ethanol: water = 1: 4). After stirring to completely dissolve, add 10 g of olanzapine, uniformly stir, add 30 g of polyoxyethylene, uniformly stir, and add 0.5 g of sucralose. Shear at high speed for 2 minutes at (10000 rpm), repeat 5 times, and let stand for 8 hours under vacuum to remove air bubbles, that is, the gel for scraping is obtained. Scrape the glue onto the plastic film and dry at a temperature between 75 ° C and 80 ° C. Then, the film agent obtained by scraping is peeled off from the plastic film, cut and packaged, and the film agent can be obtained.

Example 2

The prescription amount is 2000 tablets (specification 5mg) or 1000 tablets (specification 10mg)

step:

1) Weigh 20g of mannitol, put it in an appropriate container, and add 50g of ethanol / water solution (ethanol: water = 1: 4). Add 10g of olanzapine after stirring to dissolve completely. Stir uniformly and record as A.

2) Weigh 30g of hydroxypropyl methylcellulose, put it in an appropriate container, add 160g of distilled water at 85 ° C to 95 ° C, stir uniformly, and cool to completely dissolve to obtain gum solution B.

3) Add gum B to A, and add 0.5 g of sucralose. Shear at high speed for 2 minutes at (10000 rpm), repeat 5 times, and let stand for 8 hours under vacuum to remove air bubbles, that is, the gel for scraping is obtained. Scrape the glue onto the plastic film and dry at a temperature between 75 ° C and 80 ° C. Then, the film agent obtained by scraping is peeled off from the plastic film, cut and packaged, and the film agent can be obtained.

Example 3

The prescription amount is 2000 tablets (specification 5mg) or 1000 tablets (specification 10mg)

step:

1) Weigh 20g of mannitol, put it in an appropriate container, and add 50g of ethanol / water solution (ethanol: water = 1: 4). Add 10g of olanzapine after stirring to dissolve completely. Stir uniformly and record as A.

2) Weigh 30g of hydroxypropyl cellulose, put it in an appropriate container, and add 160g of distilled water. Stir for more than 2h until the glue is uniform to obtain glue B.

3) Add gum B to A, and add 0.5 g of sucralose. Shear at high speed for 2 minutes at (10000 rpm), repeat 5 times, and let stand for 8 hours under vacuum to remove air bubbles, that is, the gel for scraping is obtained. Scrape the glue onto the plastic film and dry at a temperature between 75 ° C and 80 ° C. Then, the film agent obtained by scraping is peeled off from the plastic film, cut and packaged, and the film agent can be obtained.

Example 4

The prescription amount is 2000 tablets (specification 5mg) or 1000 tablets (specification 10mg)

Steps: Weigh 20g of mannitol, put it in a suitable container, and add 200g of ethanol / water solution (ethanol: water = 1: 4). After stirring and dissolving completely, add 10g of olanzapine and stir uniformly, add 30g of polyvinyl alcohol and stir uniformly; add 0.5g of sucralose. Shear at high speed for 2 minutes at (10000 rpm), repeat 5 times, and let stand for 8 hours under vacuum to remove air bubbles, that is, the gel for scraping is obtained. Scrape this glue onto the plastic film, in Dry at a temperature between 75 ° C and 80 ° C. Then, the film agent obtained by scraping is peeled off from the plastic film, cut and packaged, and the film agent can be obtained.

Example 5

The prescription amount is 2000 tablets (specification 5mg) or 1000 tablets (specification 10mg)

Steps: Weigh 20g of mannitol, put it in a suitable container, and add 200g of ethanol / water solution (ethanol: water = 1: 4). After stirring and dissolving completely, olanzapine 10g was added and stirred uniformly. Polyvinylpyrrolidone (PVP) was added and stirred uniformly; sucralose 0.5g was added. Shear at high speed for 2 minutes at (10000 rpm), repeat 5 times, and let stand for 8 hours under vacuum to remove air bubbles, that is, the gel for scraping is obtained. Scrape the glue onto the plastic film and dry at a temperature between 75 ° C and 80 ° C. Then, the film agent obtained by scraping is peeled off from the plastic film, cut and packaged, and the film agent can be obtained.

Example 6

The prescription amount is 2000 tablets (specification 5mg) or 1000 tablets (specification 10mg)

step:

1) Weigh 20g of mannitol, put it in an appropriate container, and add 50g of ethanol / water solution (ethanol: water = 1: 4). Add 10g of olanzapine after stirring to dissolve completely. Stir uniformly and record as A.

2) Weigh 30g of sodium alginate, put it in a suitable container, and add 160g of distilled water. Stir until the glue is uniform to obtain glue B.

3) Add gum B to A, and add 0.5 g of sucralose. Shear at high speed for 2 minutes at (10000 rpm), repeat 5 times, and let stand for 8 hours under vacuum to remove air bubbles, that is, the gel for scraping is obtained. Scrape the glue onto the plastic film and dry at a temperature between 75 ° C and 80 ° C. Then, the film agent obtained by scraping is peeled off from the plastic film, cut and packaged, and the film agent can be obtained.

Test example 1 Determination of melting time

The film preparations prepared in the above six examples were cut into a given size, and the melting time limit was measured.

Take this product, cut into 6 pieces of 1cm ² size film, respectively sandwiched by two layers of stainless steel wire with an inner diameter of 2.0mm, and observe the time of complete dissolution of the product according to the method of measuring the disintegration time limit.

The measurement results are as follows:

As can be seen from the table above, if a polymer material is used as the film agent alone The film-forming material of Example 1, ie polyoxyethylene as a film-forming material, exhibits outstanding dissolution effect, and the obtained film can quickly dissolve in water and release the drug.

Example 7

The prescription amount is 2000 tablets (specification 5mg) or 1000 tablets (specification 10mg)

step:

1) Weigh 12g of sucrose, place it in an appropriate container, and add 60g of ethanol / water solution (ethanol: water = 1: 2). After stirring and dissolving completely, 10 g of olanzapine was added, the mixture was uniformly mixed, 15 g of polyoxyethylene was added, and the mixture was uniformly mixed to obtain glue A.

2) Weigh 10g of hydroxypropyl methylcellulose, place it in a suitable container, and add 200g of distilled water from 85 ° C to 95 ° C. Stir uniformly and cool until completely dissolved. Then add 6g of polyvinylpyrrolidone (PVP), 10g of polyoxyethylene, and 5g of polyethylene glycol, and stir until completely dissolved to obtain gum solution B.

3) Add glue B to glue A, and add 0.2g of sucralose, Peppermint oil 0.5g, sheared at (10000rpm) at high speed for 2 minutes, repeated 5 times, and allowed to stand for 8 hours under vacuum to remove air bubbles, that is, the gel for scraping was obtained. Scrape the glue onto the plastic film and dry at a temperature between 75 ° C and 80 ° C. Then, the film agent obtained by scraping is peeled off from the plastic film, cut and packaged, and the film agent can be obtained.

Example 8

The prescription amount is 2000 tablets (specification 5mg) or 1000 tablets (specification 10mg)

step:

1) Weigh 15g of dextran, put it in an appropriate container, and add 60g of ethanol / water solution (ethanol: water = 1: 2). After stirring and dissolving completely, 10 g of olanzapine was added and stirred uniformly, and 10 g of polyoxyethylene was added and stirred uniformly to obtain glue A.

2) Weigh 25g of polyoxyethylene, 10g of sodium alginate, and 2g of lecithin, place in a suitable container, and add 140g of distilled water. Stir until completely dissolved to obtain gum solution B.

3) Add glue B to glue A, and add 0.5g of aspartame, shear at high speed (10000rpm) for 2 minutes, repeat 5 times, and leave it under vacuum for 8h to remove air bubbles. Apply gel. Scrape the glue onto the plastic film and dry at a temperature between 75 ° C and 80 ° C. Then scrape the film from the plastic film The film can be obtained by peeling off and cutting and packaging.

Example 9

The prescription amount is 2000 tablets (specification 5mg) or 1000 tablets (specification 10mg)

step:

1) Weigh 12g of mannitol, put it in an appropriate container, and add 60g of ethanol / water solution (ethanol: water = 1: 2). After stirring and dissolving completely, 10 g of olanzapine was added and stirred uniformly, and 10 g of polyoxyethylene was added and stirred uniformly to obtain glue A.

2) Weigh 30g of polyoxyethylene and 10g of polyvinylpyrrolidone (PVP), place in a suitable container, and add 160g of distilled water. Stir until completely dissolved to obtain gum solution B.

3) Add glue B to glue A, and add 0.5g of menthol oil, shear at high speed (10000rpm) for 2 minutes, repeat 5 times, and leave it under vacuum for 8h to remove air bubbles. gel. Scrape the glue onto the plastic film and dry at a temperature between 75 ° C and 80 ° C. Then, the film agent obtained by scraping is peeled off from the plastic film, cut and packaged, and the film agent can be obtained.

Example 10

The prescription amount is 2000 tablets (specification 5mg) or 1000 tablets (specification 10mg)

Olanzapine 10g

step:

1) Weigh 20g of mannitol, put it in an appropriate container, and add 60g of ethanol / water solution (ethanol: water = 1: 2). After stirring and dissolving completely, 10 g of olanzapine was added, the mixture was uniformly mixed, 15 g of polyoxyethylene was added, and the mixture was uniformly mixed to obtain glue A.

2) Weigh 8g of hydroxypropyl cellulose, put it in a suitable container, stir for more than 2h until the glue solution is uniform, then add 20g of polyethylene glycol, and stir until completely dissolved to obtain glue solution B.

3) Add glue B to glue A, add aspartame 0.5g, sweet orange oil 0.3g, shear at (10000rpm) at high speed for 2 minutes, repeat 5 times, and let stand for 8h under vacuum Remove the air bubbles, you have to scrape the gel. Scrape the glue onto the plastic film and dry at a temperature between 75 ° C and 80 ° C. Then, the film agent obtained by scraping is peeled off from the plastic film, cut and packaged, and the film agent can be obtained.

Test Example 2 Test of tensile properties

Take an appropriate amount of the uncut olanzapine oral instant film preparation prepared in Examples 7 to 10, and cut 5 samples of 100mm × 20mm in size. The edges of the samples must be smooth, free of nicks and damage. First measure the thickness of the film, and then determine the breaking force Test the tensile properties on the instrument.

Place the film agent in the upper and lower clamps of the tensile force measuring instrument, so that the connection between the sample and the center of the upper and lower clamps coincides, and the clamps are suitable for tightness. Start the testing machine at a speed of 100 ± 10mm / min. After the sample is broken, read the tensile strength and elongation.

The measurement results are as follows:

From the above table, it can be seen that the tensile strengths of the films obtained in the above examples are all greater than 10N (100 mm × 20 mm size film).

Test Example 3 Measurement of melting time

The film preparations prepared in Examples 7 to 10 were cut into a given size, and the melting time limit was measured.

Take this product, cut into 6 pieces of 1cm ² size film, respectively sandwiched by two layers of stainless steel wire with an inner diameter of 2.0mm, and observe the time of complete dissolution of the product according to the method of measuring the disintegration time limit.

The measurement results are as follows:

As can be seen from the above table, the film obtained in the above examples can be quickly dissolved in water. The drug is released.

Test Example 4 Recognition test of taste

Each rater places the film strip in his or her mouth until it dissolves. Then ask the assessor about the taste, and evaluate the taste according to 1 to 5 points. 1 is the unacceptable taste, 2 is the reluctant acceptance, 3 is the acceptance, 4 is the good taste, and 5 is delicious.

The specific results are as follows:

It can be seen from the above table that the olanzapine oral instant film, after adding flavoring agent, has acceptable taste and high recognition.

Test Example 5 Comparison of bioavailability

The olanzapine oral fast-dissolving film (test preparation, 5 mg / tablet, prepared in Example 7) and olanzapine oral disintegrating tablet (control preparation, 5 mg / tablet, Eli Lilly and Company) were investigated in Beagle The relative bioavailability in dogs. The test used a two-cycle crossover design, with a clearance period of 7 days between the two weeks. Plasma samples were collected at different time points after drug administration, and the concentration of olanzapine in plasma was determined by liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters were calculated. The results are as follows:

It can be seen from the experimental results that after the beagle dog was given olanzapine oral fast-dissolving film and oral disintegrating tablets, the plasma concentration peak time was about 1.5 h, and the relative bioavailability after oral fast-dissolving film was 117.6% ( The geometric mean is 115.4%). After paired t-test, the pharmacokinetic parameters of olanzapine were not statistically different between the test preparation and the control preparation ( P > 0.05).

Claims (9)

An olanzapine oral fast-dissolving film agent, characterized in that it comprises the following components in weight percentage:

Among them, the polymer film-forming material includes polyoxyethylene (PEO). Olanzapine oral fast-dissolving film agent as described in item 1 of the patent application range, wherein the polymer film-forming material further includes hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyethylene Alcohol (PVA), polyvinylpyrrolidone (PVP), sodium alginate and / or corn starch; the plasticizer is selected from polyethylene glycol (PEG), glycerin and / or Tween 80; the flavoring agent is selected from sweet Flavors and / or fragrances; the sweetener is selected from sucrose, mannitol, dextran, sucralose and / or aspartame; the other adjuncts include coloring, antioxidants and / or preservatives; also include A fragrance selected from tree oil, sweet orange oil, peppermint oil, menthol oil and / or menthol. Olanzapine oral fast-dissolving film agent as described in item 2 of the patent application scope, which includes the following components by weight:

The olanzapine oral fast-dissolving film agent described in any one of the items 1 to 3 of the patent application range can be quickly dissolved and dispersed in water. The olanzapine oral fast-dissolving film agent as described in item 4 of the patent application range can be completely dissolved in water at 25 ° C for 60 seconds, and the olanzapine main drug is dispersed. The olanzapine oral fast-dissolving film agent as described in item 5 of the patent application range has a certain toughness, and its 2 × 10cm ² film agent has a breaking force greater than 10 Newtons. The olanzapine oral fast-dissolving film agent as described in item 6 of the patent application range, wherein the average particle diameter of the olanzapine main drug is 10 μm or less. A method for preparing the olanzapine oral fast-dissolving film agent according to any one of the items 1 to 7 of the patent application includes the following steps: 1) crushing olanzapine by grinding, sieving, or airflow crushing, etc., The average particle size is controlled to be less than 10μm; 2) The olanzapine main drug is dispersed in an aqueous ethanol solution, and after stirring, the polymer film-forming material aqueous solution is added, and then mixed evenly to obtain a polymer glue for scraping, wherein, the The aqueous solution of the polymer film-forming material includes polyoxyethylene (PEO); 3) Add flavoring agent to disperse; if bubbles are generated in the solution, place the defoaming under vacuum; and 4) Scrape the polymer glue to the plastic After drying the film, peel the film from the plastic film, cut it to a certain size, and seal it. An application of the olanzapine oral fast-dissolving film preparation according to any one of the patent application items 1 to 7 in the preparation of medicines for treating schizophrenia, bipolar disorder, anxiety and depression.