CN1250208C - Fluoxetine enteric coated tablet - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical preparations. The invention provides an enteric-coated preparation of the antidepressant fluoxetine. The formulation is in the form of an ordinary tablet core coated with an enteric coating. Wherein the isolation layer contains one or more of HPMC, PVP and HPC, and the enteric coating layer contains one or more of acrylic resin, HPMCP and CAP. The preparation of the invention releases the active ingredient in the small intestine, overcomes the taste discomfort and gastric mucosal irritation side effects of common fluoxetine capsules, tablets and oral liquids, and is administered once a day, which is convenient for taking.

Description

Fluoxetine enteric-coated tablets

Technical field:

The invention belongs to the technical field of pharmaceutical preparations. It specifically relates to a common enteric-coated preparation containing fluoxetine hydrochloride and a preparation method thereof.

Background technique:

Fluoxetine, N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, is an antidepressant. This drug is disclosed in, for example, US Patent Nos. 4,314,081 and 4,626,549. The antidepressant effect of fluoxetine is to inhibit the reuptake of 5-HT by the central nervous system. It is suitable for the treatment of depression and related anxiety symptoms; treatment of bulimia nervosa and obsessive-compulsive ideas and behavioral disorders.

At present, the dosage forms of fluoxetine at home and abroad include: solution, dispersible tablet, ordinary tablet, capsule, sustained-release capsule and so on. Eli Lilly Company has applied for fluoxetine sustained-release capsule patent (US 4847092) in the United States, and this patent protects skeleton type sustained-release antidepressant capsules; US5985322 has applied for the patent of fluoxetine enteric-coated pellets; China has applied for the patent of fluoxetine enteric-coated pellets (CN1285189, CN1200924); Eli Lilly company has applied for the patent of fluoxetine pharmaceutical preparation (dispersible tablet) in China (CN1123142A).

Fluoxetine has a strong bitter taste and other unpleasant tastes. Oral administration of ordinary solid preparations affects the patient's sense of taste, and excessive local concentration in the stomach stimulates the gastric mucosa to cause side effects such as nausea and vomiting. Therefore, fluoxetine is commonly used in clinical practice. Pharmaceutical dosage forms include capsules, ordinary tablets and more recently solutions, all of which have a series of limitations and disadvantages:

1. Oral oral solid preparation;

——In terms of patient administration, the limiting factor is that some patients have difficulty swallowing capsules, especially children and the elderly, and may actually not be able to swallow at all;

——The strong bitter taste and other unpleasant tastes of fluoxetine are difficult for patients to accept;

——Excessive local concentration of fluoxetine in the stomach stimulates the gastric mucosa and causes side effects such as nausea and vomiting;

——In terms of dosage, only single dosage is possible.

2. Taking fluoxetine hydrochloride solution also has disadvantages:

- Dosing of active ingredients needs to be calculated, which is often inaccurate.

- Medication restrictions for diabetics.

——Children's medication is easy to get out of control, and there is a risk of overdose.

——The dosage is complicated, which limits the operation and transportation.

On the other hand, effective doses of fluoxetine need to be administered continuously (average 2 to 6 months) for the treatment of depression. Therefore, when long-term intake is required, administration of capsules, tablets or oral liquids is especially important for patients. Sensory characteristics create unpleasant phenomena, create problems with patient acceptance, and can lead to failure to complete treatment, which greatly reduces efficacy. Therefore, generally speaking, the existing dosage forms of fluoxetine cannot fully meet some requirements required for the treatment of depression and other related diseases.

With regard to enteric-coated formulations, there are currently some difficulties in the preparation of conventional enteric-coated formulations of fluoxetine. In particular, fluoxetine has been found to react with many enteric coatings to form slowly dissolving or even insoluble coatings. Similar reactions with enteric coatings have been observed with other drugs such as duloxetine, nortriptyline, desipramine, sertraline. The current candidate antidepressant duloxetine is (+)-N-methyl-3-(1-naphthyloxy)-2-phenothiazine, which is usually used in the form of hydrochloride. Enteric coated formulations of duloxetine are claimed in US Patent 5508276 to prevent acid degradation of the compound in the stomach.

Invention content:

The technical problem to be solved by the present invention is to overcome the above disadvantages and provide a new enteric-coated type of fluoxetine that is clinically needed, which can facilitate the administration of patients and reduce gastric irritation symptoms.

The invention provides a fluoxetine enteric-coated tablet, which contains fluoxetine or its optical enantiomer or its acid addition salt and pharmaceutically acceptable enteric coating materials, diluents and other excipients. Formulations. And it is suitable for preparing the pharmaceutical composition of enteric-coated tablets. The tablet of the present invention contains:

(1) A tablet core consisting of fluoxetine and one or more excipients Specification 10mg Specification 20mg fluoxetine hydrochloride 11.2mg 22.4mg starch 25mg 50mg lactose 30mg 60mg L-Hydroxypropylcellulose (HPC) 10mg 20mg Carboxymethyl starch (CMS-Na) 5mg 10mg 8% starch slurry Appropriate amount Appropriate amount Magnesium stearate 0.8mg 1.6mg

(2) Containing one or more of hypromellose (HPMC), HPC, polyvinylpyrrolidone (PVP), cellulose acetate phthalate (CAP) and one or more excipients plus polyethylene A gastric-soluble coating layer composed of one or more porogens in glycol (PEG), triethyl citrate, triacetin, diethyl phthalate (DEP), and silicone oil.

HPMC 3～10mg

PEG 0.3～0.6mg

Talc powder (100 mesh) 0.6～1.5mg

(3) Containing one or more of acrylic resin, hypromellose phthalate (HPMCP), cellulose acetate phthalate (CAP) and one or more excipients plus PEG, citric acid Enteric coating layer composed of one or more porogens in triethyl ester, triacetin, DEP, silicone oil.

Acrylic resin 15～45mg

PEG 1.5～4.5mg

Talc powder (100 mesh) 2.5～9.5mg

The present invention relates to the preparation of the main drug and various excipients into granules with binders to form granules containing all active ingredients; the tablet core made of granules contains granules, flavoring agents and other dispensable excipients agent; the present invention also relates to ordinary film coating layer and enteric coating layer.

The most preferred embodiments of the present invention will now be described in detail, also referring to other preferred compositions of the present invention. The various components and coating layers of the tablet will be discussed separately below, and the method for gradually constructing fluoxetine enteric-coated tablets by adding various components will be discussed at the same time.

Another object of the present invention is to provide the preparation method of fluoxetine enteric-coated tablet, and this method comprises the following steps: (1) main ingredient is mixed with multiple excipients, then add binding agent or wetting agent system granule , dry, whole grain.

(2) Mix (1) with lubricant.

(3) Compress (2) on an ordinary tablet press or a high-speed tablet press to obtain shallow round or oval tablets with a hardness of 5-8 kg.

(4) Mix HPMC, PEG, and talcum powder, dissolve them in water to form a coating solution, and coat the tablet with an isolation layer.

(5) Mix acrylic resin, PEG and talcum powder, dissolve with water or ethanol to form an enteric coating solution, and coat (4) with an enteric coating.

The invention improves the smoothness and roundness of the coating layer through plasticizers, and the plasticizers reduce the occurrence rate of defects.

The roughness of the film coating increases with the viscosity of the coating solution used, which is related to the type of polymer. The present invention preferably HPMC E6～E15, preferably acrylic resin E30D or L100 or L100-55, preferably PEG is plasticizer, critical temperature 30 ℃. The polymer coating material can be applied as a coating in the form of a solution in water or an organic solvent or in the form of powder, and the addition of additives can increase the internal stress of the film and increase the elasticity of the film coating. Talc or magnesium carbonate can reduce the incidence of film coating defects. The particles exist in flakes, parallel to the surface, so that the shrinkage of the coating surface is limited.

The present invention can use defoamer, suspending agent, surfactant etc. to improve the smoothness of tablet surface, usually can use Tween-80, sodium lauryl sulfate etc. and suspending agent such as CMC etc.

Usually, powdered excipients such as talc, glyceryl monostearate or hydrated silicon dioxide are added to the enteric coating layer to increase the thickness of the layer, make it firm, and reduce electrostatic charge to reduce particle adhesion. Such solids may be added to the enteric polymer mixture at levels of from about 1% to about 15% of the final product, while the enteric polymer itself typically comprises from about 5% to about 30%, preferably 10% to 25%.

The invention provides 10mg or 20mg enteric-coated tablets of fluoxetine, wherein 20mg is administered once a day, and 10mg can be administered according to the disease condition or the curative effect can be consolidated, especially suitable for long-term administration once a day. Unit dosage forms may also be formulated with 1 mg, 5 mg, 15 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, or 80 mg of fluoxetine or an enantiomer or salt thereof. The dosage form has the advantages of low frequency of taking and few side effects, and has a series of advantages compared with the known dosage forms (capsule, common tablet and solution) of fluoxetine, as follows:

- suitable for the treatment of patients who have difficulty in taking solid dosage forms (capsules);

——Suitable for diabetic depression patients, because it does not contain sucrose sweetener;

——The special feeling of no bitterness when taken orally, avoiding the discomfort caused by common dosage forms, and acceptable to patients;

——Avoid excessive local concentration in the stomach, eliminate side effects such as nausea and vomiting caused by gastric sticky stimulation, and have good patient compliance;

——Better stability, the enteric coating has superior moisture resistance, and its shape and size can be packed into a capsule-shaped aluminum-plastic plate, which is easy to carry and take, and can ensure that patients complete treatment and improve curative effect;

- Eliminates the danger of overdose of oral solution, making it safer, especially suitable for children or elderly patients.

The following examples illustrate the specific implementation of the present invention, and the example used starch, anhydrous lactose, LS-HPC, CMS-Na and HPMC (E6～E15), the high-viscosity acrylic acid derivative (formed by methyl) of German RohmPharm Copolymer composition of about 7:3 of acrylic acid and methyl methacrylate) Eudragit series.

The formulations of the present invention are useful in the treatment of patients suffering from depression, atypical depression, psychotic depression, subsyndromal depression, agitated depression, motor inhibited depression, comorbidity with cancer Depression, psychotic depression, intrinsic and reactive depression, depression complicated by diabetes or myocardial infarction, menopausal depression, bulimia nervosa, obsessive-compulsive and behavioral disorders or bulimia, anorexia nervosa, alcoholism, Anorexia nervosa, anxiety, panic disorder, social panic, appetite disturbance, mood and/or appetite swings associated with PMS, depressed mood and/or sugar addiction associated with PMS, mood swings, appetite swings, Fluctuations due to nicotine withdrawal tendency to relapse, circadian rhythm disturbances, borderline personality disorder, hypochondria, postmenstrual syndrome luteal phase anxiety, trichotillomania, symptoms following discontinuation of other antidepressants, aggression/intermittent irritability , compulsive gambling, compulsive spending, compulsive sexual behavior, neurological disorders due to psychotropic substance use, sexual intercourse disorders, schizophrenia, premature diarrhea or psychiatric symptoms such as nervousness, anxiety, anger, sensitivity to rejection and lack of intelligence or physical fitness.

In addition to the above-mentioned tablets containing fluoxetine as an active ingredient, fluoxetine and other active ingredients can also be used to prepare combined administration products.

Detailed ways

Example 1: 10mg enteric-coated tablet 20mg enteric-coated tablet Chip fluoxetine hydrochloride 11.18mg 22.36mg starch 25.12mg 50.24mg lactose 28.88mg 57.76mg LS-HPC 10.56mg 21.12 mg CMS-Na 8.41mg 16.82mg Magnesium stearate 0.85mg 1.7mg Isolation layer HPMC 4.6mg 9.2mg PEG 0.45mg 0.9mg Talc powder (100 mesh) 0.95mg 1.9mg Enteric coating layer Acrylic 8.15mg 16.3mg PEG 0.91mg 1.82mg Talc powder (100 mesh) 1.94mg 3.88mg

Preparation:

1. Mix fluoxetine hydrochloride, starch, lactose, LS-HPC, CMS-Na, etc., add 8% starch

Pulp granulation, drying, granulation.

2. Mix the granules obtained in 1 with magnesium stearate.

3. Compress the mixture obtained in 2 on a tablet machine to obtain a round or oval shape with a hardness of 5-8kg

shaped tablet.

4. Mix HPMC, PEG, and talcum powder, and use water as a solvent to make a gastric-soluble coating solution, and give the obtained product in 3

Tablets are usually film-coated.

5. Mix acrylic resin, PEG and talcum powder, and use water or ethanol as a solvent to make an enteric coating solution.

The tablets obtained in 4 were enteric coated.

The preparation method described in this example has satisfactory granule fluidity and compressibility, and the tableting process is smooth; the coating process is feasible, the isolation layer and the enteric coating layer are smooth and dense, and the toughness and strength meet the requirements.

The resulting tablet features are as follows:

1. Tablet weight before coating: 85mg±5% for 10mg specification, 170mg±5% for 20mg specification. Hardness: 5~8kg;

2. Chip core friability: <0.5%;

3. The disintegration time limit of the tablet core: 5 minutes.

4. Tablet weight after coating: 10mg specification 102mg±5%, 20mg specification 204mg±5%.

5. Meet the quality standard requirements of Chinese Pharmacopoeia enteric coating preparations.

Example 2: 10mg enteric-coated tablet 20mg enteric-coated tablet Chip fluoxetine hydrochloride 11.15mg 22.30mg starch 21.25mg 42.50mg lactose 29.86mg 59.72 mg LS-HPC 12.56mg 25.12mg CMS-Na 7.48mg 14.96mg Magnesium stearate 0.91mg 1.82mg Isolation layer HPMC 5.1mg 10.2mg PEG 0.52mg 1.04mg Talc powder (100 mesh) 0.91mg 1.82mg Enteric coating layer Acrylic 9.05mg 18.10mg PEG 0.91mg 1.82mg Talc powder (100 mesh) 1.75mg 3.50mg

The product was prepared according to the method described in Example 1.

Example 3: 10mg enteric-coated tablet 20mg enteric-coated tablet Chip fluoxetine hydrochloride 11.20mg 22.40mg starch 25.25 mg 50.50mg lactose 28.86mg 57.72mg LS-HPC 11.56mg 23.12mg CMS-Na 6.48mg 12.96mg Magnesium stearate 0.91mg 1.82mg Isolation layer HPMC 6.05mg 12.10mg PEG 0.62mg 1.24mg Talc powder (100 mesh) 0.95mg 1.90mg Enteric coating layer Acrylic 9.15 mg 18.30mg PEG 0.91mg 1.82mg Talc powder (100 mesh) 1.82mg 3.64mg

The product is prepared basically according to the method used in Example 1, except that the scale of the method is scaled up, and the raw material of 1000 tablets is used for preparation.

The present invention provides following formula:

1. Chip core:

1) Scale 10mg.

Fluoxetine Hydrochloride 11.18-11.32mg

Starch 20-30mg

Lactose 20-40mg

Hydroxypropyl Cellulose 8-15mg

Carboxymethyl starch 2-8mg

8% starch slurry Appropriate amount

Magnesium stearate 0.5-1.5mg

2) Scale 20mg:

Fluoxetine Hydrochloride 22.36-22.64mg

Starch 40-60mg

Lactose 40-80mg

Hydroxypropyl Cellulose 16-30mg

Carboxymethyl starch 4-16mg

8% starch slurry Appropriate amount

Magnesium stearate 1-3mg

2. Ordinary film coating isolation layer:

HPMC 3～10mg

PEG 0.3～0.6mg

Talc powder (100 mesh) 0.6～1.5mg

3. Enteric coating layer:

Acrylic resin 15～45mg

PEG1500 1.5～4.5mg

Talc powder (100 mesh) 2.5～9.5mg

Prepare tablet according to above-mentioned example, carry out quality control according to enteric-coated tablet quality standard described in Chinese Pharmacopoeia 2000 edition, and carry out stability investigation according to stability test principle, the result shows, tablet stability is good.

Experiments also show that the tablet is in good shape within 2 hours in the gastric juice, and can release the contained fluoxetine rapidly when exposed to the general conditions of the small intestine. According to Chinese Pharmacopoeia 2000 edition, 100 turn paddle leaf method, in 750ml water, carry out in vitro dissolution test under the condition of 37 ℃ ± 0.5 ℃ and pH=1.2, release degree 10% in 2 hours; Add 250mlNa of pH=12.5 after 2 hours ₃ PO ₄ aqueous solution to obtain a buffer solution with pH=6.8, and the release rate in 45 minutes is ≥75%.

Claims (2)

1. A fluoxetine enteric-coated tablet, characterized in that the pharmaceutical composition contains fluoxetine and its optically pure enantiomer or its acid addition salt, and a pharmaceutically acceptable enteric coating material, diluent and Other excipients, and the enteric-coated tablet contains two specifications of 10mg or 20mg fluoxetine, the specific composition is: (1) A tablet core consisting of fluoxetine and one or more excipients Tablet core 10mg: Fluoxetine Hydrochloride 11.18-11.32mg Starch 20-30mg Lactose 20-40mg Hydroxypropyl cellulose 8-15mg Carboxymethyl starch 2-8mg 8% starch slurry Appropriate amount Magnesium stearate 0.5-1.5mg Tablet core 20mg: Fluoxetine Hydrochloride 22.36-22.64mg Starch 40-60mg Lactose 40-80mg Hydroxypropyl Cellulose 16-30mg Carboxymethyl starch 4-16mg 8% starch slurry Appropriate amount Magnesium stearate 1-3mg; (2) Gastric-soluble coating layer composed of excipients and porogens: HPMC 3～10mg PEG 0.3～0.6mg Talc powder (100 mesh) 0.6～1.5mg (3) Enteric coating layer containing excipient plus pore forming agent: Acrylic resin 15～45mg PEG 1.5～4.5mg Talc powder (100 mesh) 2.5~9.5mg. 2. A method for preparing fluoxetine enteric-coated tablets as claimed in claim 1, characterized in that the method comprises the following steps: (1) Mix the main ingredient with various excipients, then add binder or wetting agent to make granules, dry and granulate; (2) mixing (1) with a lubricant; (3) Compress (2) on an ordinary tablet press or a high-speed tablet press to obtain shallow round or oval tablets with a hardness of 5 to 8 kg; (4) HPMC, PEG, talcum powder are mixed, dissolve into coating liquid with water, give tablet bag isolation layer; (5) Mix acrylic resin, PEG and talcum powder, dissolve with water or ethanol to form an enteric coating solution, and coat (4) with an enteric coating.