CN1813769A - Ciclesonide oral ulcer paster and its preparing method - Google Patents

Abstract

The invention relates to a patch for treating oral ulcers, the adhesive layer of which contains 0.01-2 mg of ciclesonide. The oral patch can be an ordinary single-layer sheet, or a double-layer sheet including a drug adhesive layer and a waterproof protective layer. Layer sheet, the adhesive material is mainly selected from hydroxypropyl methylcellulose, carbopol, sodium carboxymethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, etc., the oral patch can promote the healing of oral ulcers, and at the same time Reduce pain.

Description

A ciclesonide oral ulcer patch and its preparation method

technical field

The invention relates to an anti-oral ulcer medicine, in particular to an oral patch containing ciclesonide and a preparation method thereof.

Background technique

Oral ulcer is exactly commonly called as " aphthous ulcer ", is one of common disease, frequently-occurring disease, and wherein recurrent oral ulcer is the most common, and its sickness rate is more than 20%, and wherein recurrence accounts for 10%. Oral ulcers are localized damage to the oral mucosa characterized by periodic outbreaks, specifically attacking the oral mucosa, usually appearing in the palate, throat, gums, tongue and other parts, severe cases can spread to the pharynx and mucous membranes, some with time, The ulcer area increases, the number increases, the ulcer surface has a severe burning sensation, the pain is unbearable, and it brings inconvenience to life and work. Some have mouth-eye-genital triad (Behcet's disease), which is life-threatening. Therefore, to this type of disease, need a kind of easy to use clinically, the drug dosage form of curative effect is good.

At present, there are sitosterol film, rifampicin film, clotrimazole film, etc. that have been marketed locally for oral ulcers. These films generally use polyvinyl alcohol or sodium carboxymethyl cellulose as a single-layer film, and the residence time in the oral cavity is generally not more than 30 minutes, and the problem of two-way adhesion is prone to occur, so that the drug cannot be absorbed in the oral cavity. The part exerts a longer medicinal effect. The dexamethasone acetate oral adhesive tablet that has been on the market is a double-layer tablet, and the drug-containing layer, that is, the adhesive layer, mainly adopts Carbopol as an auxiliary material. The patch is prone to side effects of glucocorticoids due to the absorption of dexamethasone acetate, which is its disadvantage.

Pharm.Int.1985, 6: 196, reported the double-layer oral adhesive tablet of triamcinolone produced in Japan in 1980, and the trade name was AFTACH. The drug-containing layer is 0.4mm thick, with carbopol and hydroxypropyl methylcellulose as the paste, and the anti-adhesive layer (backing) is 0.7mm thick, which can be pasted in the oral cavity for a long time, but it is easy to absorb and cause systemic hormones class side effects.

The chemical name of ciclesonide: [11β,16α(R)]16,17-[(cyclohexylmethylene)bis(oxygen)]-11-hydroxy-21-2-methyl-1-carboxypropoxy Pregna-1,4-diene-3,20-dione. It is characterized by strong anti-inflammatory effect, low dose, long-acting, and only used once a day. Because ciclesonide is highly sensitive to the oxidase of the liver, once the drug is absorbed, it circulates to the liver and is quickly eliminated, so the systemic side effects are small. Ciclesonide is a prodrug, which is inactive by itself, and is converted into an active metabolite by the lipase of the cell, thereby exerting anti-inflammatory activity and analgesic effect directly at the lesion site.

Due to these characteristics of ciclesonide, in addition to the aerosol that has been marketed abroad for the treatment of asthma, ciclesonide is currently being developed into a nasal mucosal drug delivery preparation for the treatment of rhinitis, and the third phase is in progress clinical.

The research found that: making ciclesonide into an oral adhesive tablet can make the main drug ciclesonide effectively contact with the oral ulcer surface, and the bioadhesion of the polymer prolongs the residence time of the drug in the affected area, significantly improving the ciclesonide. Ned's therapeutic effect on oral ulcers.

Contents of the invention

The object of the present invention is to provide a kind of oral patch containing ciclesonide for the treatment of oral ulcer, wherein its adhesive layer contains main drug ciclesonide 0.01-2mg in each single dose patch, preferably content is 0.05-1mg , more preferably 0.1-0.6 mg.

The ciclesonide oral patch of the present invention can be a single-layer tablet or a double-layer tablet, and the single-layer tablet here is a common single-layer tablet, only containing the tablet of the adhesion layer of the main drug ciclesonide.

The oral patch of the present invention is preferably a double-layer tablet, which is characterized in that it includes an adhesive layer containing the main drug ciclesonide and a water-insoluble protective layer.

The ciclesonide oral patch of the present invention, its adhesive material is selected from the following one or more substances: hydroxypropyl methylcellulose, carbopol, sodium carboxymethylcellulose, hydroxypropyl cellulose, Polyvinylpyrrolidone, starch, dextrin; in each patch, the total weight of said adhesive material is 10-60 mg.

The ciclesonide oral patch of the present invention also includes a pharmaceutically acceptable filler, glidant or lubricant, wherein the filler is selected from the group consisting of starch, dextrin, mannitol, xylitol, lactose One or more of them, preferably dextrin, lactose, microcrystalline cellulose; glidants are selected from talcum powder and micronized silica gel or their composition, preferably talcum powder; lubricants are selected from talcum powder and magnesium stearate , preferably magnesium stearate. If necessary, a co-solvent is further included, and the co-solvent is selected from one or more of the following substances: sodium lauryl sulfate, sodium dodecyl sulfate and Tween-80.

In the ciclesonide oral patch of the present invention, said water-insoluble protective layer mainly uses acrylic resin or ethyl cellulose as a film-forming agent (if necessary) and is equipped with an appropriate amount of pharmaceutical plasticizer and The solution formed by the filler is sprayed on a surface of the drug-containing adhesion layer to form a waterproof protective layer. The plasticizer is selected from: dibutyl phthalate, diethyl phthalate, dioctyl phthalate, and castor oil; the filler is titanium dioxide, and an appropriate amount of food coloring can be added as required.

Oral patch of the present invention is mainly realized by the following scheme

An oral ulcer patch is composed of a drug-containing adhesive layer and a protective layer.

Preparation of adhesive layer tablets: Dissolve adhesives such as polyvinylpyrrolidone in ethanol, add drug ciclesonide to dissolve and set aside; after mixing adhesive materials such as hypromellose, carbopol and dextrin, add The above solution is stirred evenly, and the soft material is obtained by passing the soft material through a 30-mesh sieve. After the wet granules are dried, the granules are sized through a 30-mesh sieve, added with magnesium stearate, mixed evenly, and compressed into tablets.

One side of the above-mentioned pressed tablet is sprayed with a mixed ethanol solution of ethyl cellulose, yellow aluminum lake, magnesium stearate and dibutyl phthalate to form a waterproof protective layer, and then the protective layer is dried to adhere to the Obtain ciclesonide oral adhesive tablets on the drug layer.

It is also possible to implement the following scheme

An oral ulcer patch is composed of a drug-containing adhesive layer and a protective layer. Dissolve an adhesive such as polyvinylpyrrolidone in ethanol, add the drug ciclesonide and dissolve it for later use; the drug adhesive layer is mixed with adhesive materials such as hydroxypropyl cellulose, carbopol and dextrin, and then add the above The solution is stirred evenly, and the soft material is passed through a 30-mesh sieve to obtain the soft material. After the wet granules are dried, the granules are sized through a 30-mesh sieve, and magnesium stearate is added to mix uniformly to obtain adhesion layer granules.

Dissolve ethyl cellulose or propionic acid resin in ethanol to make a 3% solution for later use. After mixing ethyl cellulose, yellow aluminum lake and titanium dioxide, add an appropriate amount of the above ethyl cellulose or propionic acid resin solution to make a soft material, pass the soft material through a 40-mesh sieve to obtain wet granules, and dry the wet granules at 60°C Finally, add magnesium stearate and mix well for later use.

The above-mentioned two kinds of granules are compressed into double-layer tablets on a double-layer tablet press.

The adhesive materials used are hydroxypropyl methylcellulose, carbopol, sodium methylcellulose, sodium carboxymethylcellulose, starch, dextrin, polyvinylpyrrolidone, starch, dextrin. In some formulations, one or several adhesive materials in different proportions can be used to make oral adhesive tablets with good adhesive properties. In addition to the adhesive properties, these adhesive materials also have the effect of delaying the release of the main drug ciclesonide, so that the drug has a long acting time.

The protective layer of the double-layer design is made of ethyl fiber, acrylic resin, titanium dioxide and magnesium stearate, which are insoluble polymer materials under oral conditions, which reduces the dissolution of the drug to the opposite side of the oral mucosa and the two-way movement of the tablet between the oral cavity Adhesion. In addition, the protective layer can be sprayed, or can be pressed with the drug-containing layer on a double-layer tablet press to form a double-layer tablet.

Since ciclesonide is a steroidal compound, its water solubility is extremely poor, and the particle size of ciclesonide affects its curative effect. It is dissolved in polyvinylpyrrolidone ethanol solution during preparation, and is mixed with auxiliary materials to prepare soft materials. The wet granules are prepared by sieving, and after the wet granules are dried, the ciclesonide in them becomes an amorphous powder with a very small particle size, so as to improve the curative effect.

In order to adjust the release rate of the main drug in the drug-containing layer and the formability of the tablet, excipients are sometimes added to the tablet prescription, and these excipients include lactose, xylitol, sorbitol, mannitol, dextrin, starch, etc. , Micronized Silica Gel and Magnesium Stearate, Sodium Lauryl Sulfate, Sodium Lauryl Sulfate, Tween-80.

The present invention will be further described below in conjunction with the examples, but not as a limitation of the present invention.

Example 1

Drug-containing layer:

Ciclesonide 0.1g

  Hydroxypropyl Methyl Cellulose                                                                                                 

Carbopol 5g

Dextrin 25g

12% polyvinylpyrrolidone solution 9-13ml

Magnesium stearate 0.5g

Manufactured into 1000 pieces

Preparation method: Dissolve ciclesonide in 12% polyvinylpyrrolidone ethanol solution. In addition, after hydroxypropyl methylcellulose and carbopol are passed through a 80-mesh sieve, they are mixed with dextrin, and the soft material made of the polyvinylpyrrolidone solution containing the drug ciclesonide is added, stirred evenly, and passed through a 35-mesh sieve. Prepare wet granules, boil and dry the wet granules at about 50°C to obtain dry granules, add magnesium stearate and mix well, and then press into tablets. One side of the pressed tablets is coated with ethyl cellulose, yellow aluminum lake and stearin The ethanol solution of magnesium acid is coated, and the protective layer is dried and attached to the drug-containing layer to obtain the ciclesonide oral adhesive sheet.

Example 2

The present invention will be further described below in conjunction with the examples, but not as a limitation of the present invention.

Drug-containing layer particles:

Ciclesonide 0.1g

                                                 

Carbopol 5g

Dextrin 25g

12% polyvinylpyrrolidone solution 9-13ml

Magnesium stearate 0.5g

Manufactured in 1000 pieces

Protective layer particles:

Ethyl cellulose 5g

Titanium Dioxide 15g

                                                       

                          Appropriate amount

Magnesium stearate 0.01g

Manufactured in 1000 pieces

Preparation Process:

Drug-containing layer granule preparation method: deep ciclesonide in 12% polyvinylpyrrolidone ethanol solution. In addition, after hydroxypropyl methylcellulose and carbopol are passed through a 80-mesh sieve, they are mixed with dextrin, and the soft material made of the polyvinylpyrrolidone solution containing the drug ciclesonide is added, stirred evenly, and passed through a 35-mesh sieve. Prepare wet granules, boil and dry the wet granules at about 50°C to obtain dry granules, add magnesium stearate and mix well for later use.

Preparation method of protective layer particles: Dissolve ethyl cellulose in ethanol to make a 3% solution for later use. After mixing ethyl cellulose, yellow aluminum lake and titanium dioxide, add an appropriate amount of the above ethyl cellulose solution to make soft material, pass the soft material through a 40-mesh sieve to obtain wet granules, dry the wet at 60°C, add stearin Magnesium acid mixed for later use.

The above-mentioned two kinds of granules are compressed into double-layer tablets on a double-layer tablet press.

Example 3

Drug-containing layer:

Ciclesonide 0.6g

  Hydroxypropyl Methylcellulose                                      

Carbopol 5g

Dextrin 25g

12% polyvinylpyrrolidone solution 9-13ml

Magnesium stearate 0.5g

Manufactured in 1000 pieces

Preparation method: Put ciclesonide deep in 12% polyvinylpyrrolidone ethanol solution. In addition, after hydroxypropyl methylcellulose and carbopol are passed through a 80-mesh sieve, they are mixed with dextrin, and the soft material made of the polyvinylpyrrolidone solution containing the drug ciclesonide is added, stirred evenly, and passed through a 35-mesh sieve. Prepare wet granules, boil and dry the wet granules at about 50°C to obtain dry granules, add magnesium stearate, mix well, and then press into tablets, and coat one side of the pressed tablets with ethyl cellulose, magnesium stearate and o-phthalic acid The ethanol solution of dibutyl diformate (6%) is coated, and the protective layer is blown dry to be attached to the drug-containing layer to obtain ciclesonide oral adhesive tablets.

Example 4

The present invention will be further described below in conjunction with the examples, but not as a limitation of the present invention.

Ciclesonide 0.6g

  Hydroxypropyl Methyl Cellulose                                                                                                 

Carbopol 5g

Dextrin 25g

12% polyvinylpyrrolidone solution 9-13ml

Magnesium stearate 0.5g

Manufactured into 1000 pieces

The protective layer:

Ethyl cellulose 5g

Titanium Dioxide 15g

3% Ethylcellulose Ethanol Solution Appropriate amount

                                                         

Magnesium stearate 0.01g

Manufactured into 1000 pieces

Preparation Process

Drug-containing layer granule preparation method: deep ciclesonide in 12% polyvinylpyrrolidone ethanol solution. In addition, after hydroxypropyl methylcellulose and carbopol are passed through a 80-mesh sieve, they are mixed with dextrin, and the soft material made of the polyvinylpyrrolidone solution containing the drug ciclesonide is added, stirred evenly, and passed through a 35-mesh sieve. Prepare wet granules, boil and dry the wet granules at about 50°C to obtain dry granules, add magnesium stearate and mix well for later use.

Preparation method of protective layer particles: Dissolve ethyl cellulose in ethanol to make a 3% solution for later use. After mixing ethyl cellulose and carbon dioxide, add an appropriate amount of the above ethyl cellulose solution to prepare soft material, pass the soft material through a 40-mesh sieve to obtain wet granules, dry the wet at 60°C, add magnesium stearate and mix well Backup.

The above-mentioned two kinds of granules are compressed into double-layer tablets on a double-layer tablet press.

The product of the present invention passes through light (2500Lux), high temperature (40 DEG C, 60 DEG C), the influence factor experiment of placing 10 days, accelerates (40 DEG C, relative humidity 75%) the stability of 3 months and room temperature retention sample 24 months Investigate, its tablet outward appearance traits, related substance, content etc. all have no obvious change, illustrate that the product stability that the present invention makes is good.

Paste the product of the present invention containing 0.1 mg and 0.6 mg ciclesonide in a single dose on the oral ulcers of rats with oral ulcers in the two groups, 2 times/day; at the same time, with another group that also has oral ulcers but does not give any treatment rats (control group) for comparison. Experimental result shows that in the 2nd, 4th, 6th, and 8th day of administration, the ulcer area of the rats of two groups using the product of the present invention is all less than matched group (P＜0.05); The average healing speed of the product group of the present invention is faster than Control group (P＜0.05); The degree of edema and hyperemia in the ulcer of the product group of the present invention is obviously better than that of the control group; the inflammatory cell quantity in the ulcer of the product group of the present invention is all less than the control group at each time point (P <0.05); the number of fibroblasts in the product group of the present invention was higher than that of the control group (P<0.05). And the degree of change of the above indicators using the product group of the present invention is dose-dependent. The above results show that the product of the present invention can significantly promote the healing of experimental oral ulcers when the product contains a single dose of 0.1-1 mg ciclesonide.

Patients with oral ulcers are administered once or twice a day. One tablet at a time, stick to the affected area.

Claims (11)

1. A ciclesonide oral ulcer patch, characterized in that its adhesive layer contains the principal agent ciclesonide 0.01-1mg in the single-dose patch. 2. The ciclesonide oral patch according to claim 1, wherein the content of ciclesonide is preferably 0.1-0.6 mg. 3. The ciclesonide oral patch according to claim 1 or 2, characterized in that said patch is a single-layer sheet or a double-layer sheet. 4. The ciclesonide oral patch according to claim 3, wherein said double-layer sheet is characterized in that comprising an adhesive layer containing the main drug ciclesonide and a water-insoluble protective layer. 5. The ciclesonide oral patch according to claim 1 or 2 is characterized in that the adhesive material is selected from one or more of the following materials: hydroxypropyl methylcellulose, carbopol, carboxymethyl cellulose Sodium Sulfate, Hydroxypropyl Cellulose, Polyvinylpyrrolidone, Starch, Dextrin. 6. The ciclesonide oral patch according to claim 5, the weight of said adhesive material is 10-60 mg. 7. The ciclesonide oral adhesive tablet according to claim 1 or 2, characterized in that: it also includes pharmaceutically acceptable fillers, glidants or lubricants. 8. ciclesonide oral patch according to claim 7, its filler is selected from one or more among microcrystalline cellulose, starch, dextrin, mannitol, xylitol, lactose; The agent is selected from talcum powder and micronized silica gel or their combination; the lubricant is selected from talcum powder and magnesium stearate. 9. The ciclesonide oral patch according to claim 7, is characterized in that: it further comprises a co-solvent selected from one or more of the following substances: sodium lauryl sulfate, sodium lauryl sulfate and Tween-80. 10. ciclesonide oral patch according to claim 4, is characterized in that: said water-insoluble protective layer mainly uses acrylic resin or ethyl cellulose as a film-forming agent, or is equipped with an appropriate amount of The solution formed by pharmaceutical plasticizer or filler is sprayed on one surface of the drug-containing adhesive layer to form a waterproof protective layer. 11. A method for preparing ciclesonide oral patch, characterized in that: comprising the following process: 1) Preparation of drug-containing adhesion layer: Dissolve adhesive materials such as polyvinylpyrrolidone in ethanol, add the drug to dissolve and set aside, mix adhesive materials such as hydroxypropyl cellulose, carbopol and dextrin, add the above solution, and stir evenly; A 30-mesh sieve is used to obtain the soft material. After the wet granules are dried, the 30-mesh sieve is used for sizing, and magnesium stearate is added to mix to obtain the adhesion layer granules; 2) Preparation of waterproof protective layer: Dissolve ethyl cellulose or acrylic resin in ethanol to make a 3% solution for later use. After mixing adhesive materials such as ethyl cellulose, food coloring such as yellow aluminum lake and fillers such as titanium dioxide, add the above ethyl cellulose The soft material is prepared in an appropriate amount of plain or acrylic resin solution, and the soft material is passed through a 40-mesh sieve to obtain wet granules. After the wet granules are dried, magnesium stearate is added and mixed evenly for later use; 3) The two kinds of granules prepared in 1) and 2) are pressed into a double-layer tablet on a double-layer tablet press to obtain an oral patch.