TW201707691A - Oral dissolving film for achieving fast onset of action, enhancing medicine availability, fully developing therapeutic effect and reducing side effects - Google Patents

Abstract

The present invention relates to an oral dissolving film, which employs the edible material, such as gelatin, pectin and hydroxyethyl cellulose, as thickener, so as to greatly reduce the consideration of material cost. The oral dissolving film made thereby may achieve fast onset of action, enhance the medicine bioavailability, fully develop the therapeutic effect of medicine, reduce the side effects, convenient for administration by children and elders, easy for carrying, storage, transportation, and may be prepared in a simple method to be suitable for mass production.

Description

Mouth soluble film

The present invention relates to a medicament or food, especially an oral film.

Oral preparations commonly used in clinical practice are usually absorbed through the gastrointestinal mucosa, and it is not suitable for oral administration for drugs which are unstable, irritating and have a first pass effect in the gastrointestinal tract. Such as peptide drugs, Propranolol (Propranolol), Lidocaine (Lidocaine) and some antibiotics; in the past these drugs were generally administered by injection, long-term medication caused inconvenience and pain to patients.

Recent studies have shown that drug absorption through partial oral mucosa can avoid first-pass effects, improve bioavailability, and achieve systemic therapeutic goals. At the same time, oral mucosal drug delivery methods are simple and easy for patients to accept. Therefore, the development of new dosage forms for oral mucosal absorption by this part of oral mucosa has been paid more and more attention.

Oral mucoadhesive drug delivery system is a new type of bioadhesive drug delivery system developed in recent years. It is a research hotspot in pharmacy in recent years. It uses adhesive polymer as a carrier to extend the preparation in the oral cavity through the bioadhesion of the carrier. The localization effect and systemic treatment effect of residence time can avoid the degradation of the drug in the gastrointestinal tract and the first-pass effect of the liver, improve the bioavailability of the drug, and have the advantages of sustained release and localization, and have broad application prospects. Oral dissolving films (ODF) is a new drug delivery system, drug-loaded multimer film, which is similar in size, shape and thickness to stamps. It is placed on the tongue and dissolves quickly in saliva. Release the drug. Since 2003, more than 80 products have been listed in North America. InnoZen and Novartis have developed and marketed a number of oral fast-dissolving OTC products for the treatment of colds, including diphenhydramine hydrochloride and dextromethorphan. Agent, menthol film, and the like. The total value of oral film products marketed in 2007 reached US$500 million and is expected to reach US$2 billion in 2012. According to past growth trends, it is expected to reach US$13 billion in 2015. The current development trend of the orally soluble film is observed by the following prior art known patent documents (patent literature):

Prior Art 1, the patent publication No. 200413026 was discovered by the early publication of Taiwan: LTS Lohmann Therapie-Systeme AG invented a multilayer (double layered structure or triple layered structure) The transmucosal treatment system consists of a backing layer (or called a reservoir layer) and a mucoadhesive layer (or an adhesive layer); the system of the three-layered structure is backed by a backing The layer (including an intermediate layer and a boundary layer) and the adhesive layer of the mucosa. The intermediate layer and the boundary of the active substance, a neutral of polymethyl methacrylate ^{(Eudragit ® NE 30 D, Röhm} ), solvents, cosolvents, and a pigment composed; different place, in that the intermediate layer does not contain or Contains only a small amount of pigment. The mucoadhesive layer consists of 10% by weight aqueous solution of polyvinyl alcohol (Mowiol 28-99, Clariant) and poly(methyl vinyl ether maleic anhydride) (Gantrez ^® S-95, ISP). After the solution of the boundary layer, the intermediate layer and the mucoadhesive layer is completed, the boundary layer is sequentially applied to the inert support; after the boundary layer is dried, the intermediate layer is applied to the boundary layer; after the intermediate layer is dried, A multi-layered transmucosal treatment system can be prepared by applying a mucoadhesive layer to the intermediate layer and waiting for drying. The poly(methyl vinyl ether maleic anhydride) used in the invention is not a food-usable raw material and food additive listed in the Food and Drug Administration (FDA) of the Ministry of Health and Welfare of Taiwan, and the copolymer is expensive; In addition, the materials used in the invention must be applied in a sequential lamination manner, the boundary layer is applied to the inert support/to be dried, the intermediate layer is applied to the boundary layer/to be dried, and the mucoadhesive layer is applied to the intermediate layer/ For multi-stage operations such as drying, personnel, processes and equipment are costly.

Prior Art 2, known from Taiwan's Early Public Gazette, Publication No. 200502008, Teikoku Seiyaku Co., Ltd. invented an oral mucosal patch containing fentanyl, which is attached to the oral mucosa. The applicator consists of a PET film, a layer of the agent, a carrier layer and a carrier. The agent layer is composed of 80% ethanol solution of methyl vinyl ether-maleic anhydride copolymer, hydroxypropyl cellulose (viscosity: 150-400 mP·S) in ethanol solution, glycerin, polyethylene glycol 400, N- Methyl-2-pyrrolidone and phenantiryl citrate; the carrier layer is dispersed in ethanol solution of ethyl cellulose, 50% ethanol solution of hydroxypropyl methylcellulose 2910, castor oil and titanium oxide. The composition of the liquid. After the solution of the agent layer and the carrier layer is prepared, the agent layer is sequentially applied to the liner; after the layer is dried, the carrier layer is applied to the agent layer; the carrier is adhered to the carrier layer, and is dried, and then prepared. An oral mucosal patch containing fentanyl was obtained. The methyl vinyl ether-maleic anhydride copolymer used in the invention is not a food-usable raw material and food additive listed in the Food and Drug Administration (FDA) of the Ministry of Health and Welfare, and the copolymer is expensive; In addition, the materials used in the invention are applied in a sequential lamination manner, and the agent layer is applied to a plurality of stages such as a liner/to be dried, a carrier layer applied to the agent layer, and a carrier layer adhered to the carrier/to be dried. People, processes and equipment are costly.

Prior Art 3, known from Taiwan's Early Public Gazette, Publication No. 200514579, Smithkline Beecham Corporation invented an oral dissolution film which is used for the dissolution of the film from the intestinal polymer layer and a buffer layer;

Prior Art 4, known from the early publication of Taiwan, publication No. 200906451, Lintec Corporation, invented an oral administration agent and a method for producing the same, which is formed by a gel forming layer, a drug-containing layer and a gel-forming layer;

According to the prior art 5, the patent publication No. 404838 of the invention is known from the patent publication of Taiwan. The pharmaceutical industry technology research and development center invents a long-acting agent base for oral mucosa, and the long-acting base of the oral mucosa is composed of an adhesive layer. Composed of the bottom layer;

The patent documents of the prior art three-five are also prepared by sequential lamination, which is extremely costly in personnel, process and equipment.

In view of the problems of the prior art, the inventors believe that there should be an improved substance production, for which an oral dissolving film is designed, including:

First thickener: between 0.1 and 5 wt%;

It is selected from sodium carboxymethyl cellulose (CMC-Na), methyl cellulose (MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (hydroxypropyl). Cellulose, HPC), hydroxypropyl methyl cellulose (HPMC), microcrystalline cellulose, modified starch, sodium polyacrylate or polyvinyl pyrrolidone , PVP) one of the groups;

Second thickener: between 0.1 and 10 wt%;

Is selected from the group consisting of gelatin, casein, sodium caseinate, chitin, chitosan, whey protein isolate, whey concentrate Whey protein concentrate, isinglass, xanthan gum, gellan gum, pullulan, condensation polysaccharide, zymosan, agar (agar), carrageenan, alginate (salt), propylene glycol alginate, furcellaran or fucoidan;

Gelling agent: between 0.1~10wt%;

It is selected from the group consisting of guar gum, locust bean gum, tamarind gum, flaxseed gum, honey locust gum, gum arabic ( Acacia gum), tragacanth gum, Indian gum, karaya gum, peach gum, pectin, konjac glucomannan, KGM, India Aloe extract (india aloe extract), inulin (synanthrin) or mesona chinensis polysaccharide; and the effect ingredients and water to make up to 100%.

Compared with the above patent documents, the raw materials used in the present invention are convenient to obtain, easy to manufacture and process, and low in cost. Further, since the above raw materials are used, the present invention is only a simple process, that is, a first thickener (hydroxyethyl fibers). (), second thickener (gelatin), gelling agent (pectin), effect components (including active substances and other ingredients) and sterile water, (1) homogenization, (2) ultrasonic shock, (3 ) heating dissolution and (4) homogenization/degassing, after four steps of mixing, the coating operation can be carried out; the invention does not need to use the sequential lamination method, and only needs to use a single layer coating method. It can be obtained that after drying and slicing, the orally dissolvable film of the present invention can be prepared. In addition, the product prepared according to the present invention can exhibit the advantages of: (1) the oral film is placed in the oral cavity, and the adhesion is very good; (2) the oral film can contain one or more activities. a substance, and its drug release property is good; (3) drug release property can also be adjusted by the ratio of the first thickener/second thickener/gelling agent, that is, it can be prepared simply and quickly. An immediate-release type or a sustained-release type of orally soluble film. Further, an immediate release type or a sustained release type oral solution film containing one or more active substances is prepared; respectively, which are suitable for different needs. Provide a rapid onset of action to the majority of patients and medical workers, improve the bioavailability of drugs, fully exert drug efficacy, reduce adverse reactions, facilitate the reduction of young children and the elderly, easy to carry, store, transport, and prepare methods Simple, new formulation for mass production.

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The content, features and embodiments of the present invention are described below, so that the trial has a further understanding of the present case.

The present invention is an oral dissolving film comprising:

First thickener: between 0.1 and 5 wt%;

It is selected from sodium carboxymethyl cellulose (CMC-Na), methyl cellulose (MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (hydroxypropyl). Cellulose, HPC), hydroxypropyl methyl cellulose (HPMC), microcrystalline cellulose, modified starch, sodium polyacrylate or polyvinyl pyrrolidone , PVP) one of the groups;

Second thickener: between 0.1 and 10 wt%;

Is selected from the group consisting of gelatin, casein, sodium caseinate, chitin, chitosan, whey protein isolate, whey concentrate Whey protein concentrate, isinglass, xanthan gum, gellan gum, pullulan, condensation polysaccharide, zymosan, agar (agar), carrageenan, alginic acid (salt), propylene glycol alginate, red algae (furcellaran) or fucoidan (fucoidan);

Gelling agent: between 0.1~10wt%;

It is selected from the group consisting of guar gum, locust bean gum, tamarind gum, flaxseed gum, honey locust gum, gum arabic ( Acacia gum), tragacanth gum, Indian gum, karaya gum, peach gum, pectin, konjac glucomannan, KGM, India Indica aloe extract, synanthrin or mesona chinensis polysaccharide;

And the effect ingredients and water make up to 100%.

It can be seen from the foregoing that the raw materials used in the present invention are easy to obtain, easy to manufacture and process, and low in cost. Further, since the above raw materials are used, the present invention is only a simple process, that is, a first thickener (hydroxyethyl cellulose), Second thickener (gelatin), gelling agent (pectin), effect components (including active substances and other ingredients) and sterile water, (1) homogenization, (2) ultrasonic vibration, (3) heat dissolution And (4) homogenization/degassing, after the four steps are uniformly mixed, the coating operation can be performed; the invention does not need to be used in the sequential lamination manner, and only needs to be obtained by using a single layer coating method. After drying and slicing, the orally dissolvable film of the present invention can be prepared. In addition, the product prepared according to the present invention can exhibit the advantages of: (1) the oral film is placed in the oral cavity, and the adhesion is very good; (2) the oral film can contain one or more activities. a substance, and its drug release property is good; (3) drug release property can also be adjusted by the ratio of the first thickener/second thickener/gelling agent, that is, it can be prepared simply and quickly. An immediate-release type or a sustained-release type of orally soluble film. Further, an immediate release type or a sustained release type oral solution film containing one or more active substances is prepared; respectively, which are suitable for different needs. Provide a rapid onset of action to the majority of patients and medical workers, improve the bioavailability of drugs, fully exert drug efficacy, reduce adverse reactions, facilitate the reduction of young children and the elderly, easy to carry, store, transport, and prepare methods Simple, new formulation for mass production.

In a more specific embodiment of the present invention, the effect component comprises a first sweetener selected from the group consisting of corn syrup, galactose, lactose, maltose, sorbitol, corn syrup transformed with an enzyme, glucose, Maltitol, sucrose, xylitol, fructose, cyclohexyl sulfonamide, aspartame, potassium sulfamate, stevioside, mangosteen, saccharin, sucralose or 5-nitro-2-propanol The oxyaniline and neotame impart a sweet taste to the orally soluble film through the first sweetener, increase the taste sensation, and modify or reduce the taste sensation of bitterness.

In a more specific embodiment of the present invention, the effect component further comprises a second sweetener, the second sweetener is trehalose, and the second sweetener can impart a crystallization inhibiting effect to the orally soluble film, inhibiting the mint Crystallization occurs.

In a more specific embodiment of the present invention, the effect component comprises a moisture absorbent selected from the group consisting of fumed silica, sodium bentonite, organic bentonite, diatomaceous earth, aluminum citrate, calcium citrate, and strontium. One of a group of sodium aluminate, attapulgite, molecular sieve or strontium gel, which imparts oil and water adsorption capacity to an oral solution through the moisture absorbent, reduces oil phase and water phase release, and causes moisture or The situation of swelling occurs.

A more specific embodiment of the present invention further comprises a third thickener selected from the group consisting of polyvinyl alcohol EG-03P (3.0 to 3.7 mPa·s) and EG-05P (4.8 to 5.8 mPa·s). ), EG-18P (16.0~20.0 mPa·s), EG-22P (20.0~24.5 mPa·s), EG-30P (27.0~33.0 mPa·s), EG-40P (40.0~46.0 mPa·s) or One of the groups of EG-48P (45.0 to 52.0 mPa·s), which imparts rigidity to an orally-soluble film through the third thickener, and reduces the occurrence of insufficient strength.

In a more specific embodiment of the invention, the effect component comprises a coloring agent selected from the group consisting of red number six (0.5) - KIRIYA, red number six (1) - MAP, red number seven (0.5) - KIRIYA, red seven No. (1) - MAP, Red Forty (1) - MAP, Yellow No. 4 (0.5) - KIRIYA, Yellow No. 4 (1) - MAP, Yellow No. 5 (0.5) - KIRIYA, Yellow No. 5 (1) One of the MAP, Green B (0.5) or Blue No. 1 (1)-MAP groups, which imparts a color to the orally soluble film through the toner to increase its visual perception.

In a more specific embodiment of the invention, the effect component comprises a flavor enhancer selected from the group consisting of stevioside, sorbitol, mannitol, maltitol, xylitol, glycyrrhizin, hay extract, cyclohexylamino Sodium sulfonate, banana flavor, grape flavor, cocoa flavor, pineapple flavor, sweet orange flavor, peach flavor, apple flavor, mint flavor, strawberry flavor, fennel, vanillin, lemon flavor, cherry flavor or rose flavor group First, the odorant is imparted with an odor of an orally soluble film to increase the feeling of smell.

In a more specific embodiment of the invention, the effect component comprises an active drug selected from the group consisting of acetaminophen, ascorbic acid, caffeine anhydrous, and chlorpheniramine maleate. (chlorpheniramine maleate), dextromethorphan hydrobromide, guaifenesin, L-menthol / cooling agent, meclizine HCl, DL - DL-methylephedrine HCl, noscapine HCl, paracetamol, pseudoephedrine HCl, riboflavin, thiamine mononitrate And one or more combinations of triprolidine HCl, which can increase the application value of the oral solution by the active drug.

The present invention will be further described below by exemplifying three specific products and their production methods.

Example 1

3.0 wt% sodium carboxymethylcellulose and 5.0 wt% guar gum were added to an appropriate amount of sterile water for homogenization to prepare a solution A; then, 0.1 wt% sorbitol, 1.2 wt% trehalose and 1.0 wt% were prepared. % calcium citrate, added to the appropriate amount of sterile water, ultrasonic shock, made solution B, poured solution B into solution A; then, 5.0wt% agar and 2.0wt% polyvinyl alcohol EG-05P, added to solution A heating Dissolving; finally, 0.2wt% red No.6, 1.0wt% strawberry flavor, 0.1wt% anhydrous caffeine, added to solution A for homogenization and degassing; after the above operation, coating, drying and slice. The total weight is 100.0% by weight, and about 100 pieces of orally soluble film can be prepared, each having an area of 10.00 cm 2 and each piece having a thickness of about 70 μm.

Example 2

3.0 wt% hydroxyethyl cellulose and 7.0 wt% pectin were added to an appropriate amount of sterile water to homogenize to prepare a solution A; then, 0.1 wt% of aspartame, 5.0 wt% of trehalose, and 0.5 wt% Sodium strontium aluminate, added to an appropriate amount of sterile water, ultrasonically oscillated to form solution B, and solution B is poured into solution A; then, 5.0 wt% xanthan gum and 2.0 wt% polyvinyl alcohol EG-03P are added to the solution. A, heating and dissolution; finally, 0.2wt% blue No.1, 1.0wt% grape essence and 0.1wt% ascorbic acid are added to solution A for homogenization and degassing; after the above operation is completed, coating and drying can be carried out. Dry and sliced. 100.0 wt% of the total weight, from about 150 can be made orally disintegrating film, an area per 7.59cm ^2, each of a thickness of about 70μm.

Example 3

2.5 wt% hydroxyethyl cellulose and 8.0 wt% pectin were added to an appropriate amount of sterile water to homogenize to prepare a solution A; then, 0.1 wt% stevioside, 5.0 wt% trehalose, and 1.0 wt% citric acid were added. Aluminum, adding appropriate amount of sterile water, ultrasonic vibration, to make solution B, P solution B into solution A; then, 4.0 wt% gelatin and 1.0 wt% polyvinyl alcohol EG-30P, added to solution A, heated to dissolve; Finally, 0.2wt% green B, 1.0wt% mint flavor, 3.0wt% L-menthol and 1.5wt% cool sensitizer are added to solution A for homogenization and degassing; after the above operation is completed, coating can be carried out. Dry and slice. The total weight is 100.0% by weight, and about 200 pieces of orally soluble film can be prepared, each having an area of 7.59 cm ² and each piece having a thickness of about 50 μm.

In summary, the present invention is indeed in line with industrial utilization, and is not found in publications or publicly used before application, nor is it known to the public, and has non-obvious knowledge, conforms to patentable requirements, and patents are filed according to law. . However, the above description is a preferred embodiment of the industry of the present invention, and all the equivalent changes made by the scope of the patent application of the present invention are within the scope of the claim.

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Claims (8)

An oral dissolving film comprising:
First thickener: between 0.1 and 5 wt%;
It is selected from sodium carboxymethyl cellulose (CMC-Na), methyl cellulose (MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (hydroxypropyl). Cellulose, HPC), hydroxypropyl methyl cellulose (HPMC), microcrystalline cellulose, modified starch, sodium polyacrylate or polyvinyl pyrrolidone , PVP) one of the groups;
Second thickener: between 0.1 and 10 wt%;
Is selected from the group consisting of gelatin, casein, sodium caseinate, chitin, chitosan, whey protein isolate, whey concentrate Whey protein concentrate, isinglass, xanthan gum, gellan gum, pullulan, condensation polysaccharide, zymosan, agar (agar), carrageenan, alginate (salt), propylene glycol alginate, furcellaran or fucoidan;
Gelling agent: between 0.1~10wt%;
Selected from guar gum, locust bean gum, tamarind gum, flaxseed gum, honey locust gum, acacia (acacia) Gum), tragacanth gum, Indian gum, karaya gum, peach gum, pectin, konjac glucomannan (KGM), Indian aloe Indra aloe extract, inulinthrin or mesona chinensis polysaccharide;
And the effect ingredients and water make up to 100%. The orally soluble film according to claim 1, wherein the effect component comprises a first sweetener selected from the group consisting of corn syrup, galactose, lactose, maltose, sorbitol, and an enzyme. Transformed corn syrup, glucose, maltitol, sucrose, xylitol, fructose, cyclohexyl sulfonamide, aspartame, acesulfame potassium, stevioside, mangosteen, saccharin, sucralose or 5 -Nitro-2-propoxyaniline and neotame. The orally soluble film according to claim 2, wherein the effect component further comprises a second sweetener, and the second sweetener is trehalose. The oral solution film according to claim 1, wherein the effect component comprises a moisture absorbent selected from the group consisting of fumed silica, sodium bentonite, organic bentonite, diatomaceous earth, and tannic acid. One of a group of aluminum, calcium citrate, sodium strontium aluminate, attapulgite, molecular sieve or strontium gel. The oral solution film according to claim 1, further comprising a third thickener selected from the group consisting of polyvinyl alcohol EG-03P (3.0-3.7 mPa·s), EG-05P. (4.8~5.8 mPa·s), EG-18P (16.0~20.0 mPa·s), EG-22P (20.0~24.5 mPa·s), EG-30P (27.0~33.0 mPa·s), EG-40P (40.0) One of the groups of ~46.0 mPa·s) or EG-48P (45.0~52.0 mPa·s). The oral dissolution film according to claim 1, wherein the effect component comprises a coloring agent selected from the group consisting of red No. 6 (0.5) - KIRIYA, red No. 6 (1) - MAP, and red No. 7 ( 0.5) – KIRIYA, Red No. 7 (1) – MAP, Red Forty (1) – MAP, Yellow No. 4 (0.5) – KIRIYA, Yellow No. 4 (1) – MAP, Yellow No. 5 (0.5) – KIRIYA , yellow 5 (1) - MAP, green B (0.5) or blue 1 (1) - one of the MAP groups. The oral solution according to claim 1, wherein the effect component comprises a flavor enhancer selected from the group consisting of stevioside, sorbitol, mannitol, maltitol, xylitol, glycyrrhizin, Hay leaf, sodium cyclamate, banana flavor, grape flavor, cocoa flavor, pineapple flavor, sweet orange flavor, peach flavor, apple flavor, mint flavor, strawberry flavor, fennel, vanillin, lemon flavor, cherry flavor Or one of the rose flavor groups. The oral solution according to claim 1, wherein the active ingredient comprises an active drug selected from the group consisting of acetaminophen, ascorbic acid, caffeine anhydrous, Chlorpheniramine maleate, dextromethorphan hydrobromide, guaifenesin, L-menthol / cooling agent, chlorpheniramine hydrochloride Meclizine HCl, DL-methylephedrine HCl, noscapine HCl, paracetamol, pseudoephedrine HCl, riboflavin, nitric acid One or a combination of thiamine mononitrate and triprolidine HCl.