EA046553B1 - COMPOSITION IN THE FORM OF A THIN PLATE FOR ORAL ADMINISTRATION - Google Patents

Description

Field of technology

The present invention relates to a thin wafer formulation for oral administration; more specifically, it relates to an oral thin wafer formulation that masks the bitter taste of scopolamine butyl bromide and is malleable.

State of the art

Recently, there has been an increasing need for formulations that are easy to administer orally even to elderly people with reduced physiological function, for example, and patients with dysphagia. For example, thin-wafer formulations for oral administration are being developed, which are generally in the form of thin films that dissolve or disintegrate in saliva when placed on the tongue and can be swallowed without water.

Sometimes components with a strong bitter taste are included in the formulations in the form of a thin plate for oral administration and are used as medicines. For example, oral wafer formulations that have been formulated with scopolamine butyl bromide are problematic in that they have a very strong bitter taste when swallowed and the willingness to swallow the formulation is reduced.

The technology by which a combination of a stevioside sweetener and a very sweet sweetener is administered has already been described as a method of producing a thin wafer formulation that conceals the bitter taste of an off-tasting drug such as scopolamine butyl bromide (Patent Cited 1). However, such a thin slab formulation for oral administration is disadvantageous in that it uses pullulan as a base and therefore has low ductility and is easily cracked when stored under dry conditions such as extremely low humidity environments.

Therefore, there is a need for a thin slab composition with excellent ductility that does not crack even when stored under dry conditions.

Citation list.

Patent literature.

PTL 1 Japanese patent number 5539503.

Summary of the invention

Technical problem.

Therefore, the object to be solved by the present invention is to provide a thin-wafer composition for oral administration that reduces the bitter taste of scopolamine butyl bromide and has excellent plasticity and has the ability to prevent cracking under dry conditions.

The solution of the problem.

The inventors of the present invention have conducted extensive research to develop an oral thin wafer formulation that reduces the bitter taste of scopolamine butyl bromide, has a soft and pleasant texture on the tongue and does not pose quality problems; and have made the present invention by discovering that by using a cellulose polymer as the base of a thin wafer formulation and incorporating a particular combination of sweetener and menthol into scopolamine butyl bromide, a thin wafer formulation for oral administration can be prepared in which the unpleasant bitter taste of scopolamine butyl bromide is masked, and which has good ductility and does not crack under dry conditions.

In particular, the present invention is a thin-wafer formulation for oral administration, characterized in that it contains a cellulose polymer as a base and contains the following components (A) to (C):

(A) scopolamine butyl bromide, (B) sucralose and/or sodium saccharin, (C) menthol.

Useful effects of the invention.

The thin-wafer formulation of the invention for oral administration is of great practical importance since the intense bitter taste caused by scopolamine butyl bromide is reduced by the administration of a combination of sucralose and/or sodium saccharin and menthol. In addition, its ductility is increased by using cellulose polymer as the base of the thin plate.

Description of Embodiments

The thin strip formulation of the invention for oral administration contains scopolamine butyl bromide as the active ingredient, and a combination of sucralose and/or sodium saccharin and menthol is included to mask the bitterness of scopolamine butyl bromide. Cellulose polymer is also used as the base of the thin plate.

Scopolamine butyl bromide (hereinafter referred to as component (A)), which is the active ingredient in the thin strip formulation of the invention for oral administration (hereinafter referred to as the thin strip formulation of the invention), is a well-known drug

- 1 046553 a herbal remedy that effectively relieves abdominal pain, abdominal pain and pain from stomach cramps by easing excess gastrointestinal tension and spasms; its molecular formula is C21H ₃₀ BrNO ₄ and its molecular weight is 440.37.

There is no particular limitation on the amount of component (A) contained in the thin plate composition of the invention; for example, the composition contains preferably 1-50% by weight (hereinafter simply %), more preferably 2-35% and even more preferably 20-30%.

As for the sucralose and/or sodium saccharin (hereinafter referred to as component (B)) in the thin-wafer composition of the invention, both of these components are known as sweeteners. There is no particular limitation on the amount of component (B) contained in the thin plate composition of the invention. For example, the composition preferably contains about 0.1-30%, more preferably 0.3-20%, and even more preferably 0.5-10%. Most preferably it contains 2-5%.

In addition, component (C) menthol (hereinafter referred to as component (C)) in the thin plate composition of the invention is a compound that is also widely known as a cooling agent, stabilizer, flavoring agent, refreshing agent, etc. d. Examples of component (C) include DL-menthol and L-menthol, and of these, L-menthol is preferred. There is no particular limitation on the amount of component (C) contained in the thin plate composition of the invention. For example, the composition preferably contains 0.1-40%, more preferably 0.2-30% and even more preferably 0.5-30%.

It should be noted that when sucralose is used as the above-mentioned component (B) in the thin plate composition of the invention, there is no particular limitation on the weight ratio with component (C); for example, preferably 0.0025-300 parts by weight, more preferably 0.01100 parts by weight and even more preferably 0.1-20 parts by weight of component (C) per 1 part by weight of sucralose.

In addition, when sodium saccharin is used as the above-mentioned component (B) in the thin plate composition of the invention, there is no particular limitation on the mass ratio with component (C); for example, preferably 0.0025-300 parts by mass, more preferably 0.01-100 parts by mass, and even more preferably 0.1-20 parts by mass of component (C) per 1 part by mass of sodium saccharin.

The thin plate composition of the invention contains one cellulose polymer or a plurality of cellulose polymers as its base. Examples of these cellulose polymers may include cellulose ethers and, in particular, cellulose ethers in which some of the hydroxyl groups on the cellulose are replaced by methyl groups, ethyl groups, hydroxyethyl groups, hydroxypropyl groups, carboxyl groups or the like.

There are no particular limitations on specific examples of cellulose polymers used, and examples include methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose. Of these, hydroxypropylcellulose and hypromellose are preferred. In addition, other polymer compounds can also be used simultaneously in the present invention, provided that it does not adversely affect the ductility of the thin plate.

There is no particular limitation on the amount of the above cellulosic polymer contained in the thin plate composition of the invention. For example, the composition preferably contains about 10-95%, more preferably 10-75%, and even more preferably 10-50%. Most preferably, it contains 30-45%.

The thin plate composition of the invention can be prepared in a known manner. For example, it can be obtained by adding the above-mentioned components (A) to (C) to a solution obtained by dissolving or suspending a cellulose polymer to be a base, and then molding the resulting solution into a thin plate.

More specifically, for example, components (A) to (C), cellulose polymer, drug and necessary optional components are added to a suitable amount of purified water, lower alcohol or a mixture thereof and dissolved or dispersed by mixing to obtain a solution containing the drug. The resulting drug-containing solution is then applied to a release film of polyethylene phthalate or the like and dried to form a thin plate formulation.

When preparing the thin plate composition of the invention as described above, optional components may be added provided that the effects of the present invention are not impaired. Examples of such optional components include sweeteners other than component (B), acidifiers, plasticizers, excipients, emulsifiers, colors and flavors.

Examples of the above-mentioned sweeteners other than component (B) include reconstituted mizuame maltose, powdered reconstituted mizuame maltose, fructose, saccharobiose, maltose, lactose, sucrose, glucose, maltitol, erythritol, xylitol, mannitol, lactitol, trehalose, acesulfame potassium, aspartame, thaumatin, disodium glycyrrhizinate, trisodium glycyrrhizinate and dipotassium glycyrrhizinate.

Examples of acidulants include citric acid, malic acid, tartaric acid, mo

- 2 046553 lactic acid, ascorbic acid, erythorbic acid, succinic acid and fumaric acid.

In addition, examples of the above-mentioned plasticizers include polyethylene glycol (Macrogol 400, Macrogol 1500, etc.), propylene glycol and glycerin; and examples of excipients include titanium oxide, aluminum magnesium hydroxide, magnesium hydroxide, aluminum silicate, silicon dioxide, anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, amorphous aqueous silicic acid, magnesium aluminate silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, heavy anhydrous silicic acid, magnesium oxide, calcium chloride, calcium sulfate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate and sodium dihydrogen phosphate.

In addition, examples of the above emulsifiers include lecithin, soy lecithin, purified soy lecithin, purified egg yolk lecithin, sodium lauryl sulfate, glycerol fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil , polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters; and examples of colorants include food coloring, food varnish coloring, iron sesquioxide and yellow iron oxide.

The thin-wafer composition prepared as described above may be a single-layer or multi-layer composition obtained by laminating multiple individual layers. From a production point of view, one layer is preferred.

There is no particular limitation on the thickness of the thin plate composition of the invention. Preferably it is 20-500 µm, more preferably 30-300 µm. Moreover, there is no particular specification on the size of the thin plate composition of the invention, and it is preferably 0.5-12 cm ² , more preferably 1.0-10 cm ² . There are no particular restrictions on the form as long as it is easy to swallow; for example, rectangle, circle, ellipse or the like may be selected as the shape depending on the situation.

There are no particular limitations on the thin plate composition of the invention described above; for example, as an over-the-counter drug, the formulation preferably contains about 10 mg of scopolamine butyl bromide per oral dose not to exceed 3 times daily. However, as a drug used in therapeutic treatment, 10-20 mg of scopolamine butyl bromide can be administered per dose, preferably administered orally about 3-5 times a day. Needless to say, the dose may be increased or decreased depending on the age and condition of the patient.

Thus, the resulting thin plate formulation of the invention is such that the bitterness of scopolamine butyl bromide is masked and it has a soft and pleasant texture on the tongue. Another distinguishing feature is that it is ductile and therefore unlikely to crack.

Examples

The present invention is described in more detail below with the help of examples and comparative examples, but the present invention is in no way limited to them.

Example 1.

The thin plate formulation products of the invention 1-6 and the comparative thin plate formulation products 1 and 2 were prepared as set forth in Table 1 below. Specifically, 10.0 g of scopolamine butyl bromide, 2.0 g of Macrogol 400, 6.0 g of mizuame reduced maltose powder, and 1.0 g of sucralose or sodium saccharin were added to and dissolved in 40.0 g of suspended water. Then, 35.0 g of pharmacopoeial ethanol was added to the resulting liquid, then 1.0 g of titanium oxide was added and thoroughly dispersed, and then 7.5 g of hypromellose TC-5R and 7.0 g of hydroxypropyl cellulose HPC-SSL were added and dissolved. To this solution was added 25.0 g of pharmacopoeial ethanol or a solution prepared by adding the required amount of L-menthol to 25.0 g of pharmacopoeial ethanol and dissolving to obtain a prepared solution containing the drug.

The oral thin-wafer formulation was prepared by uniformly applying a predetermined amount of the above prepared solution onto a PET film to form a drug-containing layer and then drying in warm air (at 70° C. for 2 hours). Thus, thin-wafer oral formulation products of the invention 1-6 and comparative oral thin-wafer formulation products 1 and 2 were prepared. Ten testers used the resulting oral thin-wafer formulations, and after 30 seconds After ingestion, they performed sensory bitterness tests according to the evaluation criteria below. The scores were averaged and the results are shown in the table (mg).

- 3 046553

Product according to the invention 1 Product according to the invention 2 Product according to the invention 3 Product according to the invention 4 Product according to the invention 5 Product according to the invention 6 Comparative example 1 Comparator ny example 2 Scopolamine butyl bromide 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 Hypromellose TC5R* * ¹ 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 Hydroxypropylcellulose HPC-SSL* ² 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Titanium oxide 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Macrogol 400 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Powdery 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0

reduced maltose mizuame

Sucralose 1.0 1.0 1.0 1.0 Sodium saccharin 1.0 1.0 1.0 1.0 L-menthol 0.5 2.5 10.0 0.5 2.5 10.0 Total 35.0 37.0 44.5 35.0 37.0 44.5 34.5 34.5 average rating 3.3 3.1 3.4 3.4 3.6 3.1 4.0 3.8

*1 Hypromellose TC-5R (manufactured by Shin-Etsu Chemical Co., Ltd.).

*2 Hydroxypropyl cellulose HPC-SSL (manufactured by Nippon Soda Co., Ltd.).

Criteria for evaluation.

Rating: bitter.

5: Unacceptably unpleasant.

4: Somewhat unpleasant.

3: I find it difficult to answer in any way.

2: Somewhat noticeable, but not unpleasant.

1: Not noticeable at all.

From the results for the products of the invention 1-3, it was confirmed that the bitterness of scopolamine butyl bromide was masked by the inclusion of sucralose and L-menthol. In addition, from the results for the products of the invention 4-6, it was confirmed that the bitterness of scopolamine butyl bromide was masked by the inclusion of sodium saccharin and L-menthol.

*Bitterness rating without masking agent was 4.8.

However, the bitterness of scopolamine butyl bromide was not masked in Comparative Example 1 or Comparative Example 2, which contained sucralose or sodium saccharin but no L-menthol.

Example 2.

Plasticity test.

Invention products 1-6 obtained in Example 1 were dried at 60°C for 12 hours as model overdrying conditions, and then 1 cm X 2 cm test specimens with a thickness of 100-200 μm were prepared. The test specimens were then returned to room temperature and bent 180° using a finger to confirm ductility. The results showed that formulations prepared using cellulose polymer retained sufficient ductility to not crack even when dried at 60°C for 12 hours. In comparison, formulations (comparative examples) prepared using water-soluble pullulan polysaccharide instead of cellulose polymer, did not have ductility to such an extent that they cracked even with slight impact.

Industrial applicability.

In the thin strip formulation of the invention, the bitter taste of scopolamine butyl bromide is masked such that the thin strip formulation of the invention can be swallowed without

- 4 046553 water; Therefore, the thin plate composition of the invention is suitable, for example, for the treatment of elderly people and patients with dysphagia. The thin plate composition of the invention also has high plasticity and therefore has high commercial value since it is easy to accept and is unlikely to crack even when stored under very dry conditions.

Claims (9)

1. A thin film formulation for oral administration comprising a thin film formulation base and components (A) to (C) below: (A) 20-30% active ingredient; (B) 0.5-10% sweetener selected from sucralose and/or sodium saccharin; and (C) 0.2-30% menthol, wherein the base of the thin film composition consists of a cellulose ether polymer, and where the thin film composition contains 30-45% cellulosic cellulose polymer, wherein the active ingredient consists of scopolamine butyl bromide, wherein the thin the film is flexible and masks the bitter taste of scopolamine butyl bromide. 2. The thin plate composition of claim 1, wherein the cellulose ether polymer is selected from the group consisting of cellulose ethers in which some of the cellulose hydroxyl groups are replaced by methyl groups, ethyl groups, hydroxyethyl groups, hydroxypropyl groups or carboxyl groups. 3. The thin plate composition of claim 1, wherein the cellulose ether polymer is (i) hydroxypropylcellulose, (ii) hypromellose, or (iii) hypromellose and hydroxypropylcellulose. 4. The thin plate composition according to claim 1, wherein component (B) is sucralose. 5. The thin plate composition according to claim 1, wherein component (B) is sodium saccharin. 6. A composition in the form of a thin plate according to any one of claims 1 to 5, which contains 2-5% by weight of component (B). 7. A composition in the form of a thin plate according to any one of claims 1 to 6, which contains 0.5-30% by weight of component (C). 8. The thin plate composition according to any one of claims 1 to 3, wherein component (B) is sucralose, and the weight ratio of said sucralose to component (C) is 1:0.0025-300 parts by weight. 9. A thin plate composition according to any one of claims 1 to 3, wherein component (B) is sodium saccharin and the weight ratio of said sodium saccharin to component (C) is 1:0.0025-300 parts by weight.