KR100617856B1 - New Composition of Chewing Gum Type Containing Sibutramine - Google Patents

Abstract

The present invention relates to a new gum-type sibutramine preparation composition for the treatment of obesity, in particular, a gum-type new sibutramine which improves the absorption rate of the drug by increasing the disintegration and dissolution rate of the drug by chewing and prolonging the oral mucosal retention time of the drug. It relates to a formulation composition. The present invention provides a gum-type sibutramine preparation composition comprising 20-80 parts by weight of a gum base based on 0.001-10 parts by weight of sibutramine hydrochloride, which is administered by chewing for 5 minutes or more. The new type of sibutramine preparation according to the present invention can solve the hassle of taking the existing oral medications and can greatly improve the compliance of the obese patients with the simple dosage method suitable for the new tastes of consumers. By increasing the rate of disintegration and dissolution and prolonging the oral mucosal retention time of the drug, it is possible to improve the rate of absorption of the drug, thereby speeding up the expression of the drug.

Gum, anti-obesity agent, sibutramine, absorption rate, oral mucosa

Description

New composition of Chewing Gum Type Containing Sibutramine

1 is a graph showing the blood drug concentration per hour after administration of a gum-type sibutramine preparation of the present invention to commercially available tablets.

The present invention relates to a gum-type sibutramine preparation composition for treating obesity, in particular, a new gum-type sibutramine preparation which improves the absorption rate of the drug by increasing the disintegration and dissolution rate of the drug by chewing and prolonging the oral mucosal retention time of the drug. To a composition.

Pharmaceutical formulations include various types of formulations, such as powders, granules, tablets, capsules, solutions, and injections, depending on the form, preparation method, administration method, and the like. Among them, preparations classified as oral administration agents are expected to be effective by absorbing medicines through the digestive tract biofilm, and there are solid preparations such as tablets and capsules and liquid preparations such as liquids and syrups.

Oral medications are the most commonly used form and account for 70% of the marketed products, especially in the field of medicine, such as obesity, hyperlipidemia, diabetes, hypertension that requires long-term medications occupy most of the method of administration. However, most of the oral administration can be taken only with water, and it is difficult to take in patients or elderly people who are difficult to swallow, and because it is absorbed through the digestive tract biomembrane, solubility and fat solubility of the drug, gastric acid and digestion The effects of enzymes, foods in the gastrointestinal tract, and the like have many disadvantages such as a large number of factors that affect the absorption of the administered drug.

Sibutramine hydrochloride (Sibutramine HCl: C ₁₇ H ₂₆ CIN HCl) is chemical name {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethylamine hydrochloride, which was originally developed as an antidepressant. The drug has been found to give weight to patients taking this drug and has been developed to treat obesity. Sibutramine hydrochloride reduces appetite by inhibiting the reuptake of serotonin and noradrenaline, the neurohormones that regulate appetite in the brain. Sibutramine is currently widely used as an anti-obesity agent, and commercially available formulations have the same problems as those of general oral administration as tablet type oral administration. In particular, in the case of obesity drugs, the patient's compliance with the oral administration is very low since the consumer is mainly young.

On the other hand, conventional gum used as a favorite product generally consists of 20-30% of base, 60-80% of sugar, 1-2% of fragrance. Recently, bad breath and tooth decay, drowsiness prevention, brain function activation, health promotion Many functional gums which add functional ingredients, such as these, are also being developed. However, there have not been any examples formulated in the form of gum in the field of anti-obesity medicines, including sibutramine hydrochloride.

The present invention aims to solve the above problems with sibutramine formulations in the form of oral administration and to develop the formulation in a new formulation, gum type, in order to further improve patient compliance. That is, an object of the present invention is to provide a new gum-type sibutramine preparation composition which can solve the hassle of taking oral administration while having a faster drug absorption condition.

Other objects and advantages of the invention will be described below, and will be better understood by practice of the invention.

In the present invention, there is provided a new gum type sibutramine preparation composition comprising 20-80 parts by weight of a gum base relative to 0.001-10 parts by weight of sibutramine hydrochloride, which is administered by a method of chewing for 5 minutes or more.

The sibutramine hydrochloride is preferably included at 5-20 mg per unit formulation.

Conventional chewing gum is added with sugars such as sugar, glucose, isomalt or xylitol to sweeten, and the gum type sibutramine formulation composition of the present invention is also added in an amount of 20-80% by weight in the total formulation composition for the addition of an appropriate sweetness. May contain sweeteners. However, it is preferable to use low-calorie low-calorie sweeteners instead of general sugars such as sugar and glucose due to the characteristics of anti-obesity drugs. In one embodiment of the present invention, isomalti powder, isomaltitol syrup, xylitol, and the like are used as a sweetener, and low calorie such as stevioside may be used.

As the gum base, a conventional gum base mainly composed of a resin called chickle obtained from the bark of a plant called sapodilla is used. In one embodiment of the present invention, natural gum and / or vinyl acetate were used as the gum base. In the present formulation composition, when the gum base is included in a small amount, the gum base is hardly agglomerated and crumbled during molding of the gum, and when the gum base is included in a large amount, the gum base is added so that the texture of the gum becomes tough.

As in general drug formulations, the gum type sibutramine formulation compositions of the present invention may include pharmaceutically acceptable conventional excipients and the like. In one embodiment of the present invention, although sucralose and glycerin were used as excipients, excipients that can be used are not limited thereto. In addition, in one embodiment of the present invention, lubricants such as Aerosil 200 and / or talc are included in the present sibutramine formulation compositions, and other known lubricants may be used for similar purposes.

In addition to the above components, conventional additives used in gums such as perfumes, pigments, stabilizers, emulsifiers, polishes, and the like may be selectively added to the gum type sibutramine preparation composition of the present invention according to a known method.

As a fragrance for improving the fragrance of the gum, a known fragrance component added to the gum, such as mint, fruit, herb, may optionally be used. The fragrance is preferably included in the range of 5% by weight or less in the total formulation composition. In one embodiment of the present invention used as a flavor strawberry micron or banana micron.

As a pigment for imparting a color to the gum, a pharmaceutically acceptable ingredient may be selectively used among known natural or synthetic coloring agents used in gum such as gardenia blue, gardenia yellow, caramel, and grape skin extract. have.

As the stabilizer, known stabilizers such as gum arabic, gelatin or konjac carrageenan can be used as necessary. Stabilizers increase tack and emulsification stability and help preserve the freshness and form of the product against changes in heating or preservation during processing. In addition, stabilizers are generally added to enhance the texture and texture of food. Since excessive use of the stabilizer may already cause odor, it is preferable that the stabilizer is included in 10% by weight or less of the total formulation composition.

As the emulsifier, known emulsifiers such as sucrose fatty acid ester and lecithin can be used as necessary. Excessive use of the emulsifier, like the stabilizer, may already cause odor, and therefore, it is preferably included in the total formulation composition at 10% by weight or less.

In order to increase the commercialization of the product, a brightening agent such as carnauba wax or shellac may be further added to the formulation composition. Polishing agents are preferably included in up to 10% by weight of the total formulation composition when used.

In the gum-type sibutramine preparation composition according to the present invention, when the dosage form is first collapsed by chewing, the effective drug component is eluted, some of which are first absorbed into the oral mucosa, and most of the remaining drug is eluted. It reaches the gastrointestinal tract and is quickly absorbed through the biofilm of the gastrointestinal tract. Drugs absorbed into the oral mucosa reach the heart through the internal jugular vein and are distributed throughout the body, thus preventing the first pass effect by the liver. In addition, since most of the drugs eluted by chewing, which are not absorbed into the oral mucosa, reach the gastrointestinal tract in the eluted state, the conventional oral solid preparations such as tablets are absorbed through the steps of disintegration and elution in the gastrointestinal tract during administration. Unlike this, it tends to be rapidly absorbed through the biofilm of the gastrointestinal tract as it is. Therefore, the new sibutramine preparation of the gum type of the present invention is improved in absorption conditions due to the disintegration and dissolution rate of the drug by chewing, and to increase the absorption time of the mucosal retention time of the drug, the absorption rate of the drug compared to the conventional oral administration It has an advantage in formulation that is increased to speed up the expression of the drug.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the scope of the present invention is not limited by the following examples, and those of ordinary skill in the art to which the present invention pertains without departing from the spirit and scope of the appended claims. Of course, various modifications and variations are possible.

Examples 1-6

The gum base was added to the associated container with the composition as shown in Table 1 below, warmed to 38-40 ° C., melted, combined with other excipients and drugs, and then flavored and molded using a tablet press to prepare a gum-type sibutramine formulation. .

Test Example 1

Stability of the drug in saliva

Sibutramine hydrochloride was added to the filtered human soak and stored at 36.5 ° C. and 25 ° C. for 1 hour, and the content was visually observed by high performance liquid chromatography (HPLC).

The results are shown in Table 2, and sibutramine hydrochloride did not show a significant change in initial concentration and properties. As the stability of the drug in salivary solution was confirmed for 1 hour, a new type of gum type containing it was determined to be very stable in the oral cavity during chewing after administration.

Test Example 2

Test of dissolution rate of drug by chewing

After chewing 5 g of the sibutramine preparation of the gum type prepared in Examples 1 to 6, each of them was chewed, the gum was recovered per hour, and the amount of drug remaining in the gum was quantified by HPLC. The dissolution rate of the drug was calculated by subtracting the concentration after chewing from the initial gum drug concentration.

The results are shown in Table 3. The sibutramine formulations of Examples 1 to 6 showed a dissolution rate of 70% or more after 3 minutes, and a dissolution rate of 95% or more after 5 minutes, regardless of the composition of the base. In view of the general dissolution rate of the general tablets in the stomach for more than 80% for 30 minutes, the drug dissolution rate of the gum type formulation of the present invention was found to be higher than the conventional tablets. In addition, the drug dissolution rate of the gum-type preparation of the present invention was found to have no correlation with the amount of the gum base, and this dissolution rate was determined to be an effect by chewing.

Test Example 3

Stability test

Chewing gum type preparation of sibutramine hydrochloride prepared in Example 1 was stored at 25 ° C. and 45 ° C. for 12 months to determine the properties of the gum and the content of sibutramine hydrochloride. About 100 mg of the preparation of Example 1 was finely cut and then placed in 50 ml of distilled water, stirred for 5 minutes, filtered through a Millipore filter, and quantified by high performance liquid chromatography (HPLC).

The results are shown in Table 4 below. The formulation content of Example 1 was not significantly different for 12 months, and the content of sibutramine hydrochloride in the formulation was found to maintain at least 99% at 25 ° C and 45 ° C. From these results it was determined that the formulation was stable for at least 1 year at 45 ° C.

Test Example 4

In-body Dynamics Test

Twelve healthy volunteers were divided into two groups, one group (6 volunteers) was chewed with the gum type preparation of Example 1, and the other group (6 volunteers) was orally administered with the same amount of commercially available sibutramine hydrochloride tablets. Blood was collected at a predetermined time after administration and pretreated to quantify sibutramine hydrochloride in blood by high performance liquid chromatography.

The results are shown in FIG. 1 and Table 5. As shown in Fig. 1, the initial concentration of the gum type preparation of Example 1 was significantly higher than that of commercially available sibutramine hydrochloride tablets. In addition, as shown in Table 5, in the kinetic parameters, the Tmax of the gum type preparation of Example 1 was found to be significantly faster, and other parameters, AUC, Cmax, K _el and t _1/2, were almost significant. There was no change. Therefore, the gum-type preparation of Example 1 was found to have fast drug efficacy because the absorption rate was improved while the bioavailability was almost equal to that of commercial tablets.

* P <0.05 compared with semi-solid suppository.

** Each value represents the mean + S.E. (n = 6).

The new sibutramine preparation composition of the gum type according to the present invention solves the hassle of taking the existing oral medications and can easily improve the compliance of the obese patients with the convenient dosage method suitable for the new tastes of consumers. Formulation into a new type of gum type formulation can increase the disintegration and dissolution rate of the drug by chewing and prolong the oral mucosal residence time of the drug, thereby improving the rate of absorption of the drug and thus speeding up the expression of the drug.

Claims (7)

chicle; Vinyl acetate; A gum-type sibutramine preparation composition comprising 20-80 parts by weight of a gum base selected from the mixture thereof and 0.001-10 parts by weight of sibutramine hydrochloride, and eluting at least 95% by chewing for at least 5 minutes. The gum type sibutramine preparation composition according to claim 1, comprising 5-20 mg of sibutramine hydrochloride per unit preparation. The method according to claim 1, A gum-type sibutramine formulation composition further comprising a sweetener at 20-80 wt% in the formulation composition. The method according to claim 3, Isomalty powder as the sweetener; Isomaltitol syrup; A gum-type sibutramine formulation composition comprising at least one component selected from xylitol and stevioside. delete The method according to any one of claims 1 to 4, A gum-type sibutramine formulation composition further comprising a pharmaceutically acceptable conventional excipient. The method according to any one of claims 1 to 4, Conventional perfumes used in gum; Pigments; stabilizator; A gum-type sibutramine formulation composition further comprising at least one of an emulsifier and a brightener.

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