KR101759973B1 - Orally disintegrating drug delivery system for treating oral diseases - Google Patents

Abstract

The present invention relates to a drug-disintegrating drug delivery system for preventing or treating oral diseases, wherein the drug delivery system according to the present invention disintegrates in the oral cavity by an enzyme contained in saliva, Or in the short term, the treatment or prevention effect of the intraoral disease can be maintained constantly, so that it can be effectively used as a drug delivery vehicle for the prevention or treatment of oral diseases.

Description

[0001] The present invention relates to oral disintegrating drug delivery systems for the prevention or treatment of oral diseases,

The present invention relates to oral disintegrating drug carriers for the prevention or treatment of oral diseases.

With the advent of an aging society around the world, the number of patients with oral diseases due to various causes has reached 1,600,000 and is increasing. In particular, it is necessary to develop a bioactive agent or drug delivery system for the treatment of diseases of the oral or salivary glands such as intractable dry mouth, salivary gland, salivary glands, salivary glands, etc. Salivary gland tissue damage is a serious refractory disease There is a very large clinical and policy demand, and it is an urgent disease that can cause increase of health finances.

The mouth area is anterior to the lips, the back has a mouth and the mouth is in contact with the pharynx, the upper side is the soft palate and upper lip, the lower wall is the tongue and the upper lip, and the side wall is surrounded by the ball. Oral disease refers to various diseases among these.

Salivary glands (salivary glands) are located around the mouth and neck. The salivary glands are the parotid gland, submandibular glands, and sublingual glands. In addition to these three major salivary glands, there are about 100 small salivary glands called small salivary glands. It is located in the mucous membranes of the lips, mouth and neck. These salivary glands secrete saliva, moisturize the mouth, help digest food, and prevent teeth from forming in the teeth.

The salivary gland disease is largely divided into salvageal obstruction, salivary gland inflammation, salivary gland infection and salivary gland disease treatment. If a systemic disease is associated with the underlying cause of treatment, and the closure of the salivary gland with infection, if there is an antibiotic is used. Surgical removal is necessary if the salivary gland has a mass. Surgical treatment is sufficient for benign tumors, but malignant tumors may require radiation therapy after surgery. During surgery, especially parotid injuries may cause facial nerve damage.

In recent years, there has been a growing interest in the development of drug delivery systems for long-term or short-term drug delivery as interest in medical polymers has increased. Therefore, much research has been conducted to maximize the therapeutic effect by controlling the drug release rate.

As a result of the above studies, a drug delivery system using a polymer having characteristics such as biocompatibility and biodegradability has been produced. Representative types of drug delivery systems using polymers include microspheres, films, wafers, and patches.

Research on the development of a drug delivery system using such a polymer material has been actively carried out. However, currently, a drug delivery system using a copolymer has a limited range of application when it is used for medical use. As a drug delivery system for prevention or treatment of oral diseases, There is a need to develop a new biocompatible delivery system which can be delivered more efficiently and simply to the oral cavity.

Accordingly, the present inventors have made efforts to overcome the problems of the prior art as described above, and as a result, they have developed a drug-disintegrating drug delivery vehicle containing a biodegradable polymer and a saliva sensitive polymer and confirmed that they can be used for the treatment of oral diseases. Thereby completing the invention.

It is an object of the present invention to provide an oral disintegrating drug delivery system for prevention or treatment of oral diseases.

In order to solve the above problems, the present invention provides a drug-disintegrating drug delivery vehicle comprising a biodegradable polymer and a saliva responsive polymer.

The drug delivery system according to the present invention disintegrates in the oral cavity by an enzyme contained in the saliva, thereby effectively delivering the drug to the oral cavity and maintaining the therapeutic or prophylactic effect of the intraoral disease in the long term or short term. Can be usefully used as a drug delivery vehicle for prevention or treatment.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an illustration showing the action of the drug delivery system of the present invention by amylase. FIG.
FIG. 2 is a diagram illustrating a process of manufacturing the microparticulate drug delivery system of the present invention.
FIG. 3 is a view showing a microscopic observation of the surface of the microspherical drug delivery system manufactured in Production Example 1. FIG.
FIG. 4 is a graph showing microscopic and fluorescence microscopic observation of the microsphere drug carrier prepared in Production Example 2 (a: surface, b: fluorescence photograph, c: a photograph combining (a) and (b) .
FIG. 5 is a graph showing microscopic and fluorescent microscopic observation of the microparticulate drug carrier prepared in Production Example 3 (a: surface, b: fluorescence photograph, c: photographs of merging (a) and (b) .
FIG. 6 is a diagram illustrating a process of manufacturing the wafer-type drug carrier according to the present invention.
Fig. 7 is a diagram showing the wafer-shaped drug carrier prepared in Production Examples 4 to 6. [a: Preparation Example 4, b: Preparation Example 5, c: Preparation Example 6].
Fig. 8 is a diagram showing the film-shaped drug carrier prepared in Production Examples 7 to 9; [a: Preparation Example 7, b: Preparation Example 8, c: Preparation Example 9].
FIG. 9 is a diagram showing an injection-type hydrogel containing the microparticulate drug carrier prepared in Production Example 10 and the result of implantation thereof in vivo.
FIG. 10 is a graph showing the drug release test results of amylase of the wafer type drug delivery vehicle prepared in Production Examples 4 and 6. FIG.
FIG. 11 is a graph showing the results of drug release experiments by the amylase of the film-type drug delivery vehicle prepared in Production Examples 7 and 9. FIG.

Disclosed is a drug disintegrating drug delivery vehicle comprising a biodegradable polymer and a saliva responsive polymer.

Hereinafter, the present invention will be described in more detail.

The biodegradable polymer according to the present invention may be selected from the group consisting of polycaprolactone, polyalkylcarbonate, polyamino acid, polyhydroxybutyric acid, polyorthoester, polyanhydride, Polyanhydride, poly (ethylene oxide) poly (ethylene oxide), Pluronic), polylactides, polyglycolides, polylactide-co-glycolide (PLGA), carboxymethylcellulose, alginic acid, alginate, gelatin, casein, chitin derivatives and chitosan, preferably polylactide-co-glycolic acid Id (PLGA) is

The saliva responsive polymer according to the present invention may be Starch, Dextrin, Dextran or gamma-cyclodextrin, preferably starch or gamma-cyclodextrin.

The saliva responsive polymer is capable of being disrupted by the enzyme contained in the saliva, and the enzyme contained in the saliva is amylase (ptyalin).

The drug delivery system of the present invention may be in the form of a microsphere, a film, a wafer, a patch, or an injection.

The microspheres form a microsphere by enclosing a biodegradable polymer, which is an outer wall material surrounding the microsphere, and a drug inside the biodegradable polymer, and the drug release rate is controlled according to the type and composition of the biodegradable polymer. The microspheres may further include one or more additives such as preservatives, preservatives and excipients, and the microspheres may be prepared by a single-axis ultrasonic spray method [B. S. Kim, J. M. Oh, K. S. Kim et al., Biomaterials, 30, 902 (2009); B. S. Kim, J. M. Oh, H. Hyun et al., MOLECULAR PHARMACEUTICS, 6, 353 (2009)]. By the single-axis ultrasonic atomization method, it is possible to produce a double-structured microparticle having a different composition of the inner core part and the outer wall material. In this case, the filling rate of the microparticles is 60 to 70%.

The wafer type is prepared by directly compressing a mixture of the biodegradable polymer and the saliva responsive polymer and the drug, and the mixture is put into a mold for wafer production and pressurized using a press.

The film type is prepared by solvent casting method. The solution obtained by dissolving the biodegradable polymer, the saliva responsive polymer and the drug is thinly applied to a casting die using an applicator, and then the solvent is evaporated.

The drug delivery vehicle of the present invention can carry a drug, and the drug can be an antioxidant, an anti-cancer drug, an immunosuppressant, an angiogenesis inhibitor, a vitamin, a protein or a peptide drug, an analgesic or an anti- Preferably, it may be dexamethasone or Curcumin.

Since the oral cavity-disintegrating drug delivery system according to the present invention contains the saliva sensitive polymer, it can be disintegrated by the saliva in the oral cavity and disintegrated in the oral cavity, thereby effectively delivering the drug into the oral cavity. The therapeutic or prophylactic effect can be kept constant. The action of the drug delivery system of the present invention is shown in Fig.

The oral diseases may include dry mouth, stomatitis, inflammation around the gums or teeth, dental acidosis, dental caries, gangrene (gangrene) or salivary gland disease. The salivary gland diseases include salivary glands, Salivary gland carcinoma or saline-gland conduit closure, and the like.

Desirable dosages of the drug delivery vehicle of the present invention carrying the drug are appropriately selected by those skilled in the art depending on the condition and body weight of the individual, the degree of disease, the type of drug and gene, administration route and period. For the desired effect, the drug delivery vehicle of the present invention may contain 1 mg / kg to 100 mg / kg of the gene per administration, and may be administered once a day or several times.

The drug delivery system of the present invention may be administered to a subject in various routes, but oral administration is preferred.

The drug delivery system of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers for the prevention and treatment of oral diseases.

Hereinafter, preferred examples and examples of the present invention are presented to facilitate understanding of the present invention. However, the following production examples and examples are only for the purpose of easier understanding of the present invention, and the present invention is not limited by the production examples and examples.

Manufacturing example  One. Single axis  Using an ultrasonic sprayer Dexamethasone  Containing γ-cyclodextrin / PLGA Microparticle  Preparation of drug delivery system

The manufacturing process of the microspherical drug delivery system is shown in Fig.

As shown in Fig. 2, polylactide-co-glycolide (PLGA) having a molecular weight of 33,000 g / mol was dissolved in a 9: 1 mixed solution of ethyl acetate and dimethyl sulfoxide in an amount of 3 wt% Cyclodextrin was dissolved in an amount of 0.5% by weight and dexamethasone was dissolved in an amount of 0.3% by weight to prepare a drug dispersion solution. The solution was poured into a 30 ml syringe and then poured into a single-axis sonicator at a flow rate of 4 ml / min. An aqueous solution of polyvinyl alcohol (PVA) as an aqueous 1 wt% solution was prepared, and the prepared polymer and drug dispersion solution was sprayed at a vibration frequency of 60 Hz and dispersed in the polyvinyl alcohol aqueous solution to form microspheres. Thereafter, the mixture was stirred at room temperature for 2 hours at 400 rpm for stabilization. Then, the resulting microspheres were separated, washed with distilled water and lyophilized to obtain a drug-containing microparticle drug carrier. The surface of the obtained drug delivery vehicle was observed under a microscope and is shown in Fig.

Manufacturing example  2. Single axis  Using an ultrasonic sprayer Curcumin  Containing γ-cyclodextrin / PLGA Microparticle  Preparation of drug delivery system

As shown in Fig. 2, polylactide-co-glycolide (PLGA) having a molecular weight of 33,000 g / mol was dissolved in a 9: 1 mixed solution of ethyl acetate and dimethyl sulfoxide in an amount of 3 wt% (Gamma-cyclodextrin) was dissolved in an amount of 0.5% by weight and Curcumin was dissolved in an amount of 0.3% by weight to prepare a drug dispersion solution. The solution was poured into a 30 ml syringe and then poured into a single-axis sonicator at a flow rate of 4 ml / min. An aqueous solution of polyvinyl alcohol (PVA) which is an aqueous 0.5 wt% solution was prepared, and the prepared polymer and drug dispersion solution was sprayed at a vibration frequency of 60 Hz and dispersed in the polyvinyl alcohol aqueous solution to form microspheres. Thereafter, the mixture was stirred at room temperature for 2 hours at 400 rpm for stabilization. Then, the resulting microspheres were separated, washed with distilled water and lyophilized to obtain a drug-containing microparticle drug carrier. The resulting drug delivery system was observed under a microscope and a fluorescence microscope, which is shown in FIG. At this time, (a) is a surface, (b) is a fluorescence photograph, and (c) is a photograph combining (a) and (b).

Manufacturing example  3. Single axis  Using an ultrasonic sprayer Curcumin  Starch / PLGA Microparticle  Preparation of drug delivery system

As shown in FIG. 2, polylactide-co-glycolide (PLGA) having a molecular weight of 33,000 g / mol was dissolved in ethyl acetate in an amount of 3% by weight and curcumin was dissolved in 0.3% (Starch) was dissolved in 0.5% by weight of dimethylsulfoxide. The solution was put into a 5 ml syringe, and the solution was passed through a syringe at a flow rate of 0.3 ml / min. It was poured into a single-axis ultrasonic sprayer. An aqueous solution of polyvinyl alcohol (PVA) which is a 2 wt% aqueous solution was prepared, and the prepared polymer and drug dispersion solution was sprayed at a vibration frequency of 60 Hz and dispersed in the polyvinyl alcohol aqueous solution to form microparticles. Thereafter, the mixture was stirred at room temperature for 2 hours at 400 rpm for stabilization. Then, the resulting microspheres were separated, washed with distilled water and lyophilized to obtain a drug-containing microparticle drug carrier. The obtained drug carrier was observed under a microscope and a fluorescence microscope, and it is shown in Fig. At this time, (a) is a surface, (b) is a fluorescence photograph, and (c) is a photograph combining (a) and (b).

Manufacturing example  4 to 6. Mold  Manufacture of a wafer type drug delivery system

The manufacturing process of the wafer type drug delivery device is shown in Fig.

6, polylactide-co-glycolide (PLGA) having a molecular weight of 33,000 g / mol, starch as a saliva sensitive polymer and dexamethasone were physically mixed and then mixed into the reagent in 3 mm molded by using a press pressure of 5 seconds was added to 60 kg _f / cm ² pressure to prepare a wafer-type drug delivery system. The content ratios of the components are shown in Table 1 below.

Constituent Production Example 4 Production Example 5 Production Example 6 PLGA 2 2 2 Starch 0.5 One 2 Dexamethasone 0.1 0.1 0.1

The prepared drug carriers are shown in Figs. 7A to 7C, respectively.

Manufacturing example  7 to 9. Preparation of Film-like Drug Delivery System Using Solvent Casting Method

After dissolving polylactide-co-glycolide (PLGA) having a molecular weight of 33,000 g / mol, starch starch and dexamethasone as a saliva sensitive polymer in methyl chloride (MC) And the solvent was evaporated at 4 DEG C to prepare a film having a diameter of 6 mm. The content ratios of the components are shown in Table 2 below.

Constituent Production Example 7 Production Example 8 Production Example 9 PLGA 2 2 2 Starch 0.5 One 2 Dexamethasone 0.1 0.1 0.1

The prepared drug carriers are shown in Figs. 8A to 8C, respectively.

Manufacturing example  10. MPEG- PCL Injectable Hydrogel  Preparation of drug delivery system

(MPEG) -polycaprolactone (PCL) block copolymer having a molecular weight of 3,150 g / mole was synthesized to prepare an injectable hydrogel. First, methoxypolyethylene glycol (1.5 g, 2 mmol, Mn = 750 g / mole) as an initiator and 80 ml of toluene were placed in a well-dried 100 ml round-bottomed flask and subjected to azeotropic distillation Respectively. Then, the methoxypolyethylene glycol-polycaprolactone (MPEG-PCL) block copolymer was completely dissolved in a phosphate buffer solution (PBS, pH 7.4) at a concentration of 20% by weight, and then, to maintain the equilibrium of the uniformly dispersed polymer, Gt; C < / RTI > for one day to prepare a hydrogel. Thereafter, 0.5% by weight of starch / PLGA microcapsules containing curcumin and gamma-cyclodextrin as a saliva sensitive polymer prepared in Preparation Example 3 were mixed to prepare an injectable hydrogel drug carrier . The injectable hydrogel drug carrier prepared as described above was subcutaneously injected into SD-rat to confirm gel formation. The results are shown in FIG.

As shown in FIG. 9, it was confirmed that when the hydrogel was injected, gel was formed in the body within a few seconds.

Experimental Example  1. A wafer-type drug delivery system On amylase  Drug Release Experiment by

The wafers prepared in Preparation Examples 4 and 6 were suspended in 4 ml of PBS to confirm the drug release, and 0.5 ml of the drug release solution was collected at each hour, mixed with ACN at a ratio of 1: 1, Were measured. The time for collecting the solution was 1 hour, 2 hours, 4 hours, 8 hours, 20 hours, 40 hours, 60 hours, 5 days, 7 days, 12 days, 17 days, 22 days, 27 days And the release of the drug was confirmed by measuring at a wavelength of 242 nm in a mobile phase solvent of ACN: PBS = 50:50 ratio.

In addition, the wafer type drug carrier prepared in Production Examples 4 and 6 was suspended in 4 ml of PBS solution containing amylase at a concentration of 125 U / ml to confirm drug release, and then the floating wafer was assayed for drug release amount This is shown in FIG.

As shown in FIG. 10, the drug delivery system of the present invention increased the drug release amount in the solution containing amylase, and the drug release amount was also increased when the starch content in the drug delivery system was high.

Experimental Example  2. Film-type drug delivery system On amylase  Drug Release Experiment by

The films prepared in Preparative Examples 7 and 9 were suspended in 4 ml of PBS to confirm drug release, and then the amount of drug released was determined by the same method as in Experimental Example 1.

The film-like drug delivery vehicle prepared in Preparation Examples 7 and 9 was suspended in 4 ml of PBS containing amylase at a concentration of 125 U / ml to confirm release of the drug, and then the suspended film was measured for drug release Was determined according to the starch content. The results are shown in Fig.

As shown in FIG. 11, the film-type drug delivery vehicle of the present invention showed an increase in drug release amount in a solution containing amylase, and the drug release amount was also increased when the starch content in the drug delivery vehicle was high.

As described above, the drug delivery system of the present invention according to the present invention includes the saliva sensitive polymer, thereby being disintegrated in the oral cavity by the enzyme contained in the saliva. Therefore, it is possible to efficiently deliver the drug into the oral cavity, Can be used as a drug delivery system for preventing or treating oral diseases.

Claims (10)

Polylactide-co-glycolide (PLGA), a saliva sensitive polymer, and a therapeutic agent for oral diseases;
The salivating responsive polymer is starch or gamma-cyclodextrin;
The saliva responsive polymer is 0.5 to 2 parts by weight based on 2 parts by weight of the PLGA;
Wherein the carrier is of wafer type or film type.
delete delete The drug delivery system according to claim 1, wherein the saliva comprises amylase.
delete delete The oral therapeutic agent according to claim 1, wherein the therapeutic agent for oral diseases is at least one selected from the group consisting of an antioxidant, an anti-cancer agent, an immunosuppressant, an angiogenesis inhibitor, a vitamin, a protein or a peptide drug, an analgesic agent and an anti- ≪ / RTI >
The method of claim 7, wherein the oral disease is selected from the group consisting of dry mouth, stomatitis, inflammation around the gums and teeth, dental acidosis, dental caries, gangrene gangrene, salivary glands, Wherein the drug delivery system comprises at least one selected from the group consisting of:
delete The drug delivery system according to claim 1, wherein the drug delivery vehicle is disintegrated in the oral cavity.

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