Title:  Locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis and process for preparation thereof

United States Patent:  6,193,994

Assignee:  Samyang Corporation (KR)

Filed:  March 4, 1999

PCT NO:  PCT/KR97/00093

102(e) Date:  March 4, 1999

PCT PUB. Date:  November 27, 1997

Foreign Application Priority Data:  May 23, 1996[KR] (96-17798); May 23, 1996[KR] (96-17799)

This invention relates to locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis and process for preparation thereof, which can show continuous drug effect for a long time by controlling the release time and by making the drug remain in the periodontal pocket for a prolonged time. The composition is prepared by i) making a microsphere containing the physiologically active substance, ii) making the mixture of the microspheres and water-soluble polymer such as polysaccharides iii) making the mixture into the form of film or strip or/and iv) coating the film or strip with a cation aqueous solution such as calcium and barium. The present pharmaceutical composition can be easily administered using forceps, has minimized side effects and maximizes the effect by releasing the active substance at the minimum dose, and make the patients feel comfortable.

DETAILED DESCRIPTION OF THE INVENTION

The physiologically active substance of the present invention which can be used for treating periodontitis contains antibiotics, local anesthetics antiinflammatory analgesics, and steroid hormones. Antibiotics which can be used in the present invention contain ampicillin, amoxicillin, erythromycin, tetracycline, minocycline, oxytetracycline, doxycycline, metronidazol, bacitracin, kitasamycin, spiramycin, ornidazole, and salts thereof, which are used generally to treat periodontitis, and local anesthetics which can be used in the present invention contain lidocaine, procaine, dibucaine, and benzocaine, antiinflammatory analgesics which can be used in the present invention contain diclofenac, flubiprofen, ibuprofen, ketoprofen, aspirin, mefenamic acid and acetaminophen, and steroid hormones which can be used in the present invention contain dexamethasone, triamcinolone acetonide, hydrocortisone and epihydrocortisone.

Biodegradable polymers used in preparing the microsphere of the present invention are polymers of the derivatives of .alpha.-hydroxy-carboxylic acid, for example, polymers of glycolic acid(PGA), polymers of lactic acid(PLA), and copolymers of lactic acid and glycolic acid(PLGA) which can be hydrolyzed into water and carbon dioxide which are not harmful to human body.

The molecular weight of these polymers have an important effect on the period of drug release and degradation of the microspheres.

When we use a polymer group of PLA, PGA and PLGA, the more the molecular weight increases, the longer the drug release time as well as degradation of the polymers occurs. The release time and degradation of the polymers is postponed when the ratio of lactic acid increased in the use of PLGA copolymer.

If we make use of this property, we can control the releasing time of microspheres. Therefore when the releasing time is determined as two weeks to treat periodontitis, the desirable range of molecular weight is 4,000 to 50,000, and the more desirable range is 5,000 to 15,000. In order to administer the various kinds of drugs simultaneously, we can make microspheres using polymers of different molecular weight, and each microspere will show the independent release pattern.

The inventors invented a pharmaceutical composition in the form of film or strip made up of the mixture of the microspheres and wafer-soluble polymer hydrogel in order to administer an active substance quantitatively into the periodontal pocket. In other words, if the microspheres can be maintained in their original form in the film or strip made up of the mixture of microspheres and water-soluble polymer, the quantity of the microsphere in the film or strip can be calculated and the quantity of administered drug into the periodontal pocket can be determined by the mixture ratio of the microspheres and water-soluble polymer, and quantitative administration can be possible.

The desirable water-soluble polymer used in the pharmaceutical composition of the present invention should be harmless to human body and viscous in the aqueous solution, and easy to be formed into the film or strip after drying. These contain the polysaccharides such as pectin, carrageenan, gelan, sodium alginate or chitosan.

In the present invention, if we coat the above-mentioned film or strip with the aqueous solution of cation such as calcium and barium, it is possible to delay the disintegrating time.

That is, if film or strip without coating is administered into the periodontal pocket, it swells so feast on contacting with saliva or gingival crevice fluid that a part of the film or strip can be cut of the periodontal pocket, and there is a large opportunity to lose the part of the film or strip, and to decrease the amount of an active substance in the periodontal pocket, and we can not have a desirable treatment effect, because the dosage is practically diminished with respect to the amount delivered to the periodontal pocket. To solve this problem, the present inventors invented the pharmaceutical composition using a complex of the polysaccharides and metal ion.

When water-soluble polymer such as polysaccharides forms complex with the metal ion, its solubility to the water decreases and the rate of the swelling gets slow. Therefore, in the early stage of the administration, the possibility of the loss of the film or strip disappears, and the administered drug remains in the periodontal pocket more safely.

Since the solubility to the water and swelling rate of the complex make up of the polysaccharides and metal depend on the kinds of the metal cation, we can choose a proper metal ion considering the treatment period, etc.

The desirable cation salt may contain cation chlorides, such as calcium chloride, magnesium chloride, barium chloride, and aluminum chloride.

Especially calcium chloride is suitable to the formulation which is hydrated by saliva or gingival crevice fluid in the short time, 3 to 6 hrs, and barium chloride is suitable to the pharmaceutical formulation for longer time, one week to two weeks.

It is possible to make film or strip coated with cation aqueous solution utilizing a simple step such as spray-coating when we use polysaccharides.

It is found that different formulations have their has own disintegration time. The formulation which is not combined with metal ion maintains its original shape in the periodontal pocket only for two hours, calcium-polysaccharides for 3 to 6 hrs, and barium-polysaccharides for more than one week. When the formulation is disintegrated, only the microspheres remain in the periodontal pocket, and release an active substance continuously.

Therefore, in the present invention it is possible to administer an active substance into the periodontal pocket quantitatively by using film or strip made up of polysaccharides and microspheres, and it is possible to control the maintenance of the film or strip in the periodontal pocket by controlling the disintegration time by coating the film or strip with aqueous solution of cation salt.

The following explains the process for preparing the locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis,

1) the step of making microspheres, by dissolving a biodegradable polymer such as PLA or PLGA in methylene chloride, by suspending a finely-powdered active substance, and by emulsifying the suspended solution in an aqueous solution containing a surfactant,

2) the step of making hydrogel, by mixing microspheres and polysaccharides and by adding distilled water,

3) the step of foming into film or strip.

In addition, another process for preparing locally administrable, biodegradable and sustained-release pharmaceutical composition includes step

4) for coating the film or strip with aqueous solution of cation salt in addition to the above-mentioned step i.), step 2), and step 3).

The process for preparing the locally administrable, biodegradable pharmaceutical composition for periodontitis will be explained by steps in detail in the following.

I. Step 1

The microspheres used in the present invention are prepared by the process which is in applied for patent by the present inventors' Korean patent No. 95-10671, on which the priority of the present invention is based.

Microspheres which contain more than 20 weight % of an active substance and release the active substance at the effective concentration and within 2 weeks are made as the following.

First of all, in the case that an active substance is water-soluble, we crushed the substance into the average diameter below 5 .mu.m by using a Jet-mill. In the case of organic-soluble substances, this process is not necessary.

We mixed biodegradable polymer, PLA or PLGA, with the active substance in the proper ratio, addition of methylene chloride into it, and the mixutre is mixed well, followed by cooling down below 20^oC.

After emulsifying the polymer solution by addition to aqueous polyvinyl alcohol was precooled below 5^oC., the emulsion is diluted with distilled water. Finally, methylene chloride is evaporated to achieve our goal was mentioned above. When we made microspheres according to the above method using D, L-PLA whose molecular weight is 6,500 to 8,000, the release of active substance was completed within 2 weeks.

When we used PLGA whose molecular weight is 8,000 to 10,000 the release of substance was accomplished within 2 weeks also. The desirable amount of active substance contained in the microspheres is about 10 to 30 weight %. Especially 20 to 25 weight % is more desirable.

In addition, the particle size of microspheres have important effect on the drug content and the rate of the drug release. The average particle size which can be used is 1 to 500 .mu.m, and 10 to 200 .mu.m is desirable, and 20 to 150 .mu.m is more desirable.

It is desirable that the microspheres release the active substance continuously for more than 7 days and less than 20 days.

II. Step 2

The process for mixing polysaccharide and microspheres will be explained in the following.

First of all, we mixed sustained-release microspheres containing the active substance and polysaccharides. At this time the mixing ratio is the important factor not only on the administration volume of the formulation, but also on the extent of loss of microspheres from the periodontal pocket due to increased volume as polysaccharide is swollen. Therefore, it is desirable to use polysaccharide as little as possible, and it is desirable that the ratio of polysaccharide to the total mixed pharmaceutical composition is 5 to 50 weight %, and more desirable is 5 to 30 weight %.

Then we added distilled water to the above mixture and made hydrogel of polysaccharide in which microspherses are suspended. The concentration of polysaccharide, that is, the quantity of the added distilled a very important factor, when we make film or strip. If the quantity of the added distilled water is too large, it is difficult to form film or strip, and if the quantity of the added distilled water is too small, it is difficult to make film or strip containing an active substance homogeneously because it is difficult to disperse microspheres in the hydrogel evenly. Thus, considering the above factors, it is desirable to add the distilled water enough to make hydrogel which contains polysaccharide below 50 weight %, and it is more desirable to make hydrogel which contains polysaccharide at the ratio of 1 to 20 weight %.

III. Step 3

In order to insert the above hydrogel into the periodontal pocket, it is formed into the film or strip as the following.

First, hydrogel is put and flattened on an acryl board or metal board, and then covered with a polyester film coated with silicon, and compressed with a roller to even the thickness, and then polyester film is removed, and dried in the air. The resultant film is cut into the proper size to insert it into periodontal pocket. We can make strip by another method wherein the above water-soluble polymer hydrogel is put in a frame and compressed. On making film or strip, we determine the thickness of the film or strip considering the size of the periodontal pocket. The desirable thickness of the film or strip is below 2 mm, and the more desirable thickness is 0.1 to 1.0 mm. The desirable example of the pharmaceutical composition is 6 mm-2 mm in width and 0.1 to 2 mm in thickness are wedge type in the shape.

IV. Step 4

To increase the maintenance of the formulation in the periodontal pocket, it is desirable to decrease the viscosity after hydration and to the disintegration time by coating film or strip with aqueous solution of cation salt. The desirable cation salt contains calcium chloride, magnesium chloride, barium chloride and aluminum chloride, and especially calcium chloride is suitable to the pharmaceutical composition of the present invention which is hydrated by saliva or gigival crevice fluid in 3 to 6 hrs, and barium chloride is suitable to the compositions which can be maintained for 1 to 2 weeks.

The desirable concentration of 2(II) or 3(III) cation aqueous solution is 1 to 10%, and 2 to 5% is more desirable.

There are two kinds of coating methods. One is to coat film or strip by soaking it in aqueous solution of cation and the other is to coat the film or strip by spraying the aqueous solution of cation. The latter is more desirable.

The pharmaceutical composition for periodontitis of the present invention is inserted into the periodontal pocket, and polysaccharide is hydrated by saliva and dissolved, and only the biodegradable microspheres remain in the periodontal pocket and release the active substance for 1 to 2 weeks.

Because the present invention is for local administration, we formulate with the minimum dosage for the periodontal pocket. Consequently one can minimize the side effect which can be accompanied when one administers an excess amount for extended time.

And because the pharmaceutical composition contains sustained-release microsphere, administering effect of single dose can last for two weeks. In addition, because the form of pharmaceuticalcomposition is film or strip, we can administer the drug with forceps conveniently, and because the composition consists of biodegradable substance, there is no need to remove the remnant after the release of an active substance is completed.

And by coating the drug with 2(II) cation chloride aqueous solution, the pharmaceutical composition of the present invention can remain in the periodontal pocket more safely.

Claim 1 of 8 Claims

What is claimed is:

1. A locally administrable, biodegradable and sustained-release delivery system for treatment of periodontitis comprising:

A) microspheres releasing therapeutically active substances for treating periodontitis which comprises:

1) active substance in an amount of more than 20 weight % of the microsphere,

2) biodegradable polymer selected from the group consisting of polylactic acid and poly(lactic-co-glycolic) acid whose weight average molecular weight is in the range of 4,000 to 50,000; and

B) bivalent metal ion complex of polysaccharides selected from the group consisting of pectin, carrageenan, gellan gum, sodium alginate and chitosan,

wherein the release of the active substance is determined by said microspheres and is not affected by polysaccharide which is used as a supporter or a binder of the microspheres and has a property of disintegrating slowly in accordance with substituting the complexed bivalent metal ion with monovalent metal ion abundant in body fluid.

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