CA2253980C - Locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis and process for preparation thereof - Google Patents
Locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis and process for preparation thereof Download PDFInfo
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- CA2253980C CA2253980C CA002253980A CA2253980A CA2253980C CA 2253980 C CA2253980 C CA 2253980C CA 002253980 A CA002253980 A CA 002253980A CA 2253980 A CA2253980 A CA 2253980A CA 2253980 C CA2253980 C CA 2253980C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0063—Periodont
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
Abstract
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 ration 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 makes the patients feel comfortable.
Description
Title of Invention Locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis and process for preparation thereof Background of the Invention This invention relates to locally administrable, biodegradable and sustained-release pharmaceutical compositions for periodontitis, and its 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 wherein they are prepared by i) making a microsphere containing the physiologically active substance, ii) making a 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 aqueous solution of cation such as calcium and barium chlorides.
Periodontitis is an inflammation of the teeth supporting tissue caused by bacterial toxin, which is a metabolizing product of oral bacteria. If periodontitis in the initial stage that is gingivitis is not treated properly, it will develop into severe periodontitis with swelling gingiva, bleeding and bad breath. If periodontitis goes on, the collagen supporting the periodontal membrane is destroyed, and alveolar bone under the teeth is resolved. As a result, periodontal ligament is separated, and a periodontal pocket is formed, and in severe cases, it will develop into advanced periodontal disease which can lead to loss of teeth. Most of the germs causing periodontitis are anaerobic gram-negative bacteria, and they secrete collagenase which destroy ligament that is connective tissue of the periodontal membrane, and metabolite from above reaction cause periodontitis.
For prevention and treatment of the advanced periodontal disease, removal of the plaque in the periodontal pocket is essential. The methods for removal of the bacterial plaque can be divided into apparatotherapy and chemotherapy. Apparatotherapies include scaling and root planing, and require the patient's ability to control plaque continuously, but have the disadvantage that apparatotherapies have a limited effect on the part at which it is difficult to brush teeth due to anatomical reason. For supplement of the above disadvantagE: of apparatotherapies, the plaque control using chemotherapies has been studied and it is reported that chemotherapies are very effective on the removal of bacteria which live in the deep part where instruments are diffic;ult to reach.
The most important thing in the clinical use is to retain the effective concentration of the active substance which control plaque in the bacterial invasion site for a long time without side-effect. The examples of chemical method include irrigating the invaded region with an antibiotic solution, and administering antibiotics systemically. It is known that local administration of antibiotics has a limited effect on the removal of the bacteria causing periodontal disease because antibiotics cannot reach the deep part of the subgingival area or cannot last for enough time. It is reported that the systemic administration is effective on the treatment for the periodontal disease, but in the case of the systemic administration in order to maintain the effective concentration at the infected region it is required that a large dosage of medicine is administered and subsequently side effects result, for example, the appearance of resistant bacteria and undesired action to intestinal bacteria. Therefore, to overcome this defect, the research :for the direct administration into the periodontal pocket has been conducted, and it is reported that if tetracycline is administrated locally, only 1/1000 dosage oaf the systemic administration can bring the same effect (Goodson, J.M. et al., J.
Periodontol, 56 265-272, 1985).
In order to bring the maximum effect and minimum side-effect, it has been attempted to develop the local drug delivery system using the controlled release system of physiologically active substances such as antibiotics.
There are a fE:w problems that must be solved to treat the periodontitis by a local drug delivery system.
First, a carrier is necessary to transport a physiologically active substance such as antibiotics to the periodontal pocket. A large number of carriers developed so far are substances not absorbed biologically, which must be removed after the drug is released completely and if not, they irritate the periodontal tissue and inhibit the regeneration of the periodontal tissue.
According to U.~. Patent 5,599,553, it is L
reported that a pharmaceutical preparation composed of minocycline HC1 and polycaprolactone in the form of strip can release thE; active substance for 7 days in the periodontal pocket. In this case polycaprolactone must be removed after the drug is released completely because it takes too long a time to be decomposed in the body.
Second, to treat the periodontitis, effective concentration of the active substance in the periodontal pocket must be maintained for a long time. It is reported that to treat the periodontitis the effective concentration of antibiotics such as minocycline HC1 must be maintained far at least 7 to 10 days (Lawter J.
R. et al, Int. sym. cont. Rel, Bioact. Mater. , 230-31, 1990). It is reported that the therapeutic agent should be retained as long as possible because dental disease is generally chronic (Friedman M. et al., Pharmaceutical Research, Vol. 7, No. 4, 313 - 317, 1990). In addition, it is known that, if administered orally, administration for more than two weeks is effective for the treatment for periodontitis (Lilijenberg B et al., J. Clin.
periodontol., 7, 48-6.1, 1980).
According to U.S. Patent 4,933,182, a pharmaceutical prep~jration wherein polymeric microparticles containing one or more substances is dispersed into the continuous phase of water soluble polymer. This has an advantage that it can release substance in an independent pattern and it does not give an unpleasant feeling to the patients, but it has disadvantage that administration should be made often because the release of substance is completed in about 6 hours.
Third, it is needed that the process of administration is convenient and quantitative on the basis of the amount of active substance.
According to U.S. Patent 4,175,326, a pharmaceutical preparation containing the active substance in a hollow fiber device made up of cellulose acetate is reported. In order to administer this preparation into the periodontal pocket, fiber should be cut into the length ~Eor the dosage, and then the cut fiber must be coiled around the teeth, and then it must be administered in the way of pushing it into the periodontal pocket. 'This method has disadvantage that it is inconvenient to administer drug into the periodontal pocket quantitatively.
According to 'WO A1 92/07555 and U.S. Patent 5,324,520, an in situ gel has been reported which is in a liquid state before administration and becomes a little hardened states after administration. Because the formulations are in a liquid state before administration, a special administering tool is needed in the form of a syringe and these formulations also have disadvantage that it is inconvenient to administer quantitatively.
In order to satisfy the most important things for treating the periodontitis, that is to say, biodegradation and continuous drug release, microspheres made up of biodegradable polymer has been provided which is dissolved when it is administered into the periodontal pocket and releases drug continuously. For example, it is reported that they suspended PLGA microspheres including tetracycline in Pluronic* F 127 gel and then inserted the prepared formulation in the periodontal pocket (EP Al 244118). In addition, it is reported that they can maintain the effective concentration in the periodontal pocket for 14 days by inserting microsphere containing minocycline and PLGA (Lawter J.R. et al., Int. Symp. Cont.
Rel. Bioact. Mater., :?30 - 231, 1990), and filed a patent application therefor. The formulation for treating periodontitis using such biodegradable microspheres can retain the effective drug concentration in the periodontal pocket for a long timE: by single dose, and the feeling * Trademark of foreign substance does not exist because the formulation was prepared by microparticle, and there is no need to remove after treatment because the formulation is biodegradable. However, since microspheres prepared in the form of gel can not last for a long time due to its hydrolytic property, there is inconvenience that it should be prepared just before use, and that a special administering tool is needed in order to insert gel into the periodontal pocket. And it is difficult to administer quantitatively and accurately when we insert the microspheres directly into the periodontal pocket.
Therefore, in order to develop ideal formulations for periodontitis, its is desirable that a biodegradable substance is used to control drug release, the effective drug concentration is maintained continuously and the administration is convenient for patients.
The present inventors have been conducted the continuous study for the ideal formulation for periodontitis, and wE: found that if the biodegradable microspheres containing physiologically active substance for periodontitis is mixed with the hydrogel of water soluble polymer and then the mixture is made into the form of thin film or strip, and this film or strip is inserted into the periodontal pocket, it will show the continuous effect fo:r a long time, since water soluble polymer is decomposed slowly, on contacting saliva and the gingival crevice fluid, and subsequently only the microspheres became left alone in the periodontal pocket and these microspheres release the active substance continuously. In addition, the inventors discovered that when the film or strip is spray-coated with aqueous solution of cation salt such as Ca2+ or ga2+
disintegration time can be controlled effectively.
Summary of the Invention The present invention relates to the locally administrable, biodegradable, and sustained-release pharmaceutical compositions and process for preparation thereof.
More specifically, the present invention provides composition in the foam of thin film or strip composed of microspheres made with biodegradable polymer and water-soluble polymer such as polysaccharides.
And the present invention provides a composition composed of the above thin film or strip coated with cation salt aqueous solution.
Periodontitis is an inflammation of the teeth supporting tissue caused by bacterial toxin, which is a metabolizing product of oral bacteria. If periodontitis in the initial stage that is gingivitis is not treated properly, it will develop into severe periodontitis with swelling gingiva, bleeding and bad breath. If periodontitis goes on, the collagen supporting the periodontal membrane is destroyed, and alveolar bone under the teeth is resolved. As a result, periodontal ligament is separated, and a periodontal pocket is formed, and in severe cases, it will develop into advanced periodontal disease which can lead to loss of teeth. Most of the germs causing periodontitis are anaerobic gram-negative bacteria, and they secrete collagenase which destroy ligament that is connective tissue of the periodontal membrane, and metabolite from above reaction cause periodontitis.
For prevention and treatment of the advanced periodontal disease, removal of the plaque in the periodontal pocket is essential. The methods for removal of the bacterial plaque can be divided into apparatotherapy and chemotherapy. Apparatotherapies include scaling and root planing, and require the patient's ability to control plaque continuously, but have the disadvantage that apparatotherapies have a limited effect on the part at which it is difficult to brush teeth due to anatomical reason. For supplement of the above disadvantagE: of apparatotherapies, the plaque control using chemotherapies has been studied and it is reported that chemotherapies are very effective on the removal of bacteria which live in the deep part where instruments are diffic;ult to reach.
The most important thing in the clinical use is to retain the effective concentration of the active substance which control plaque in the bacterial invasion site for a long time without side-effect. The examples of chemical method include irrigating the invaded region with an antibiotic solution, and administering antibiotics systemically. It is known that local administration of antibiotics has a limited effect on the removal of the bacteria causing periodontal disease because antibiotics cannot reach the deep part of the subgingival area or cannot last for enough time. It is reported that the systemic administration is effective on the treatment for the periodontal disease, but in the case of the systemic administration in order to maintain the effective concentration at the infected region it is required that a large dosage of medicine is administered and subsequently side effects result, for example, the appearance of resistant bacteria and undesired action to intestinal bacteria. Therefore, to overcome this defect, the research :for the direct administration into the periodontal pocket has been conducted, and it is reported that if tetracycline is administrated locally, only 1/1000 dosage oaf the systemic administration can bring the same effect (Goodson, J.M. et al., J.
Periodontol, 56 265-272, 1985).
In order to bring the maximum effect and minimum side-effect, it has been attempted to develop the local drug delivery system using the controlled release system of physiologically active substances such as antibiotics.
There are a fE:w problems that must be solved to treat the periodontitis by a local drug delivery system.
First, a carrier is necessary to transport a physiologically active substance such as antibiotics to the periodontal pocket. A large number of carriers developed so far are substances not absorbed biologically, which must be removed after the drug is released completely and if not, they irritate the periodontal tissue and inhibit the regeneration of the periodontal tissue.
According to U.~. Patent 5,599,553, it is L
reported that a pharmaceutical preparation composed of minocycline HC1 and polycaprolactone in the form of strip can release thE; active substance for 7 days in the periodontal pocket. In this case polycaprolactone must be removed after the drug is released completely because it takes too long a time to be decomposed in the body.
Second, to treat the periodontitis, effective concentration of the active substance in the periodontal pocket must be maintained for a long time. It is reported that to treat the periodontitis the effective concentration of antibiotics such as minocycline HC1 must be maintained far at least 7 to 10 days (Lawter J.
R. et al, Int. sym. cont. Rel, Bioact. Mater. , 230-31, 1990). It is reported that the therapeutic agent should be retained as long as possible because dental disease is generally chronic (Friedman M. et al., Pharmaceutical Research, Vol. 7, No. 4, 313 - 317, 1990). In addition, it is known that, if administered orally, administration for more than two weeks is effective for the treatment for periodontitis (Lilijenberg B et al., J. Clin.
periodontol., 7, 48-6.1, 1980).
According to U.S. Patent 4,933,182, a pharmaceutical prep~jration wherein polymeric microparticles containing one or more substances is dispersed into the continuous phase of water soluble polymer. This has an advantage that it can release substance in an independent pattern and it does not give an unpleasant feeling to the patients, but it has disadvantage that administration should be made often because the release of substance is completed in about 6 hours.
Third, it is needed that the process of administration is convenient and quantitative on the basis of the amount of active substance.
According to U.S. Patent 4,175,326, a pharmaceutical preparation containing the active substance in a hollow fiber device made up of cellulose acetate is reported. In order to administer this preparation into the periodontal pocket, fiber should be cut into the length ~Eor the dosage, and then the cut fiber must be coiled around the teeth, and then it must be administered in the way of pushing it into the periodontal pocket. 'This method has disadvantage that it is inconvenient to administer drug into the periodontal pocket quantitatively.
According to 'WO A1 92/07555 and U.S. Patent 5,324,520, an in situ gel has been reported which is in a liquid state before administration and becomes a little hardened states after administration. Because the formulations are in a liquid state before administration, a special administering tool is needed in the form of a syringe and these formulations also have disadvantage that it is inconvenient to administer quantitatively.
In order to satisfy the most important things for treating the periodontitis, that is to say, biodegradation and continuous drug release, microspheres made up of biodegradable polymer has been provided which is dissolved when it is administered into the periodontal pocket and releases drug continuously. For example, it is reported that they suspended PLGA microspheres including tetracycline in Pluronic* F 127 gel and then inserted the prepared formulation in the periodontal pocket (EP Al 244118). In addition, it is reported that they can maintain the effective concentration in the periodontal pocket for 14 days by inserting microsphere containing minocycline and PLGA (Lawter J.R. et al., Int. Symp. Cont.
Rel. Bioact. Mater., :?30 - 231, 1990), and filed a patent application therefor. The formulation for treating periodontitis using such biodegradable microspheres can retain the effective drug concentration in the periodontal pocket for a long timE: by single dose, and the feeling * Trademark of foreign substance does not exist because the formulation was prepared by microparticle, and there is no need to remove after treatment because the formulation is biodegradable. However, since microspheres prepared in the form of gel can not last for a long time due to its hydrolytic property, there is inconvenience that it should be prepared just before use, and that a special administering tool is needed in order to insert gel into the periodontal pocket. And it is difficult to administer quantitatively and accurately when we insert the microspheres directly into the periodontal pocket.
Therefore, in order to develop ideal formulations for periodontitis, its is desirable that a biodegradable substance is used to control drug release, the effective drug concentration is maintained continuously and the administration is convenient for patients.
The present inventors have been conducted the continuous study for the ideal formulation for periodontitis, and wE: found that if the biodegradable microspheres containing physiologically active substance for periodontitis is mixed with the hydrogel of water soluble polymer and then the mixture is made into the form of thin film or strip, and this film or strip is inserted into the periodontal pocket, it will show the continuous effect fo:r a long time, since water soluble polymer is decomposed slowly, on contacting saliva and the gingival crevice fluid, and subsequently only the microspheres became left alone in the periodontal pocket and these microspheres release the active substance continuously. In addition, the inventors discovered that when the film or strip is spray-coated with aqueous solution of cation salt such as Ca2+ or ga2+
disintegration time can be controlled effectively.
Summary of the Invention The present invention relates to the locally administrable, biodegradable, and sustained-release pharmaceutical compositions and process for preparation thereof.
More specifically, the present invention provides composition in the foam of thin film or strip composed of microspheres made with biodegradable polymer and water-soluble polymer such as polysaccharides.
And the present invention provides a composition composed of the above thin film or strip coated with cation salt aqueous solution.
In addition, the present invention provides a process for preparing a composition comprising the steps, 1) making the biodegradable microspheres containing the biologically active substance, 2) mixing the microsphere and water-soluble polymer such as polysaccharides, 3) making the mixture into the form of thin film or strip.
The present invention provides process for preparing composition comprising the step of coating the film or strip with metal cation aqueous solution in addition to the above-mentioned process.
Brief Description of 'The Drawings In the accompanying figures:
Fig. 1 is indices of plaque comparing control group with those of experimental group;
Fig. 2 is indices of gingiva comparing control group with those of experimental group;
Fig. 3 is pocket depth comparing control group with those of experimental group;
Fig. 4 is indices of bleeding comparing control group with those of experimental group;
Fig. 5 represents the variation of ratio of cocci, non-motile rod, motile rod and spirochete in the control group;
Fig. 6 represents the variation of ratio of c:occi, non-motile rod, motile rod and spirochete in the experimental group;
Fig. 7 is CFU of black-pigmented bacteroide in control vs experimental group;
Fig. 8 is CFU in control vs experimental group cultured on aerobic blood agar plate;
Fig. 9 is CFU in control vs experimental group cultured on anaerobic blood agar plate;
Detailed Description of the Invention The physiologically active substance of the present invention which can be used for treating periodontitis contains antibiotics, local anesthetics anti-inflammatory 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, anti-inflammatory 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 ~-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 microsphere 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 water-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 i.s administered into the periodontal pocket, it swells so fast on contacting with saliva or gingival crevice fluid that a part of the film or strip can be out 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, et:c.
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 formulatian 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 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 forming 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 ration salt in addition to the above-mentioned step 1), step 2) and step 3).
The process for preparing the locally administrable, biodegradable pharmaceutic al 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, and 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 Jum 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 mixture is mixed well followed by cooling down below 20oC.
After emulsifying the polymer solution by addition to aqueous polyvinyl alcohol which was precooled below 5°C, the emulsion is diluted with distilled water. Finally, methylene chloride is evaporated to achieve our goal which 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 550 um, and 10 to 200 um is desirable, and 20 to 150 um 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 p, and more desirable is 5 to 30 weight %.
Then we added distilled water to the above mixture and made hydrogel of polysaccharide in which microspheres are suspended. The concentration of polysaccharide, that is, the quantity of the added distilled water is 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 tao 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 rol:Ler 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 2mm, and the more desirable thickness is 0.1 to l.Omm.
The desirable example of the pharmaceutical composition is 6mm 02mm in width and 0.1 to 2mm 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 ration salt. The desirable ration 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 gingival 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) ration 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 ration and the other is to coat the film or strip by spraying the aqueous solution of ration. 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.
WO 97/44016 PCT/KIt97/00093 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.
Therefore, it has great advantage that we can maximize the drug release effect and the usage is very convenient. The present invention will be explained in more detail by examples.
The following examples are only for showing the application of the present invention, but the claims of the present invention is not limited within these examples.
Preparation example 1: The preparation of the biodegradable microsphere containing antibiotics Minocycline loaded microspheres were prepared by a modified 0/W emulsion technique. A 0.6 g of micronized minocycline HC1 (particle size was below Sum) was added to 2m1 methylene chloride containing 1.4 g polylactic acid of molecular weight 7,500. The relultant suspension was poured into a beaker containing 200m1 of 5o polyvinyl alcohol aqueous solution at 5°C that was being mechanically stirred.
Stirring continued for 1 hr to permit evaporation of the solvent. The microspheres were collected, washed with water, and lyophilized using a freeze-dryer. The average particle size was 100 ~Cm and the drug content was 24 weight o.
Preparation example 2 to preparation example 7 We prepared microspheres by the same method as described in preparation example 1 using various polymers and active substances. Table 1 shows their particle size and content of the active substances.
Table 1 Microspheres containing active substance.
Average polymer dru conte t active substancesize g (average molecular n weight) (weight ~) _.._. ( ~
m ) preparation PLA(8,000) Minocy~line 120 22 example NCI
preparation PLA(10,000) Tetracycline 75 20 example HCI
--preparation example PLGA(8,500) Minocycline 100 23 4 HCl preparation - -- -PLA(14,000) Metronidazola110 example I 25 _~
preparation pLGA(8,500) ~ Flubiprofen 100 27 example _- __ -J
preparation example 7 PLA(7,500) Dibucaine 120 21 Ezample 1: The preparation of the pectin film containing microspheres After we mixed 0.8g of microsphere prepared in preparation example 1 and 0.2g of pectin, 2.0g of distilled water is added to the mixture to obtain the hydrogel containing microspheres.
The above hydrogel is put and flattened into an acrylic mold box whose width is lOcm OlOcm, and whose thickness is 0.5 mm, and whose bottom is closed. And we covered it with polyester film coated with silicon, and compressed it by roller, and removed the polyester film and dried at the room temperature. The resultant film is cut in the size of 6mm~02mm.
Example 2 . The preparation of pectin strip containiag microspheres.
After we prepared hydrogel containing microspheres by the same method as described in example 1 we put it into the wedge type mold whose width is 6mm, and whose length is 2mm and whose depth is O.lmm to 0.5mm. And covered polyester film coated with silicon, and compressed it by roller, and removed the polyester film, and dried it at the room temperature, and separated strip from the mold.
Example 3 . The preparation of the sodium alginate film containing microspheres After we mixed a O.lg of sodium alginate and 0.85g of microsphere of the above preparation example 2, we added 1.5g of distilled water to the mixture to obtain the hydrogel containing microspheres. We prepared film with hydrogel by using the same method as described in example 1.
Example 4 . The preparation of the calcium alginate film containing microspheres The calcium alginate film is prepared by spraying 2% calcium chloride aqueous solution to the sodium alginate film prepared in Example 3 and drying it.
Example 5 to Example 16 The strip or film was prepared by the same method as described in example 1 to 4 by usincr microspheres which was prepared by the same method as described in preparation example 2 to example 7. The result is shown in table 2.
<Table 2> The film or strip containing microspheres Microspheres/
MicrospherePolysaccharides Shape Coating Polysaccharides Preparation Example5 sodium alginate80/20 Strip -Example Preparation Calcium Example6 sodium alginate85/15 ~ Strip Example Chloride Preparation Barium Example7 sodium alginate85/15 Strip Example Chloride ~ Preparation I Calcium Example8 Pectin 90/10 I Film Example I Chloride q Preparation Barium Example9 pectin 90/10 Film Example Chloride ! Preparation ~ Calcium i Example10 carrageenan 90/10 ~ Fil m Example Chloride ' ', Preparation j Example11 carrageenan 80/20 I Film Barium ~' Example j ; Chloride Preparation Example12 carrageenan 80/20 ; Strip -Example I
' ~ Preparation T I I
Example13 gelan 80/20 Strip -~ ~
Example Preparation ~ Calcium ~ Example14 gelan 70/30 I Film I
i , Example Chloride 6 , Preparation I Barium Example15 gelan 80/20 Film I
Example ~ Chloride ' Preparation Barium Exam 16 le p gelan 75/25 ~ Film Example .- ! ~ Chloride Test 1 . In vitro release test.
Films or strips of above examples were tested in lOml of lOmM phosphate buffer pH 7.4 at 37°C in a shaking water bath. The amount of released drug was analyzed by measuring the W absorbance according to the time. Table 3 shows the results.
<Table 3> Drug release Test Hour(Day) 1 2 3 4 5 6 7 8 9 1011 1213 1415 16 Exampl a 1 203039 4755 616977 8419094 9799 100- -( Example 3 1825I33 4248 566370 7680 ~ 93 9597 99 ~ ~ ~ ~ 89 ~ Example 4 192634 4349 576470 7681 8993 9598 100.
~ I ~ ~ I, Exampl a 6 22~2834 4046 525965 7177 8892 9597 99 I ; ( i ~
The Example 7 212733 3945 515763 6975180 5 90 9497 99 Cumulatin I
g , Exampl a 1 2534 4250 586674 818894 98100- - -8 ~ I ! ~ ~ ' ~ ~
I Re 1 eas i 2228~34 4046 525864 707682 879 9497 100 ng , Examp 1 I ~ , t ~
a 11 ' Quantity Example172635 43351 586674 8087~93~97100- - -12 ' Exampl a 13 182834 92502586674 808793 97100 ~ _ _ _ I Example 14 202836 4452 606775 828996 99100- - -~ ~ ~
Example 15 202836 4452 606775 828996 99100- - -I ' ~ ~
j Example 16 212836 4452 606775 82899419799 100- -Test 2 . Disintegration test of the pharmaceutical composition Among the above examples, we added the drug prepared by sodium alginate or pectin, and the drug coated with calcium chloride aqueous solution on this drug, and the drug coated with barium chloride aqueous - solution on this drug to the pH 7.4 phosphate buffer solution at 37°C, and measured the time in which the formulation disintegrated completely. The result is in table 4.
Table 4 The Result of dissolution test of the drug.
Sample Polysaccharides Coating Time necessary for the _-_.- __- dissolution__of the _dru_A__ i Example 3 sodium alginate - 1 hr Example 6 sodrum alginate -Ca" - 4 hr I
Example 7 sodium alginate l - Ba'' - 11 days -Example 1 pectin -~T~ - 1.5 hr _. j Example 8 pectin Ca"
hr t _. _;
Example 9 pectin Ba" 12 days Test 3 . Drug effect test administrated to the animal This test was conducted in order to confirm a physiological effect of the pharmaceutical composition for the periodontitis (composition composed of sodium alginate and polylactic acid microspheres containing minocycline) prepared by the method described in Example 3.
The above formulations (film cut by 6x2 mm) were administered to the periodontal pockets of dogs, and after 0, 1, 2, and 4 weeks, each clinical index was measured. The morphology of bacteria was measured with a microscope, and the colony number of bacteria by cul.tiwation was measured.
And the data like this was analyzed statistically by ANOVA method in order to confirm the significant difference between before administration and after administration.
The clinical indices such as plaque indices, gingival indices, and bleeding indices were measured by Loe & Silness method, and the depth of periodontal pocket was measured with William's probe. Regarding to the morphology of bacteria, proportion of cocci, non-motile rod, motile rod and spirochete was measured with a microscope for each week. Regarding to cultivation of microorganisms, the variation ratio dependent upon time was measured for each week. And the following result was obtained.
1. Clinical indices such as plaque indices, gingival indices, the depth of periodontal pocket and bleeding indices showed significant difference after administration compared to a control group (Table 5-8, fig. 1-4).
2. After administration, the ratio of cocci and non-motile rod was increased, and motile rod and spirochete were reduced (Table 9-12, fig. 5-6).
3. Colony Forming Unit (CFU) of each media was significantly reduced when bacteria was cultivated in aerobic or anaerobic blood agar media (Table 13-15, fig.
7-9).
According to a result of the above test, it is proved that the clinical indices, the variation of bacteria and the concentration of drug in the periodontal pocket shows that the pharmaceutical composition for periodontitis of the present invention is very effective for longer than 2 weeks, when it is locally administered.
Table 5 Comparison of plaque indices group ( -1 week ~ (:ontrol Experiment 0 3.00 0.00 3.00 0.00 1 ' 3.00 0.00 2.71 0.96~u 2 _ 1. 47 0. 60~x 4 2. 92 O. Soda 1. 33 0. 48~x~
1. 66 0. 48~x _-Note : * Significantly different from baseline (0 week) # Significantly different from control group <Table 6> Comparisoa of giagival iadices group week Control Experiment 0 3.00 0.00 3.00 0.00 1 2.71 t 0.46 2.23 0.43#
2 2. 28 t 0. 46x~1. 47 0. 51 ~x#
4 2.00 0.59 1.33 0.48#
Note : * Significantly different from base~.ine (0 week) # Significantly different from control group <Table 7> Comparison of pocket depth group week Control Experiment 0 5.85 1.15 5.80 1.12 1 5.42 1.43 4.61 0.58#
2 0 2 5. 00 0. 00~ 4.19 0. 67~#
4 4.50 0.78 3.44 0.85#
Note : * Significantly different from baseline (0 week) # Significantly different from control <Table 8> Comparison of bleeding indices group week Control Experiment 0 3.00 0.00 2.87 0.32 1 2.85 0.35 2.42 0.50#
2 2.42 0.50 1.90 t 0.43x#
4 i . 50 0. 51 1. 22 ~ 0. 42##
~
Note : * Significantly different from baseline (0 week) # Significantly different from control <Table 9> Proportion of cocci to total microorganisms for each week (particular bacteria/ total bacteria x 100, mean % ~ SD) group week Control Experiment 0 33.51 11.86 32.92 9.14 1 54.49 12.08 59.25 12.14 2 60.76 9.81 60.11 11.62 4 66.35 8.42 65.01 10.07 Note : * Significantly different from baseline (0 week}
<Table 10> Proportion of non-motile rod to total microorganism for each week (mean % t SD) group week Control Experiment 0 20.47 4.33 20.00 6.41 1 19.65 8.75 21.45 9.13 2 21.68 8.93 23.20 11.24 4 22.96 9.61 25.68 9.90 Note : * significantly dofferent from baseline (0 week) <Table 11> Proportion of motile rod to total microorganism for each week (mean% ~ SD) group week Control Experiment 0 27.99 6.49 28.02 6.43 ~
1 20. 0l 5. 28 10. 11 7. 0l ~
2 15.21 8.90 11.87 7.03 4 6. 61 4. 11 6. 2O 4. 43~
~
Note . * Significantly different from baseline (Oweek) WO 97!44016 PCT/KR97/00093 <Table 12> Proportion of spirochete to total microorganism for each week (mean% ~ SD) group week Control Experiment 0 17.94 8.12 19.05 7.19 1 7.51 7.20 9.16 5.37 2 5.86 6.46 4.25 t 3.77 4 4.32 2.60 3.13 3.19~x Note : * Significantly different from baseline (0 week) <Table 13> Comparisoa of Black-pigmented Bacteroide (mean CFU % ~ SD) group week Control Experiment 0 100.00 0.00 100.00 0.00 1 94.31 37.08 71.80 16.53#
2 122.30 48.34 71.07 24.50#
4 ~ 136.72 38.0490.98 26.02#
Note : * Significantly different from baseline (0 week) # Significantly different from control <Table 14> Comparison of aerobic blood agar plate (mean CFU % ~ SD) 8i'~P
week Control Experiment 0 100.00 t 0.00 100.00 0.00 1 109.21 13.64 63.31 43.11~~
2 101.41 19.48 29.18 17.91#
4 113.75 t 23.66 38.34 18.69~u Note : * Significantly different from baseline (0 week) # Significantly different from control <Table 15~ Comparison of Anaerobic blood agar plate (mean CFU % ~ SD) group week Control Experiment I
0 100.00 t 0.00 100.00 0.00 1 100.40 20.34 73.17 6.84#
2 92.85 13.13 65.12 15.17~~
4 ~ 108.41 13.47 67.48 16.65#
Note : v Significantly different from baseline (0 week) ~ Significantly different from control
The present invention provides process for preparing composition comprising the step of coating the film or strip with metal cation aqueous solution in addition to the above-mentioned process.
Brief Description of 'The Drawings In the accompanying figures:
Fig. 1 is indices of plaque comparing control group with those of experimental group;
Fig. 2 is indices of gingiva comparing control group with those of experimental group;
Fig. 3 is pocket depth comparing control group with those of experimental group;
Fig. 4 is indices of bleeding comparing control group with those of experimental group;
Fig. 5 represents the variation of ratio of cocci, non-motile rod, motile rod and spirochete in the control group;
Fig. 6 represents the variation of ratio of c:occi, non-motile rod, motile rod and spirochete in the experimental group;
Fig. 7 is CFU of black-pigmented bacteroide in control vs experimental group;
Fig. 8 is CFU in control vs experimental group cultured on aerobic blood agar plate;
Fig. 9 is CFU in control vs experimental group cultured on anaerobic blood agar plate;
Detailed Description of the Invention The physiologically active substance of the present invention which can be used for treating periodontitis contains antibiotics, local anesthetics anti-inflammatory 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, anti-inflammatory 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 ~-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 microsphere 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 water-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 i.s administered into the periodontal pocket, it swells so fast on contacting with saliva or gingival crevice fluid that a part of the film or strip can be out 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, et:c.
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 formulatian 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 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 forming 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 ration salt in addition to the above-mentioned step 1), step 2) and step 3).
The process for preparing the locally administrable, biodegradable pharmaceutic al 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, and 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 Jum 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 mixture is mixed well followed by cooling down below 20oC.
After emulsifying the polymer solution by addition to aqueous polyvinyl alcohol which was precooled below 5°C, the emulsion is diluted with distilled water. Finally, methylene chloride is evaporated to achieve our goal which 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 550 um, and 10 to 200 um is desirable, and 20 to 150 um 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 p, and more desirable is 5 to 30 weight %.
Then we added distilled water to the above mixture and made hydrogel of polysaccharide in which microspheres are suspended. The concentration of polysaccharide, that is, the quantity of the added distilled water is 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 tao 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 rol:Ler 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 2mm, and the more desirable thickness is 0.1 to l.Omm.
The desirable example of the pharmaceutical composition is 6mm 02mm in width and 0.1 to 2mm 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 ration salt. The desirable ration 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 gingival 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) ration 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 ration and the other is to coat the film or strip by spraying the aqueous solution of ration. 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.
WO 97/44016 PCT/KIt97/00093 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.
Therefore, it has great advantage that we can maximize the drug release effect and the usage is very convenient. The present invention will be explained in more detail by examples.
The following examples are only for showing the application of the present invention, but the claims of the present invention is not limited within these examples.
Preparation example 1: The preparation of the biodegradable microsphere containing antibiotics Minocycline loaded microspheres were prepared by a modified 0/W emulsion technique. A 0.6 g of micronized minocycline HC1 (particle size was below Sum) was added to 2m1 methylene chloride containing 1.4 g polylactic acid of molecular weight 7,500. The relultant suspension was poured into a beaker containing 200m1 of 5o polyvinyl alcohol aqueous solution at 5°C that was being mechanically stirred.
Stirring continued for 1 hr to permit evaporation of the solvent. The microspheres were collected, washed with water, and lyophilized using a freeze-dryer. The average particle size was 100 ~Cm and the drug content was 24 weight o.
Preparation example 2 to preparation example 7 We prepared microspheres by the same method as described in preparation example 1 using various polymers and active substances. Table 1 shows their particle size and content of the active substances.
Table 1 Microspheres containing active substance.
Average polymer dru conte t active substancesize g (average molecular n weight) (weight ~) _.._. ( ~
m ) preparation PLA(8,000) Minocy~line 120 22 example NCI
preparation PLA(10,000) Tetracycline 75 20 example HCI
--preparation example PLGA(8,500) Minocycline 100 23 4 HCl preparation - -- -PLA(14,000) Metronidazola110 example I 25 _~
preparation pLGA(8,500) ~ Flubiprofen 100 27 example _- __ -J
preparation example 7 PLA(7,500) Dibucaine 120 21 Ezample 1: The preparation of the pectin film containing microspheres After we mixed 0.8g of microsphere prepared in preparation example 1 and 0.2g of pectin, 2.0g of distilled water is added to the mixture to obtain the hydrogel containing microspheres.
The above hydrogel is put and flattened into an acrylic mold box whose width is lOcm OlOcm, and whose thickness is 0.5 mm, and whose bottom is closed. And we covered it with polyester film coated with silicon, and compressed it by roller, and removed the polyester film and dried at the room temperature. The resultant film is cut in the size of 6mm~02mm.
Example 2 . The preparation of pectin strip containiag microspheres.
After we prepared hydrogel containing microspheres by the same method as described in example 1 we put it into the wedge type mold whose width is 6mm, and whose length is 2mm and whose depth is O.lmm to 0.5mm. And covered polyester film coated with silicon, and compressed it by roller, and removed the polyester film, and dried it at the room temperature, and separated strip from the mold.
Example 3 . The preparation of the sodium alginate film containing microspheres After we mixed a O.lg of sodium alginate and 0.85g of microsphere of the above preparation example 2, we added 1.5g of distilled water to the mixture to obtain the hydrogel containing microspheres. We prepared film with hydrogel by using the same method as described in example 1.
Example 4 . The preparation of the calcium alginate film containing microspheres The calcium alginate film is prepared by spraying 2% calcium chloride aqueous solution to the sodium alginate film prepared in Example 3 and drying it.
Example 5 to Example 16 The strip or film was prepared by the same method as described in example 1 to 4 by usincr microspheres which was prepared by the same method as described in preparation example 2 to example 7. The result is shown in table 2.
<Table 2> The film or strip containing microspheres Microspheres/
MicrospherePolysaccharides Shape Coating Polysaccharides Preparation Example5 sodium alginate80/20 Strip -Example Preparation Calcium Example6 sodium alginate85/15 ~ Strip Example Chloride Preparation Barium Example7 sodium alginate85/15 Strip Example Chloride ~ Preparation I Calcium Example8 Pectin 90/10 I Film Example I Chloride q Preparation Barium Example9 pectin 90/10 Film Example Chloride ! Preparation ~ Calcium i Example10 carrageenan 90/10 ~ Fil m Example Chloride ' ', Preparation j Example11 carrageenan 80/20 I Film Barium ~' Example j ; Chloride Preparation Example12 carrageenan 80/20 ; Strip -Example I
' ~ Preparation T I I
Example13 gelan 80/20 Strip -~ ~
Example Preparation ~ Calcium ~ Example14 gelan 70/30 I Film I
i , Example Chloride 6 , Preparation I Barium Example15 gelan 80/20 Film I
Example ~ Chloride ' Preparation Barium Exam 16 le p gelan 75/25 ~ Film Example .- ! ~ Chloride Test 1 . In vitro release test.
Films or strips of above examples were tested in lOml of lOmM phosphate buffer pH 7.4 at 37°C in a shaking water bath. The amount of released drug was analyzed by measuring the W absorbance according to the time. Table 3 shows the results.
<Table 3> Drug release Test Hour(Day) 1 2 3 4 5 6 7 8 9 1011 1213 1415 16 Exampl a 1 203039 4755 616977 8419094 9799 100- -( Example 3 1825I33 4248 566370 7680 ~ 93 9597 99 ~ ~ ~ ~ 89 ~ Example 4 192634 4349 576470 7681 8993 9598 100.
~ I ~ ~ I, Exampl a 6 22~2834 4046 525965 7177 8892 9597 99 I ; ( i ~
The Example 7 212733 3945 515763 6975180 5 90 9497 99 Cumulatin I
g , Exampl a 1 2534 4250 586674 818894 98100- - -8 ~ I ! ~ ~ ' ~ ~
I Re 1 eas i 2228~34 4046 525864 707682 879 9497 100 ng , Examp 1 I ~ , t ~
a 11 ' Quantity Example172635 43351 586674 8087~93~97100- - -12 ' Exampl a 13 182834 92502586674 808793 97100 ~ _ _ _ I Example 14 202836 4452 606775 828996 99100- - -~ ~ ~
Example 15 202836 4452 606775 828996 99100- - -I ' ~ ~
j Example 16 212836 4452 606775 82899419799 100- -Test 2 . Disintegration test of the pharmaceutical composition Among the above examples, we added the drug prepared by sodium alginate or pectin, and the drug coated with calcium chloride aqueous solution on this drug, and the drug coated with barium chloride aqueous - solution on this drug to the pH 7.4 phosphate buffer solution at 37°C, and measured the time in which the formulation disintegrated completely. The result is in table 4.
Table 4 The Result of dissolution test of the drug.
Sample Polysaccharides Coating Time necessary for the _-_.- __- dissolution__of the _dru_A__ i Example 3 sodium alginate - 1 hr Example 6 sodrum alginate -Ca" - 4 hr I
Example 7 sodium alginate l - Ba'' - 11 days -Example 1 pectin -~T~ - 1.5 hr _. j Example 8 pectin Ca"
hr t _. _;
Example 9 pectin Ba" 12 days Test 3 . Drug effect test administrated to the animal This test was conducted in order to confirm a physiological effect of the pharmaceutical composition for the periodontitis (composition composed of sodium alginate and polylactic acid microspheres containing minocycline) prepared by the method described in Example 3.
The above formulations (film cut by 6x2 mm) were administered to the periodontal pockets of dogs, and after 0, 1, 2, and 4 weeks, each clinical index was measured. The morphology of bacteria was measured with a microscope, and the colony number of bacteria by cul.tiwation was measured.
And the data like this was analyzed statistically by ANOVA method in order to confirm the significant difference between before administration and after administration.
The clinical indices such as plaque indices, gingival indices, and bleeding indices were measured by Loe & Silness method, and the depth of periodontal pocket was measured with William's probe. Regarding to the morphology of bacteria, proportion of cocci, non-motile rod, motile rod and spirochete was measured with a microscope for each week. Regarding to cultivation of microorganisms, the variation ratio dependent upon time was measured for each week. And the following result was obtained.
1. Clinical indices such as plaque indices, gingival indices, the depth of periodontal pocket and bleeding indices showed significant difference after administration compared to a control group (Table 5-8, fig. 1-4).
2. After administration, the ratio of cocci and non-motile rod was increased, and motile rod and spirochete were reduced (Table 9-12, fig. 5-6).
3. Colony Forming Unit (CFU) of each media was significantly reduced when bacteria was cultivated in aerobic or anaerobic blood agar media (Table 13-15, fig.
7-9).
According to a result of the above test, it is proved that the clinical indices, the variation of bacteria and the concentration of drug in the periodontal pocket shows that the pharmaceutical composition for periodontitis of the present invention is very effective for longer than 2 weeks, when it is locally administered.
Table 5 Comparison of plaque indices group ( -1 week ~ (:ontrol Experiment 0 3.00 0.00 3.00 0.00 1 ' 3.00 0.00 2.71 0.96~u 2 _ 1. 47 0. 60~x 4 2. 92 O. Soda 1. 33 0. 48~x~
1. 66 0. 48~x _-Note : * Significantly different from baseline (0 week) # Significantly different from control group <Table 6> Comparisoa of giagival iadices group week Control Experiment 0 3.00 0.00 3.00 0.00 1 2.71 t 0.46 2.23 0.43#
2 2. 28 t 0. 46x~1. 47 0. 51 ~x#
4 2.00 0.59 1.33 0.48#
Note : * Significantly different from base~.ine (0 week) # Significantly different from control group <Table 7> Comparison of pocket depth group week Control Experiment 0 5.85 1.15 5.80 1.12 1 5.42 1.43 4.61 0.58#
2 0 2 5. 00 0. 00~ 4.19 0. 67~#
4 4.50 0.78 3.44 0.85#
Note : * Significantly different from baseline (0 week) # Significantly different from control <Table 8> Comparison of bleeding indices group week Control Experiment 0 3.00 0.00 2.87 0.32 1 2.85 0.35 2.42 0.50#
2 2.42 0.50 1.90 t 0.43x#
4 i . 50 0. 51 1. 22 ~ 0. 42##
~
Note : * Significantly different from baseline (0 week) # Significantly different from control <Table 9> Proportion of cocci to total microorganisms for each week (particular bacteria/ total bacteria x 100, mean % ~ SD) group week Control Experiment 0 33.51 11.86 32.92 9.14 1 54.49 12.08 59.25 12.14 2 60.76 9.81 60.11 11.62 4 66.35 8.42 65.01 10.07 Note : * Significantly different from baseline (0 week}
<Table 10> Proportion of non-motile rod to total microorganism for each week (mean % t SD) group week Control Experiment 0 20.47 4.33 20.00 6.41 1 19.65 8.75 21.45 9.13 2 21.68 8.93 23.20 11.24 4 22.96 9.61 25.68 9.90 Note : * significantly dofferent from baseline (0 week) <Table 11> Proportion of motile rod to total microorganism for each week (mean% ~ SD) group week Control Experiment 0 27.99 6.49 28.02 6.43 ~
1 20. 0l 5. 28 10. 11 7. 0l ~
2 15.21 8.90 11.87 7.03 4 6. 61 4. 11 6. 2O 4. 43~
~
Note . * Significantly different from baseline (Oweek) WO 97!44016 PCT/KR97/00093 <Table 12> Proportion of spirochete to total microorganism for each week (mean% ~ SD) group week Control Experiment 0 17.94 8.12 19.05 7.19 1 7.51 7.20 9.16 5.37 2 5.86 6.46 4.25 t 3.77 4 4.32 2.60 3.13 3.19~x Note : * Significantly different from baseline (0 week) <Table 13> Comparisoa of Black-pigmented Bacteroide (mean CFU % ~ SD) group week Control Experiment 0 100.00 0.00 100.00 0.00 1 94.31 37.08 71.80 16.53#
2 122.30 48.34 71.07 24.50#
4 ~ 136.72 38.0490.98 26.02#
Note : * Significantly different from baseline (0 week) # Significantly different from control <Table 14> Comparison of aerobic blood agar plate (mean CFU % ~ SD) 8i'~P
week Control Experiment 0 100.00 t 0.00 100.00 0.00 1 109.21 13.64 63.31 43.11~~
2 101.41 19.48 29.18 17.91#
4 113.75 t 23.66 38.34 18.69~u Note : * Significantly different from baseline (0 week) # Significantly different from control <Table 15~ Comparison of Anaerobic blood agar plate (mean CFU % ~ SD) group week Control Experiment I
0 100.00 t 0.00 100.00 0.00 1 100.40 20.34 73.17 6.84#
2 92.85 13.13 65.12 15.17~~
4 ~ 108.41 13.47 67.48 16.65#
Note : v Significantly different from baseline (0 week) ~ Significantly different from control
Claims (5)
1. A locally administrable, biodegradable and sustained-release delivery system for periodontitis comprising:
a) microspheres releasing active substances for 1 to 3 weeks continuously and containing 1) active substance in an amount of more than 20 weight % of the microsphere, 2) biodegradable polymer selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA) and polylactic glycolic acid (PLGA) whose average molecular weight is in the range of 4,000 to 50,000 ;1 b) polysaccharides selected from the group consisting of pectin, carrageenan, gellan gum, sodium alginate and chitosan; and c) bivalent metal ion to form complex with the polysacchardies;
wherein the rate of disintegration is controlled by the kind of metal ion and intensity and extent of complex.
a) microspheres releasing active substances for 1 to 3 weeks continuously and containing 1) active substance in an amount of more than 20 weight % of the microsphere, 2) biodegradable polymer selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA) and polylactic glycolic acid (PLGA) whose average molecular weight is in the range of 4,000 to 50,000 ;1 b) polysaccharides selected from the group consisting of pectin, carrageenan, gellan gum, sodium alginate and chitosan; and c) bivalent metal ion to form complex with the polysacchardies;
wherein the rate of disintegration is controlled by the kind of metal ion and intensity and extent of complex.
2. The locally administrable, biodegradable and sustained-release delivery system, according to the claim 1, wherein the active substance is selected from the group consisting of the following materials:
amphicilin, amoxicillin, erythromycin, tetracycline, minocycline, oxytetracycline, doxycycline, metronidazole, bacitracin, kitasamycin, spiramycin, ornidazole and their salts as antibiotics; lidocaine, procaine, dibucaine, and benzocaine as local anesthetics; diclofenac, flubiprofen, ibuprofen, ketoprofen, aspirin, mefenamic acid and acetaminophen as anti-inflammatory analgesics; and dexamethasone, triamcinolone acetonide, hydrocortisone, epihydrocortisone as steroid hormones.
amphicilin, amoxicillin, erythromycin, tetracycline, minocycline, oxytetracycline, doxycycline, metronidazole, bacitracin, kitasamycin, spiramycin, ornidazole and their salts as antibiotics; lidocaine, procaine, dibucaine, and benzocaine as local anesthetics; diclofenac, flubiprofen, ibuprofen, ketoprofen, aspirin, mefenamic acid and acetaminophen as anti-inflammatory analgesics; and dexamethasone, triamcinolone acetonide, hydrocortisone, epihydrocortisone as steroid hormones.
3. The locally administrable, biodegradable and sustained-release delivery system, according to the claim 1, wherein the bivalent metal ion is bivalent cation chloride which is selected from the group consisting of calcium chloride, magnesium chloride and barium chloride.
4. A process for preparation of locally administrable, biodegradable and sustained-release for periodontitis comprising the step of:
1) making microspheres containing a physiologically active substance by dissolving biodegradable polymer in a solvent, suspending the active substance ground to 1-5 µm in diameter into the solution, emulsifying the suspended solution in an aqueous solution which contains polyvinyl alcohol in an amount of 1 to 20 weight %, and evaporating the solvent:
2) making a hydrogel by mixing the microspheres and polysaccharides in ratio of 95 : 5 to 50 : 50, and then adding distilled water to make the final concentration of polysaccharides of 1 to 20 weight % of the hydrogel;
3) making films or strips from the hydrogel; and 4) coating and drying by spray-coating method onto the films or straps with an aqueous solution of bivalent metal ion.
1) making microspheres containing a physiologically active substance by dissolving biodegradable polymer in a solvent, suspending the active substance ground to 1-5 µm in diameter into the solution, emulsifying the suspended solution in an aqueous solution which contains polyvinyl alcohol in an amount of 1 to 20 weight %, and evaporating the solvent:
2) making a hydrogel by mixing the microspheres and polysaccharides in ratio of 95 : 5 to 50 : 50, and then adding distilled water to make the final concentration of polysaccharides of 1 to 20 weight % of the hydrogel;
3) making films or strips from the hydrogel; and 4) coating and drying by spray-coating method onto the films or straps with an aqueous solution of bivalent metal ion.
5. The process for preparation of locally administrable, biodegradable and sustained-release delivery system for periodontitis according to claim 4, wherein the concentration of the bivalent metal ion is 2 to 5 weight %.
39(a)
39(a)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1996/17798 | 1996-05-23 | ||
| KR1019960017798A KR100186908B1 (en) | 1996-05-23 | 1996-05-23 | Topical administration type composition for therapy of paradentitis |
| KR1996/17799 | 1996-05-23 | ||
| KR1019960017799A KR100186909B1 (en) | 1996-05-23 | 1996-05-23 | Topical adhesive for therapy of oral disease |
| PCT/KR1997/000093 WO1997044016A1 (en) | 1996-05-23 | 1997-05-22 | Locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis and process for preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2253980A1 CA2253980A1 (en) | 1997-11-27 |
| CA2253980C true CA2253980C (en) | 2004-08-17 |
Family
ID=26631858
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002253980A Expired - Fee Related CA2253980C (en) | 1996-05-23 | 1997-05-22 | Locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis and process for preparation thereof |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US6193994B1 (en) |
| EP (1) | EP0910348B1 (en) |
| JP (1) | JP3263399B2 (en) |
| CN (1) | CN1126537C (en) |
| AU (1) | AU713276B2 (en) |
| CA (1) | CA2253980C (en) |
| DE (1) | DE69720453T2 (en) |
| WO (1) | WO1997044016A1 (en) |
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-
1997
- 1997-05-22 CA CA002253980A patent/CA2253980C/en not_active Expired - Fee Related
- 1997-05-22 DE DE69720453T patent/DE69720453T2/en not_active Expired - Fee Related
- 1997-05-22 JP JP54206397A patent/JP3263399B2/en not_active Expired - Fee Related
- 1997-05-22 EP EP97922207A patent/EP0910348B1/en not_active Expired - Lifetime
- 1997-05-22 AU AU27938/97A patent/AU713276B2/en not_active Ceased
- 1997-05-22 WO PCT/KR1997/000093 patent/WO1997044016A1/en active IP Right Grant
- 1997-05-22 CN CN97197425A patent/CN1126537C/en not_active Expired - Fee Related
- 1997-05-22 US US09/180,480 patent/US6193994B1/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US6193994B1 (en) | 2001-02-27 |
| JP3263399B2 (en) | 2002-03-04 |
| AU2793897A (en) | 1997-12-09 |
| CA2253980A1 (en) | 1997-11-27 |
| CN1228692A (en) | 1999-09-15 |
| DE69720453T2 (en) | 2004-04-15 |
| DE69720453D1 (en) | 2003-05-08 |
| CN1126537C (en) | 2003-11-05 |
| JP2001504439A (en) | 2001-04-03 |
| WO1997044016A1 (en) | 1997-11-27 |
| AU713276B2 (en) | 1999-11-25 |
| EP0910348B1 (en) | 2003-04-02 |
| EP0910348A1 (en) | 1999-04-28 |
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