CN102406627B - Medicinal slow release inserted slice possessing layer-by-layer assembly mosaic structure - Google Patents
Medicinal slow release inserted slice possessing layer-by-layer assembly mosaic structure Download PDFInfo
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- CN102406627B CN102406627B CN 201110373937 CN201110373937A CN102406627B CN 102406627 B CN102406627 B CN 102406627B CN 201110373937 CN201110373937 CN 201110373937 CN 201110373937 A CN201110373937 A CN 201110373937A CN 102406627 B CN102406627 B CN 102406627B
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Abstract
The invention discloses a medicinal slow release inserted slice possessing a layer-by-layer assembly mosaic structure, the inserted slice is prepared by the following steps: preparing a polymer, mixing a medicine with a solution, spraying, passing through hot air, drying, moulding and the like. During the process of preparing the slow release type drug loaded inserted slice, the structure of the inserted slice can be controlled by adjusting pressure, temperature and spraying time, thereby the medicine release rate and degradation time of the inserted slice can be influenced for meeting the requirement of insertion, simultaneously the mechanical property of the inserted slice is influenced, so that the inserted slice possessing appropriate flexibility is obtained, and is convenient for better clinical application.
Description
Technical field
The present invention relates to the slow releasing carrier of medication technical field, particularly the implanted medicament slow release of a kind of energy long term administration is planted the preparation method of sheet.
Background technology
ICRDDS is that a class underwent operative is implanted subcutaneous or imported subcutaneous control release preparation through puncture needle.Development along with medical technology has all obtained remarkable progress in many-sided researchs such as carrier material and ranges of application thereof.Carrier is by initial single silicone rubber, develop into Biodegradable materials such as comprising at present ε-polycaprolactone, poly-anhydride, polylactic acid, polyamino acid tens of kinds, also has the Ludox, hydroxyl phosphorus stone of latest report etc.Polymer (polymer) drug sustained release system is desirable local slow administering mode, the copolymer of polylactic acid and polyglycolic acid (PLGA) is as a kind of biodegradable polymer that can be used for the medical-therapeutic treatment of human body purposes, obtained the approval of U.S. food and Drugs Directorate, be characterized in that compound with regular structure, composition are fixed, degradation property is stable and good biocompatibility.The medicinal application scope also expands to the multiple treatment fields such as antitumor, insulin administration, cardiovascular disease, ocular disease, tuberculosis, osteomyelitis, vaccine by originally contraceptive treatments.
ICRDDS has the following advantages: (1) can reduce medicining times to half-life medicine short or that need frequent drug administration, and is easy to use.This dosage form need to be specially adapted to the patients with chronic diseases of Long-term taking medicine, such as the cardiovascular diseases, and the patients such as angina pectoris, hypertension, asthma; (2) make blood drug level steady, avoid peak valley phenomenon, be conducive to reduce the toxic and side effects of medicine.Medicine this characteristics little for therapeutic index are more remarkable, guarantee simultaneously safety and the effectiveness of medicine; (3) accumulated dose of minimizing medication, therefore available minimum dose reaches maximum drug effect, effectively raises the bioavailability of medicine.
Vision is the main channel of human acquired information, and Vision Health also is one of most important index of modern's health standards simultaneously.Along with the arrival of socioeconomic development and aging society, the incidence rate of the visual problem that causes because of all kinds of eye part diseases improves constantly, and just day by day becoming affects people's work, the key factor of quality of life.Intractable eye posterior segment disease there is no gratifying Drug therapy measure at present clinically, mostly adopts intravitreal administration or Vitreous cavity topical.Prolonged and repeated ground eye drops has not only increased the patient suffering, and has increased substantially the probability of patient's intraocular infection, also has other severe complication simultaneously, such as cataract, detachment of retina and vitreous hemorrhage etc.For this situation, but at present in the urgent need to researching and developing a kind of implanted drug sustained release system for eye back segment stubborn disease treatment long term administration.
Because the existence of " cornea barrier " and " blood-retina barrier ", make the ophthalmic drug delivery approach of present routine and dosage form be difficult to reach fast, lasting, stablize, accurately drug distribution and absorption.For eye back segment intractable ophthalmic, therapeutic modality commonly used is the administration of glass intracavitary administration or the administration of Vitreous cavity device at present.The intravitreal administration, short because of drug half-life, often need multiple injection, even come prolong drug in the intravitreous time of staying by liposome or other microgranule bag medicine carrying things, also be difficult to reach and keep for a long time active drug concentration.
Intraocular implant can carry out drug release more sustainedly and stably in vitreous body, when treatment eye posterior segment disease, can make active drug extend to 8 to 30 months action time.But this method needs intraocular surgery to realize, easily causes the ophthalmic complication when implanting or change implant, such as cataract, vitreous hemorrhage, detachment of retina even endophthalmitis.The cytomegaloviral retinitis patient that acquired immune deficiency syndrome (AIDS) is relevant often will carry out 3 to 4 ganciclovir implant implant surgeries every year, and repeated multiple times operation has further increased above-mentioned complication odds.According to reported in literature, the Uveitis Patients through the treatment of fluocinolone acetonide acetic acid Vitreous cavity body has the case above 50% to develop into cataract, and 74.8% patient secondary glaucoma occurs and has to accept resisting glaucoma operation.Above-mentioned reason so that the Vitreous cavity body be very limited in the clinical practice for the treatment of eye posterior segment disease.
In order to realize low toxicity, the treatment of efficient and lasting ocular drug, research worker with target tightening on the optimal design of the choose reasonable of drug sustained release system implant site and carrier material.Nearest studies show that, will be a kind of very potential method through sclera drug treatment eye posterior segment disease, has important clinical meaning.Through sclera or choroid administration, medicine penetrates the wall of eyeball tissue and arrives the eye back segment, and does not need directly to contact eye inner tissue with medicine.The sclera area is large, the simple and easy usefulness of location tables, the content of drug degradation enzyme is very low, and its permeability is not obvious with the change at age, these all are favourable topical conditions, can greatly reduce simultaneously the generation of above-mentioned eye drops approach complication through the sclera external administration, be beneficial to clinical application.
Summary of the invention
The problem to be solved in the present invention is to improve the problems such as the complex process of human body implant slow release thing in the background technology, material are hard, effect duration is too short.
For achieving the above object, the invention provides a kind of layer assembly mosaic structure medicament slow release and plant sheet, this is planted sheet and is made by following steps and technique:
(1) prepared polymer/medicament mixed solution:
In organic solvent, the preparation solid concentration is the solution a of 10mg/ml-75mg/ml with polymer dissolution; Again with medicine dissolution in organic solvent, be made into certain density drug solution b; Again according to the requirement of drug loading, mix after taking respectively two parts of solution proper volume, through airtight supersound process;
(2) spraying:
Utilize spraying equipment, pressure selection is 0.1MPa-0.5MPa, mixed solution is sprayed on the collecting board that has been heated in advance 35 ℃-80 ℃;
(3) pass into hot-air:
Behind each spraying 1s-60s, hot-air 1s-60s of 35 ℃-80 ℃ is passed through in the collecting board top; Repeat this process, reach actual desired thickness until plant sheet;
(4) drying:
Sample is placed vacuum drying oven, and under the room temperature vacuum drying 1-7 days, the slow release medicine carrying that can make a kind of polycaprolactone and be matrix was planted sheet;
(5) molding: according to actual needs, cut into the sheet of planting of definite shape size.
In the step (1), described polymer is that number-average molecular weight is 20,000-80,000 polycaprolactone.
In the step (1), the organic solvent of described dissolve polymer and the solvent of dissolved substance, two kinds of solvents can dissolve each other.
In the step (1), the described closed ultrasonic processing time is half an hour.
In the step (2), the pressure selection of described spraying equipment is 0.15 MPa-0.3MPa, and the collecting board temperature is heated to 40 ℃-60 ℃.
In the step (3), described spray time is 20s-40s.
In the step (3), 40 ℃-60 ℃ hot-air is passed through in described collecting board top, and the time is 15s-45s.
In the step (4), vacuum drying is 2 days-5 days under the described room temperature.
A kind of layer assembly mosaic structure medicament slow release is planted sheet, and this is planted sheet and is made by following steps and technique:
(1) prepared polymer/medicament mixed solution:
In organic solvent, the preparation solid concentration is the solution a of 10mg/ml-75mg/ml with polymer dissolution; In organic solvent, being made into concentration is the drug solution b of 1mg/ml-10mg/ml with medicine dissolution; Again according to the requirement of drug loading, mix after taking respectively two parts of solution proper volume, through airtight supersound process;
(2) spraying:
Utilize spraying equipment, pressure selection is 0.1 MPa-0.5MPa, mixed solution is sprayed on the collecting board that has been heated in advance 35 ℃-80 ℃;
(3) pass into hot-air:
Behind each spraying 1s-60s, hot-air 1s-60s of 35 ℃-80 ℃ is passed through in the collecting board top; Repeat this process, reach actual desired thickness until plant sheet;
(4) drying:
Sample is placed vacuum drying oven, and under the room temperature vacuum drying 1-7 days, the slow release medicine carrying that can make a kind of Poly(D,L-lactide-co-glycolide and be matrix was planted sheet;
(5) molding: according to actual needs, cut into the sheet of planting of definite shape size.
The object of the invention is to the thickness to implant, control and the adjusting of drug loading, so that implant has the performances such as suitable drug loading, degradation property, mechanical property, drug release rate.The present invention controls the structure of planting sheet, thereby further affects drug release rate, the degradation time of planting sheet by regulating pressure, temperature, spray time, adapts to the needs of implantation; Simultaneously can affect the mechanical property of planting sheet, can obtain having the suitable flexible sheet of planting, be convenient to further clinical practice.
The present invention compared with prior art has following outstanding advantage and effect:
1, the slow release medicine carrying of the inventive method preparation density of planting sheet can be controlled in 0.20-0.75g/mL, keeps low temperature state far below its glass transition temperature in the spraying process always, plants the sheet material and can regulate within the specific limits; And according to prior art Chinese patent CN1364645(polycaprolactone-brufen composition and method for making and purposes) and Chinese patent CN101288777(polycaprolactone/polyethyleneglycol weaver's engineering support material and preparation thereof) the medicine carrying of preparation method preparation plant the density of sheet greatly about 1.0g/ml, density 1.146 g/mL close to the polycaprolactone of fusion method preparation, these two kinds of methods all are the methods by heating and melting, structure is dense, and material is hard, adjustable extent is narrower.
2, the present invention adopts spraying process preparation, plants the structure of sheet by control, makes material can keep suitable drug release concentration, degradation property and mechanical property; And material shape do not had special requirement, can be prepared into columnar material, membrane material and porous material.This medicine carrying embedded material not only can be used for the ophthalmology tissue, also can be used for the slow-released carrier of the medicine of its hetero-organization, for other field of tissue engineering technology provides treatment.
3, the relative prior art of the present invention, technique is simpler, and cost is lower, and easy and simple to handle, is easy to industrial application.
Description of drawings
Fig. 1 is that the scanning electron microscope (SEM) on polycaprolactone in the embodiment of the invention 1/triamcinolone acetonide implant material surface amplifies 1000 picture;
Fig. 2 is that the scanning electron microscope (SEM) of polycaprolactone in the embodiment of the invention 1/triamcinolone acetonide implant material section amplifies 1000 times picture;
Fig. 3 is that the embodiment of the invention 1 polycaprolactone/triamcinolone acetonide slow release is planted the vitro drug release speed of sheet in PBS;
Fig. 4 is that the embodiment of the invention 1 polycaprolactone/triamcinolone acetonide slow release is planted the external medicine cumulative release amount of sheet in PBS, and cumulative release is after 99 days.
The specific embodiment
The present invention is described in further detail below in conjunction with embodiment and accompanying drawing.
(1) mixed solution of preparation polycaprolactone/triamcinolone acetonide:
At first the polycaprolactone with number-average molecular weight 20,000 is dissolved in the dichloromethane, and the preparation solid concentration is the solution a of 10mg/ml; Again triamcinolone acetonide is dissolved in acetone, being made into concentration is the drug solution b of 5mg/ml; Again according to the requirement of drug loading, mix after taking respectively two parts of solution proper volume, after airtight ultrasonic half an hour, stand-by;
(2) spraying:
Utilize spraying equipment, pressure selection is 0.15MPa, mixed solution is sprayed on the collecting board that has been heated in advance 40 ℃;
(3) pass into hot-air:
Behind each spraying 20s, 40 ℃ hot-air 15s is passed through in the collecting board top; Repeat this process, reach actual desired thickness until plant sheet;
(4) drying:
Sample is placed vacuum drying oven, and vacuum drying is 2 days under the room temperature, and the slow release medicine carrying that can make a kind of polycaprolactone and be matrix is planted sheet;
(5) molding:
According to actual needs, cut into the sheet of planting of definite shape size.
Polycaprolactone in the present embodiment/triamcinolone acetonide implant material multinomial performance comparatively improves, and as shown in Figure 1, it is comparatively smooth to plant the sheet surface, is conducive to the operation of Implantation Test; As shown in Figure 2, medicine (triamcinolone acetonide) crystal is separated by matrix (polycaprolactone), and the discrete form of medicine and matrix is similar to the mosaic structure that distributes immediately between different layers; STD refers to the rate of release of naked medicine (triamcinolone acetonide) among Fig. 3, general its maintains about 12 μ g/ml, and the slow release of embodiment 1 preparation is planted the release concentration of sheet Chinese medicine and is maintained about 8.5 μ g/ml, and the rate of release of planting the sheet Chinese medicine from rate of release will be lower than the rate of release of naked medicine; The cumulative release amount of the naked medicine of STD is 27.36% among Fig. 4, and the cumulative release amount that slow release is planted the sheet Chinese medicine is about 16.06%, and the cumulative release amount that slow release is planted the sheet Chinese medicine approximately is 58.70% of naked medicine cumulative release amount, and slow release effect is comparatively obvious.
In following examples 2 to 6, the performance of the material of institute's output is all similar with present embodiment, so the performance data of accompanying drawing and material no longer is provided in following examples 2 to 6.
Embodiment 2
(1) mixed solution of preparation polycaprolactone/tacrolimus:
At first the polycaprolactone with number-average molecular weight 20,000 is dissolved in the dichloromethane, and the preparation solid concentration is the solution a of 75mg/ml; Again tacrolimus is dissolved in acetone, being made into concentration is the drug solution b of 3mg/ml; Again according to the requirement of drug loading, mix after taking respectively two parts of solution proper volume, after airtight ultrasonic half an hour, stand-by;
(2) spraying:
Utilize spraying equipment, pressure selection is 0.3MPa, mixed solution is sprayed on the collecting board that has been heated in advance 60 ℃;
(3) pass into hot-air:
Behind each spraying 40s, 60 ℃ hot-air 45s is passed through in the collecting board top; Repeat this process, reach actual desired thickness until plant sheet;
(4) drying:
Sample is placed vacuum drying oven, and vacuum drying is 5 days under the room temperature, and the slow release medicine carrying that can make a kind of polycaprolactone and be matrix is planted sheet;
(5) molding:
According to actual needs, cut into the sheet of planting of definite shape size.
Embodiment 3
(1) mixed solution of preparation polycaprolactone/triamcinolone acetonide:
At first the polycaprolactone with number-average molecular weight 80,000 is dissolved in the dichloromethane, and the preparation solid concentration is the solution a of 10mg/ml; Again triamcinolone acetonide is dissolved in acetone, being made into concentration is the drug solution b of 7mg/ml; Again according to the requirement of drug loading, mix after taking respectively two parts of solution proper volume, after airtight ultrasonic half an hour, stand-by;
(2) spraying:
Utilize spraying equipment, pressure selection is 0.15MPa, mixed solution is sprayed on the collecting board that has been heated in advance 40 ℃;
(3) pass into hot-air:
Behind each spraying 20s, 40 ℃ hot-air 15s is passed through in the collecting board top; Repeat this process, reach actual desired thickness until plant sheet;
(4) drying:
Sample is placed vacuum drying oven, and vacuum drying is 2 days under the room temperature, and the slow release medicine carrying that can make a kind of polycaprolactone and be matrix is planted sheet;
(5) molding:
According to actual needs, cut into the sheet of planting of definite shape size.
Embodiment 4
(1) mixed solution of preparation polycaprolactone/triamcinolone acetonide:
At first the polycaprolactone with number-average molecular weight 80,000 is dissolved in the dichloromethane, and the preparation solid concentration is the solution a of 75mg/ml; Again triamcinolone acetonide is dissolved in acetone, being made into concentration is the drug solution b of 15mg/ml; Again according to the requirement of drug loading, mix after taking respectively two parts of solution proper volume, after airtight ultrasonic half an hour, stand-by;
(2) spraying:
Utilize spraying equipment, pressure selection is 0.3MPa, mixed solution is sprayed on the collecting board that has been heated in advance 60 ℃;
(3) pass into hot-air:
Behind each spraying 20s, 60 ℃ hot-air 45s is passed through in the collecting board top; Repeat this process, reach actual desired thickness until plant sheet;
(4) drying:
Sample is placed vacuum drying oven, and vacuum drying is 5 days under the room temperature, and the slow release medicine carrying that can make a kind of polycaprolactone and be matrix is planted sheet;
(5) molding:
According to actual needs, cut into the sheet of planting of definite shape size.
Embodiment 5
(1) mixed solution of preparation Poly(D,L-lactide-co-glycolide/triamcinolone acetonide:
At first Poly(D,L-lactide-co-glycolide (50:50) is dissolved in the dichloromethane, the preparation solid concentration is the solution a of 10mg/ml; Again triamcinolone acetonide is dissolved in acetone, being made into concentration is the drug solution b of 10mg/ml; Again according to the requirement of drug loading, mix after taking respectively two parts of solution proper volume, after airtight ultrasonic half an hour, stand-by;
(2) spraying:
Utilize spraying equipment, pressure selection is 0.15MPa, mixed solution is sprayed on the collecting board that has been heated in advance 40 ℃;
(3) pass into hot-air:
Behind each spraying 40s, 40 ℃ hot-air 15s is passed through in the collecting board top; Repeat this process, reach actual desired thickness until plant sheet;
(4) drying:
Sample is placed vacuum drying oven, and vacuum drying is 2 days under the room temperature, and the slow release medicine carrying that can make a kind of Poly(D,L-lactide-co-glycolide and be matrix is planted sheet;
(5) molding:
According to actual needs, cut into the sheet of planting of definite shape size.
Embodiment 6
(1) mixed solution of preparation Poly(D,L-lactide-co-glycolide/tacrolimus:
At first Poly(D,L-lactide-co-glycolide (50:50) is dissolved in the dichloromethane, the preparation solid concentration is the solution a of 75mg/ml; Again tacrolimus is dissolved in acetone, being made into concentration is the drug solution b of 10mg/ml; Again according to the requirement of drug loading, mix after taking respectively two parts of solution proper volume, after airtight ultrasonic half an hour, stand-by;
(2) spraying:
Utilize spraying equipment, pressure selection is 0.3MPa, mixed solution is sprayed on the collecting board that has been heated in advance 60 ℃;
(3) pass into hot-air:
Behind each spraying 20s, 60 ℃ hot-air 45s is passed through in the collecting board top; Repeat this process, reach actual desired thickness until plant sheet;
(4) drying:
Sample is placed vacuum drying oven, and vacuum drying is 5 days under the room temperature, and the slow release medicine carrying that can make a kind of Poly(D,L-lactide-co-glycolide and be matrix is planted sheet;
(5) molding:
According to actual needs, cut into the sheet of planting of definite shape size.
The invention is not restricted to above embodiment.
Claims (9)
1. a layer assembly mosaic structure medicament slow release is planted sheet, it is characterized in that this plants sheet and made by following steps and technique:
(1) prepared polymer/medicament mixed solution:
In organic solvent, the preparation solid concentration is the solution a of 10mg/ml-75mg/ml with polymer dissolution; In organic solvent, being made into concentration is the drug solution b of 1mg/ml-10mg/ml with medicine dissolution; Again according to the requirement of drug loading, mix after taking respectively two parts of solution proper volume, through airtight supersound process;
(2) spraying:
Utilize spraying equipment, pressure selection is 0.1 MPa-0.5MPa, mixed solution is sprayed on the collecting board that has been heated in advance 35 ℃-80 ℃;
(3) pass into hot-air:
Behind each spraying 1s-60s, hot-air 1s-60s of 35 ℃-80 ℃ is passed through in the collecting board top; Repeat this process, reach actual desired thickness until plant sheet;
(4) drying:
Sample is placed vacuum drying oven, and under the room temperature vacuum drying 1-7 days, the slow release medicine carrying that can make a kind of polycaprolactone and be matrix was planted sheet;
(5) molding: according to actual needs, cut into the sheet of planting of definite shape size.
2. a kind of layer assembly mosaic structure medicament slow release according to claim 1 is planted sheet, it is characterized in that: in the step (1), described polymer is that number-average molecular weight is 20,000-80,000 polycaprolactone.
3. a kind of layer assembly mosaic structure medicament slow release according to claim 1 is planted sheet, it is characterized in that: in the step (1), and the organic solvent of described dissolve polymer and the solvent of dissolved substance, two kinds of solvents can dissolve each other.
4. a kind of layer assembly mosaic structure medicament slow release according to claim 1 is planted sheet, it is characterized in that: in the step (1), the described closed ultrasonic processing time is half an hour.
5. a kind of layer assembly mosaic structure medicament slow release according to claim 1 is planted sheet, it is characterized in that: in the step (2), the pressure selection of described spraying equipment is 0.15MPa-0.3MPa, and the collecting board temperature is heated to 40 ℃-60 ℃.
6. a kind of layer assembly mosaic structure medicament slow release according to claim 1 is planted sheet, it is characterized in that: in the step (3), described spray time is 20s-40s.
7. a kind of layer assembly mosaic structure medicament slow release according to claim 1 is planted sheet, it is characterized in that: in the step (3), 40 ℃-60 ℃ hot-air is passed through in described collecting board top, and the time is 15s-45s.
8. a kind of layer assembly mosaic structure medicament slow release according to claim 1 is planted sheet, it is characterized in that: in the step (4), vacuum drying is 2 days-5 days under the described room temperature.
9. a layer assembly mosaic structure medicament slow release is planted sheet, it is characterized in that this plants sheet and made by following steps and technique:
(1) prepared polymer/medicament mixed solution:
In organic solvent, the preparation solid concentration is the solution a of 10mg/ml-75mg/ml with polymer dissolution; In organic solvent, being made into concentration is the drug solution b of 1mg/ml-10mg/ml with medicine dissolution; Again according to the requirement of drug loading, mix after taking respectively two parts of solution proper volume, through airtight supersound process;
(2) spraying:
Utilize spraying equipment, pressure selection is 0.1 MPa-0.5MPa, mixed solution is sprayed on the collecting board that has been heated in advance 35 ℃-80 ℃;
(3) pass into hot-air:
Behind each spraying 1s-60s, hot-air 1s-60s of 35 ℃-80 ℃ is passed through in the collecting board top; Repeat this process, reach actual desired thickness until plant sheet;
(4) drying:
Sample is placed vacuum drying oven, and under the room temperature vacuum drying 1-7 days, the slow release medicine carrying that can make a kind of Poly(D,L-lactide-co-glycolide and be matrix was planted sheet;
(5) molding: according to actual needs, cut into the sheet of planting of definite shape size.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110373937 CN102406627B (en) | 2011-11-22 | 2011-11-22 | Medicinal slow release inserted slice possessing layer-by-layer assembly mosaic structure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110373937 CN102406627B (en) | 2011-11-22 | 2011-11-22 | Medicinal slow release inserted slice possessing layer-by-layer assembly mosaic structure |
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| Publication Number | Publication Date |
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| CN102406627A CN102406627A (en) | 2012-04-11 |
| CN102406627B true CN102406627B (en) | 2013-03-13 |
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| CN100366249C (en) * | 2002-09-29 | 2008-02-06 | 天津帝士力投资控股集团有限公司 | Control releasing administration system for temozolomide |
| WO2006071208A1 (en) * | 2004-12-23 | 2006-07-06 | Durect Corporation | Polymeric implants, preferably containing a mixture of peg and plg, for controlled release of a gnrh |
| EP2233134A1 (en) * | 2009-03-27 | 2010-09-29 | McNeil AB | Multi-portion intra-oral dosage form with organoleptic properties |
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