HRP20000142A2 - Pharmaceutical preparation comprising clodronate as active ingredient and silicified microcrystalline cellulose as excipient - Google Patents
Pharmaceutical preparation comprising clodronate as active ingredient and silicified microcrystalline cellulose as excipient Download PDFInfo
- Publication number
- HRP20000142A2 HRP20000142A2 HR20000142A HRP20000142A HRP20000142A2 HR P20000142 A2 HRP20000142 A2 HR P20000142A2 HR 20000142 A HR20000142 A HR 20000142A HR P20000142 A HRP20000142 A HR P20000142A HR P20000142 A2 HRP20000142 A2 HR P20000142A2
- Authority
- HR
- Croatia
- Prior art keywords
- microcrystalline cellulose
- clodronate
- silicified microcrystalline
- tablets
- preparation according
- Prior art date
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- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 title claims abstract description 43
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 11
- 229960002286 clodronic acid Drugs 0.000 title abstract description 37
- 239000000546 pharmaceutical excipient Substances 0.000 title description 15
- 239000004480 active ingredient Substances 0.000 title description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000006186 oral dosage form Substances 0.000 claims abstract description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 18
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 17
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 17
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 17
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 17
- 239000000377 silicon dioxide Substances 0.000 claims description 13
- HJKBJIYDJLVSAO-UHFFFAOYSA-L clodronic acid disodium salt Chemical compound [Na+].[Na+].OP([O-])(=O)C(Cl)(Cl)P(O)([O-])=O HJKBJIYDJLVSAO-UHFFFAOYSA-L 0.000 claims description 11
- 238000005550 wet granulation Methods 0.000 claims description 10
- 235000012239 silicon dioxide Nutrition 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 7
- 239000013543 active substance Substances 0.000 claims description 6
- 238000007907 direct compression Methods 0.000 claims description 5
- 238000007908 dry granulation Methods 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 25
- 230000000694 effects Effects 0.000 abstract 1
- 230000001184 hypocalcaemic effect Effects 0.000 abstract 1
- 239000008184 oral solid dosage form Substances 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 55
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 18
- 239000008117 stearic acid Substances 0.000 description 12
- 235000021355 Stearic acid Nutrition 0.000 description 11
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 11
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 11
- XWHPUCFOTRBMGS-UHFFFAOYSA-L disodium clodronate tetrahydrate Chemical compound O.O.O.O.[Na+].[Na+].OP([O-])(=O)C(Cl)(Cl)P(O)([O-])=O XWHPUCFOTRBMGS-UHFFFAOYSA-L 0.000 description 10
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 9
- 235000019359 magnesium stearate Nutrition 0.000 description 9
- 239000008187 granular material Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 4
- 239000007909 solid dosage form Substances 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- -1 clodronate Chemical compound 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 239000004067 bulking agent Substances 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical class CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000007961 artificial flavoring substance Substances 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 208000022458 calcium metabolism disease Diseases 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- 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
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Silicates, Zeolites, And Molecular Sieves (AREA)
Description
Predmet ovog izuma je farmaceutski pripravak za peroralnu primjenu, osobito tableta, koji kao aktivni sastojak sadrži farmakološki prihvatljivu sol diklorometilen bisfosfonske kiseline, tj. klodronat, osobito dinatrij klodronat, a kao ekscipijens sadrži silicificiranu mikrokristalnu celulozu. Daljnji predmeti izuma su proces za proizvodnju spomenutog farmaceutskog pripravka, kao i uporaba silicificirane mikrokristalne celuloze za proizvodnju spomenutog farmaceutskog pripravka.
Klodronat ili dinatrijeva sol diklorometilen bisfosfonske kiseline, tetrahidrat, korisna je, primjera radi, pri liječenju i profilaksi poremećaja metabolizma kalcija, kao što su resorpcija kosti, hiperkalcemija i osteoporoza. Zbog svojeg svojstva da tvori čvrst kompleks s Ca2+ ionom, klodronat uklanja višak kalcija iz krvotoka, sprečava otpuštanje kalcij fosfata iz kostiju i/ili djeluje putem stanično posredovanih mehanizama.
Klodronat se ranije primjenjivao peroralno u obliku uobičajenih stlačenih tableta ili kapsula. Takva tableta ili kapsula razgrađuje se u želucu bolesnika i oslobađa aktivnu tvar, koja u kiseloj sredini želuca prelazi u slobodni kiseli oblik. Kako se klodronska kiselina relativno slabo apsorbira, bioraspoloživost aktivne tvari bit će niska, te se klodronat treba primijeniti u relativno visokim dozama tijekom produljenog razdoblja. Prema tome, problem s pripravcima klodronata je kako postići dovoljno visoke količine i koncentracije aktivne tvari u kapsuli ili tableti bez uporabe kapsula ili tableta takvih dimenzija koje bi za bolesnika bile neugodno velike.
Slijedeći je problem s pripravcima klodronata to što je vrlo teško primiješati neobrađenu sirovu tvar klodronata u homogenu smjesu s drugim ekscipijensima i aktivnim sastojcima koji su prisutni u pripravku. Na primjer, EP 275468 opisuje proces u kojem se klodronatna sirova tvar i ekscipijens miješaju u suhom stanju, doda se tekućina za granuliranje, smjesa se podvrgne mokroj granulaciji i granulat se osuši. Radi svojstava klodronata, tako dobiveni klodronatni prašak je netočan glede svog sastava i s njim se očigledno teško rukuje (ljepljiv je, ima slabo svojstvo tečnosti). Stoga je u praksi vrlo teško njegovo miješanje s drugim tvarima koje se koriste u pripravku, kao i njegovo daljnje procesuiranje, pri čemu je, na primjer, potrebna relativno velika količina glidansa. Iz homogenog sirovog praška dobije se potom nehomogena masa proizvoda niske tečnosti, što utječe i na preciznost doziranja konačnog lijeka.
Gore spomenuti problem vezan uz sirovu tvar klodronata djelomično je riješen procesom opisanim u WO 95/13054, u kojem se klodronat specifično kristalizira kao dinatrij klodronat tetrahidrat koji se potom suho granulira stlačivanjem na takav način da se očuva kristalna struktura dinatrij klodronat tetrahidrata. Tvrdi se kako se procesom dobiju zrnca spremna za uporabu ujednačene kakvoće i dobrih svojstava pri rukovanju, pri čemu su ekscipijensi potrebni u značajno manjim količinama nego u prethodnim postupcima. Međutim, ovo ne rješava probleme vezane uz pripravu oblika za doziranje klodronata mokrim granuliranjem.
Mokro granuliranje ima široku primjenu u farmaceutskoj industriji, za pripravu krutih oblika za doziranje, radi prednosti koje nudi u poredbi sa suhim granuliranjem i izravnim stlačivanjem. Obično je količina ekscipijensa potrebna za mokro granuliranje manja od one potrebne za izravno stlačivanje, pa se tako može dobiti tableta prihvatljive veličine. Mokro granuliranje također omogućuje da se tvar stlači s povoljnijim svojstvima ovlaženosti i česticama koje sadrže nastali granulat s optimalnom veličinom i oblikom čestica. Također, količina lijeka u zrncima je približno jednaka, pa je stoga jednolikost konačnog sastava pripravka općenito poboljšana.
Mikrokristalna celuloza je čest ekscipijens koji se koristi u pripravcima koji su mokro granulirani prije tabletiranja. Prikladna je ne samo za dodavanje mase dovršenom proizvodu, već ima i dodatna svojstva koja pospješuju stvaranje peleta. Nažalost, izlaganje mikrokristalne celuloze vlazi u procesu mokrog granuliranja ozbiljno umanjuje stlačivost ovog ekscipijensa. Ovo je osobito problematično u slučajevima kada je poželjan farmaceutski pripravak s visokom dozom aktivne tvari, kao što je u slučaju klodronata, jer gubitak stlačivosti mikrokristalne celuloze znači da je potrebna veća količina ovog ekscipijensa da bi se dobio prihvatljivo stlačen konačni proizvod. Posljedica ovoga je porast mase, što čini konačni proizvod težim za gutanje i time umanje bolesnikovu suradljivost.
Prema izumu, otkriveno je kako je moguće postići peroralne oblike za doziranje klodronata prihvatljive veličine i ujednačene kakvoće, ali s dovoljno visokom količinom i koncentracijom aktivne tvari u pripravku. U procesu priprave novog peroralnog oblika za doziranje klodronata moguće je koristiti ne samo suho granuliranje, nego i mokro granuliranje i tehnike izravnog stlačivanja. Ovo se postiže ako je farmaceutski pripravak peroralni oblik za doziranje koji sadrži lako stlačivu silicificiranu mikrokristalnu celulozu kao ekscipijens.
Silicificirana mikrokristalna celuloza korištena u pripravku ovog izuma je mikrokristalna celuloza koja je suobrađena s oko 0.1 do oko 20% silicij dioksida, SiO2, prema količini mikrokristalne celuloze. Riječ je o aglomeratu mikrokristalne celuloze i silicij dioksida u kojem su mikrokristalna celuloza i silicij dioksid međusobno u bliskom dodiru. To znači da je silicij dioksid uklopljen s česticama mikrokristalne celuloze, ali nema kemijske reakcije između te dvije tvari. U praksi se ovo postiže npr. sušenjem pomoću raspršivanja suspenzije mikrokristalne celuloze i silicij dioksida.
Prednost uporabe silicificirane mikrokristalne celuloze u pripravcima klodronata je općenito poboljšana funkcionalnost u pogledu npr. protoka praška, kompaktibilnosti, tvrdoće tableta i, posebno, smanjene mrvljivosti. Kruti oblici za doziranje koji sadrže veliku količinu klodronata sada su dostupni tehnikama izravnog stlačivanja, suhog granuliranja ili mokrog granuliranja. Količina silicificirane mikrokristalne celuloze koja se mora koristiti u postupku priprave da bi se mogao dobiti prihvatljiv kruti oblik doziranja je značajno smanjena u usporedbi s količinom obične mikrokristalne celuloze koja bi bila korištena u istu svrhu. Logična posljedica ovog je značajno smanjenje veličine tablete. Kruti pripravci klodronata prema izumu također imaju ujednačenu kakvoću i posjeduju izvrsna svojstva razgradnje i otapanja.
Izdašna mrvljivost predstavljala je problem naročito kod tableta koje sadrže klodronat. Izdašna mrvljivost znači kako se tablete lako komadaju ili lome u dijelove. Iznenađujuće, i ovaj se problem može prevladati uporabom silicificirane mikrokristalne celuloze. Osoba upućena u struku očekivala bi da će silicij dioksid u silicificiranoj mikrokristalnoj celulozi djelovati na obrnut način kada se koristi u pripravcima klodronata, tj. da će smanjiti sila potrebna za lomljenje i povećati mrvljivost, što glidansi obično čine.
Međutim, jedna od prednosti uporabe silicificirane mikrokristalne celuloze za proizvodnju pripravaka klodronata jest ta da silicij dioksid iz silicificirane mikrokristalne celuloze može također djelovati kao glidans, a uz to poboljšava svojstva mikrokristalne celuloze.
U procesu priprave tableta klodronata koje sadrže silicificiranu mikrokristalnu celulozu, također je moguće najprije granulirati klodronat (tehnikom mokrog granuliranja ili suhog granuliranja), a zatim miješati suha zrnca s silicificiranom mikrokristalnom celulozom te, ako se želi, s drugim ekscipijensima prije izravnog stlačivanja smjese u tablete. Tehnički je ovaj proces vrlo zgodan i njime se dobivaju tablete klodronata sa svim gore şpomenutim prednostima.
Daljnje prednosti uporabe silicificirane mikrokristalne celuloze za proizvodnju pripravaka klodronata, osobito tableta klodronata, očituju se u povećanju brzine proizvodnje i, posljedično, tehnički i ekonomski zgodan proces proizvodnje. Tablete koje sadrže klodronat i običnu mikrokristalnu celulozu mogu se oblikovati kao tablete vrlo malom brzinom u usporedbi s tabletama koje sadrže klodronat i silicificiranu mikrokristalnu celulozu. Uporaba silicificirane mikrokristalne celuloze omogućuje značajno povećanje brzine proizvodnje bez nepovoljnog djelovanja na kakvoću tableta, kao što je prikazano u Primjeru 8.
Ako se želi, i drugi se ekscipijensi osim silicificirane mikrokristalne celuloze mogu koristiti u krutim oblicima za doziranje prema izumu. Ovi su ekscipijensi poznati osobi upućenoj u struku, a njihova uporaba u proizvodnji pripravaka klodronata je opisana npr. u EP 336851, SAD 3683080 i SAD 4234645.
Prema tome, priprava prema ovom izumu može nadalje obuhvaćati uobičajene glidanse i lubrikanse, kao što su stearinska kiselina ili njezine soli (Mg-, Ca-), talk, škrob ili smjese dvaju ili više glidansa. Ako se želi, može se dodati i dodatna količina koloidnog silicija pored onoga koji je uključen u silicificiranu mikrokristalnu celulozu.
Sredstva za ispunjavanje (sredstva za odmjeravanje težine) koja se mogu koristiti su na primjer laktoza, škrob ili njegovi derivati, manitol, glukoza, saharoza, mikrokristalna celuloza ili smjesa dvaju ili više sredstava za ispunjavanje. Također se mogu koristiti prirodne ili umjetne arome ili zaslađivači.
Ako se želi, u pripravke se mogu dodati i dezintegratori. Riječ je o dezintegratorima općenito poznatima u struci, kao što su, primjera radi, križno vezana natrij karboksimetilceluloza, škrob ili njegovi derivati, kroskarmeloza, krospovidon ili smjese dvaju ili više dezintegratora.
Uporabom pojedinih ekscipijensa moguće je regulirati, ako se želi, hoće li se pripravak razgraditi u želucu ili tek kasnije u probavnom sustavu, kao i brzina otapanja. Shodno tome, pripravak može biti obložen takvim sredstvima za stvaranje filma, koja se otapaju na željenom pH, na primjer šelakom, celuloza acetat ftalatom, hidroksipropil metilceluloza ftalatom, polivinil acetat ftalatom, celuloza acetat trimelitatom ili različitim derivatima akrilne i metakrilne kiseline. Sredstva koja tvore film poznata su osobi upućenoj u struku i dostupna su na tržištu.
Pripravak koji sadrži klodronat i silicificiranu mikrokristalnu celulozu je prikladan za primjenu ne samo kao tableta, nego i u brojnim različitim pripravcima. Primjera radi, on može biti punjen u kapsule, ili korišten u obliku zrnaca ili praška prema postupcima općenito poznatima u struci, te dodatno obložen, ako se želi. Osobito se preporučuju tablete i kapsule.
Količina klodronata u obliku dostave lijeka prema izumu može varirati u širokim granicama, npr. od 10 do 95 mas%, a tipično je 50 do 90 mas%. Količina silicificirane mikrokristalne celuloze može varirati npr. od oko 1 do oko 50 mas%, a tipično je od oko 5 do oko 25 mas%. Preporučljivo, priprava prema izumu sadrži 60 do 80 mas% bezvodnog dinatrij klodronata, oko 8-20 mas% silicificirane mikrokristalne celuloze i 0.5-10 % drugih ekscipijensa, poput lubrikansa i dezintegratora.
Slijedeći primjeri ilustriraju izum ne ograničavajući ga.
Primjer 1
Pripravljene su tablete slijedećeg sastava, po tableti:
Dinatrij klodronat tetrahidrat 1000 mg, što odgovara
bezvodni dinatrij klodronat 800 mg
silicificirana mikrokristalna celuloza 205 mg
karmeloza natrij 22 mg
stearinska kiselina 15 mg
magnezij stearat 8 mg
Silicificirana mikrokristalna celuloza koja je korištena (Prosolv 90, Mendell, SAD) imala je koncentraciju silicij dioksida 2 mas%.
U prvoj fazi priprave tablete, suhi granulirani klodronat se navlaži sa stearinskom kiselinom u etanolu i potom suši na oko 30°C, do sadržaja vlage od otprilike 18.5 - 20 %. Suha zrnca se potom prosiju kroz sito od 1.5 mm. Zatim se zrnca klodronata-stearinske kiseline miješaju s karmeloza-natrijem, silicificiranom mikrokristalnom celulozom i magnezij stearatom. Smjesa se oblikuje u tablete u uređaju za tabletiranje, sa šilom od 9 x 20 mm, čime se dobiju tablete srednje mase od 1177 mg (±2.5%) i prikladne čvrstoće, na primjer 4-10 kg.
Ako se želi, pripravljene tablete se mogu obložiti otopinom za oblaganje, čiji sastav po jednoj tableti može biti na primjer slijedeći:
metil hidroksipropilceluloza ftalat 42.8 mg
dietil ftalat 6.4 mg
etanol q.s.
pročišćena voda q.s.
Primjer 2
Pripravljene su tablete slijedećeg sastava, po tableti:
Dinatrij klodronat tetrahidrat 1000 mg, što odgovara
bezvodni dinatrij klodronat 800 mg
silicificirana mikrokristalna celuloza 155 mg
karmeloza natrij 22 mg
stearinska kiselina 15 mg
magnezij stearat 8 mg
Tablete su u osnovi pripravljene na način opisan u Primjeru 1, uporabom iste vrste silicificirane mikrokristalne celuloze kao u Primjeru 1.
Primjer 3
Pripravljene su tablete slijedećeg sastava, po tableti:
Dinatrij klodronat tetrahidrat 1000 mg, što odgovara
bezvodni dinatrij klodronat 800 mg
silicificirana mikrokristalna celuloza 155 mg
karmeloza natrij 22 mg
stearinska kiselina 15 mg
magnezij stearat 8 mg
Silicificirana mikrokristalna celuloza koja je korištena (Prosolv 50, Mendell, SAD) imala je koncentraciju silicij dioksida 2 mas%. Tablete su u osnovi pripravljene kako je opisano u Primjeru 1.
Primjer 4
Pripravljene su tablete slijedećeg sastava, po tableti:
Dinatrij klodronat tetrahidrat 1000 mg, što odgovara
bezvodni dinatrij klodronat 800 mg
silicificirana mikrokristalna celuloza 140 mg
karmeloza natrij 22 mg
stearinska kiselina 15 mg
polivinilpirolidon 15 mg
magnezij stearat 8 mg
Silicificirana mikrokristalna celuloza koja je korištena (Prosolv 90, Mendell, SAD) imala je koncentraciju silicij dioksida 2 mas%. Tablete su u osnovi pripravljene kako je opisano u Primjeru 1, s iznimkom što je stearinska kiselina otopljena u polivinilpirolidonu umjesto u etanolu.
Primjer 5
Pripravljene su tablete slijedećeg sastava, po tableti:
Dinatrij klodronat tetrahidrat 1000 mg, što odgovara
bezvodni dinatrij klodronat 800 mg
silicificirana mikrokristalna celuloza 125 mg
karmeloza natrij 22 mg
stearinska kiselina 15 mg
magnezij stearat 8 mg
Tablete su u osnovi pripravljene kako je opisano u Primjeru 1, uporabom iste vrste silicificirane mikrokristalne celuloze kao u Primjeru 1.
Primjer 6
Pripravljene su tablete slijedećeg sastava, po tableti:
Dinatrij klodronat tetrahidrat 1000 mg, što odgovara
bezvodni dinatrij klodronat 800 mg
silicificirana mikrokristalna celuloza 132 mg
karmeloza natrij 22 mg
stearinska kiselina 15 mg
magnezij stearat 8 mg
Tablete su u osnovi pripravljene kako je opisano u Primjeru 1, uporabom iste vrste silicificirane mikrokristalne celuloze kao u Primjeru 1.
Primjer 7
Pripravljene su tablete slijedećeg sastava, po tableti:
Dinatrij klodronat tetrahidrat 1000 mg, što odgovara
bezvodni dinatrij klodronat 800 mg
silicificirana mikrokristalna celuloza 165 mg
karmeloza natrij 22 mg
stearinska kiselina 15 mg
magnezij stearat 8 mg
Silicificirana mikrokristalna celuloza koja je korištena (Prosolv 50, Mendell, SAD) imala je koncentraciju silicij dioksida 2 mas%. Tablete su u osnovi pripravljene kako je opisano u Primjeru 1, brzinom tabletiranja prikazanom u Tablici 1. Rezultati mjerenja sile potrebne za lomljenje i mrvljivost su također prikazani u Tablici 1.
Tablica 1. Sila potrebna za lomljenje i mrvljivost tableta iz Primjera 7, pripravljenih različitim brzinama tabletiranja
[image]
Primjer 8
Različitim brzinama tabletiranja su pripravljene tablete istog sastava kao tablete pripravljene u Primjeru 6. Radi usporedbe, tablete su također pripravljene različitim brzinama tabletiranja, uz slijedeći sastav po tableti:
Dinatrij klodronat tetrahidrat 1000 mg, što odgovara
bezvodni dinatrij klodronat 800 mg
mikrokristalna celuloza (Emcocel 50 M) 132 mg
karmeloza natrij 22 mg
stearinska kiselina 15 mg
magnezij stearat 8 mg
Mjerene su sila potrebna za lomljenje i mrvljivost. Rezultati su prikazani u Tablici 2.
Tablica 2. Sila potrebna za lomljenje i mrvljivost tableta koje sadrže silicificiranu mikrokristalnu celulozu (A) i tableta koje sadrže običnu mikrokristalnu celulozu (B). Tablete su pripravljene različitim brzinama tabletiranja, koje su navedene u Tablici 2.
[image] np = nije provedeno * = nije se moglo tabletirati
Tablete koje sadrže običnu mikrokristalnu celulozu ne mogu se tabletirati brzinom tabletiranja većom od 30000 tableta/h, jer bi došlo do lomljenja tableta.
Claims (10)
1. Farmaceutski pripravak koji sadrži farmakološki prihvatljivu sol diklorometilen bisfosfonske kiseline kao aktivnu tvar, naznačen time, što je u peroralnom krutom obliku za doziranje koji sadrži silicificiranu mikrokristalnu celulozu.
2. Pripravak prema zahtjevu 1, naznačen time, što sadrži 5 - 25 mas% silicificirane mikrokristalne celuloze.
3. Pripravak prema zahtjevu 1, naznačen time, što sadrži:
a) od oko 60 do 80 mas% bezvodnog dinatrij klodronata;
b) od oko 8 do 20 mas% silicificirane mikrokristalne celuloze; i
c) od oko 0.5 do 10 mas% lubrikansa i/ili dezintegratora.
4. Pripravak prema bilo kojem od prethodnih zahtjeva, naznačen time, što je silicij dioksid prisutan u obliku silicificirane mikrokristalne celuloze u količini od oko 0.1 do 20 mas%, prema težini mikrokristalne celuloze.
5. Pripravak prema bilo kojem od prethodnih zahtjeva, naznačen time, što je u obliku tablete ili kapsule.
6. Pripravak prema bilo kojem od prethodnih zahtjeva, naznačen time, što je sol diklorometilen bisfosfonske kiseline dinatrijeva sol.
7. Proces za proizvodnju farmaceutskog pripravka prema zahtjevu 1, naznačen time, što se koristi tehnika mokrog granuliranja.
8. Proces za proizvodnju farmaceutskog pripravka prema zahtjevu 1, naznačen time, što se koristi tehnika suhog granuliranja.
9. Proces za proizvodnju farmaceutskog pripravka prema zahtjevu 1, naznačen time, što se koristi tehnika izravnog stlačivanja.
10. Uporaba silicificirane mikrokristalne celuloze, naznačena time, što je u svrhu proizvodnje farmaceutskog pripravka koji sadrži farmakološki prihvatljivu sol diklorometilen bifosfonske kiseline kao aktivnu tvar.
Applications Claiming Priority (2)
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| FI973733A FI109088B (fi) | 1997-09-19 | 1997-09-19 | Tabletti ja menetelmä sen valmistamiseksi |
| PCT/FI1998/000735 WO1999015155A1 (en) | 1997-09-19 | 1998-09-18 | Pharmaceutical preparation comprising clodronate as active ingredient and silicified microcrystalline cellulose as excipient |
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Families Citing this family (86)
| Publication number | Priority date | Publication date | Assignee | Title |
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| SE9901272D0 (sv) * | 1999-04-09 | 1999-04-09 | Astra Ab | New improved formulation |
| SE9903345D0 (sv) | 1999-09-17 | 1999-09-17 | Astra Pharma Prod | Novel process |
| DE10006125C2 (de) * | 2000-02-11 | 2003-08-28 | Kallies Feinchemie Ag | Modifizierte Mikrocellulose |
| US6399101B1 (en) | 2000-03-30 | 2002-06-04 | Mova Pharmaceutical Corp. | Stable thyroid hormone preparations and method of making same |
| JP4722375B2 (ja) * | 2000-06-20 | 2011-07-13 | ノバルティス アーゲー | ビホスホネートの投与法 |
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| US7862552B2 (en) | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
| US8491930B2 (en) * | 2008-04-23 | 2013-07-23 | Farmasierra Manufacturing, S.L. | Pharmaceutical formulation containing ibuprofen and codeine |
| US8603527B2 (en) | 2010-10-25 | 2013-12-10 | Signal Pharmaceuticals, Llc | Pharmaceutical formulations of a substituted diaminopurine |
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| US9844559B2 (en) | 2012-05-14 | 2017-12-19 | Antecip Bioventures Ii Llc | Neridronic acid for treating bone marrow lesions |
| US20150051175A1 (en) * | 2012-05-14 | 2015-02-19 | Antecip Bioventures Ii Llc | Co-Administration of Steroids and Zoledronic Acid to Prevent and Treat Pain |
| US9707247B2 (en) | 2012-05-14 | 2017-07-18 | Antecip Bioventures Ii Llc | Compositions for administration of zoledronic acid or related compounds for treating low back pain |
| US9669040B2 (en) | 2012-05-14 | 2017-06-06 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
| US9867839B2 (en) | 2012-05-14 | 2018-01-16 | Antecip Bioventures Ii Llc | Osteoclast inhibitors for joint conditions |
| US9925203B2 (en) | 2012-05-14 | 2018-03-27 | Antecip Bioventures Ii Llc | Compositions for administration of zoledronic acid or related compounds for treating low back pain |
| US9956237B2 (en) | 2012-05-14 | 2018-05-01 | Antecip Bioventures Ii Llc | Osteoclast inhibitors for knee conditions |
| US10028969B2 (en) | 2012-05-14 | 2018-07-24 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
| US9616078B2 (en) | 2012-05-14 | 2017-04-11 | Antecip Bioventures Ii Llc | Dosage forms for oral administration of zoledronic acid or related compounds for treating disease |
| US10016446B2 (en) | 2012-05-14 | 2018-07-10 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating Paget's disease of bone |
| US10092581B2 (en) | 2014-05-15 | 2018-10-09 | Antecip Bioventures Ii Llc | Osteoclast inhibitors such as zoledronic acid for low back pain treatment |
| US9861648B2 (en) | 2012-05-14 | 2018-01-09 | Antecip Boiventures Ii Llc | Osteoclast inhibitors for knee conditions |
| US10016445B2 (en) | 2012-05-14 | 2018-07-10 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
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| SI3436019T1 (sl) | 2016-04-01 | 2021-12-31 | Signal Pharmaceuticals, Llc | (1s,4s)-4-(2-(((3s,4r)-3-fluorotetrahidro-2h-piran-4-il)amino)-8-((2,4, 6-triklorofenil)amino)-9h-purin-9-il)-1-metilcikloheksane-1-karboksamid in metode uporabe |
| JP7014731B2 (ja) | 2016-04-01 | 2022-02-01 | シグナル ファーマシューティカルズ，エルエルシー | 置換アミノプリン化合物、その組成物、及びそれらを用いた治療方法 |
| JP2020536100A (ja) | 2017-10-04 | 2020-12-10 | セルジーン コーポレイション | シス−４−［２−｛［（３ｓ，４ｒ）−３−フルオロキサン−４−イル］アミノ｝−８−（２，４，６−トリクロロアニリノ）−９ｈ−プリン−９−イル］−１−メチルシクロヘキサン−１−カルボキサミドの製造プロセス |
| EA202090884A1 (ru) | 2017-10-04 | 2020-06-26 | Селджин Корпорейшн | Композиции и способы применения цис-4-[2-{[(3s,4r)-3-фтороксан-4-ил]амино}-8-(2,4,6-трихлоранилино)-9н-пурин-9-ил]-1-метилциклогексан-1-карбоксамида |
| CN110787140A (zh) * | 2018-08-01 | 2020-02-14 | 北京万全德众医药生物技术有限公司 | 比拉斯汀片剂及其制备方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE60711T1 (de) * | 1986-12-20 | 1991-02-15 | Boehringer Mannheim Gmbh | Clodronat-haltige arzneimittel und verfahren zur herstellung derselben. |
| NZ254765A (en) * | 1993-05-15 | 1997-02-24 | Boehringer Mannheim Gmbh | Tablet medicament; comprises dichloromethylene diphosphonic acid (clodronic acid) or a pharmaceutically acceptable salt thereof as active ingredient and microcrystalline cellulose as auxiliary |
| FI94926C (fi) * | 1993-11-12 | 1995-11-27 | Leiras Oy | Menetelmä klodronaattivalmisteen valmistamiseksi |
| US5585115A (en) * | 1995-01-09 | 1996-12-17 | Edward H. Mendell Co., Inc. | Pharmaceutical excipient having improved compressability |
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