NO311349B1 - D-mannitol og dens fremstilling, samt faststoffsammensetning inneholdende D-mannitol - Google Patents
D-mannitol og dens fremstilling, samt faststoffsammensetning inneholdende D-mannitol Download PDFInfo
- Publication number
- NO311349B1 NO311349B1 NO19984803A NO984803A NO311349B1 NO 311349 B1 NO311349 B1 NO 311349B1 NO 19984803 A NO19984803 A NO 19984803A NO 984803 A NO984803 A NO 984803A NO 311349 B1 NO311349 B1 NO 311349B1
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- Norway
- Prior art keywords
- mannitol
- crystals
- examples
- approx
- hydrochloride
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- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
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- URWAJWIAIPFPJE-YFMIWBNJSA-N sisomycin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N URWAJWIAIPFPJE-YFMIWBNJSA-N 0.000 description 1
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- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- HLFCZZKCHVSOAP-WXIWBVQFSA-M sodium;(5e)-5-(carbamoylhydrazinylidene)-1-methyl-6-oxo-2,3-dihydroindole-2-sulfonate Chemical compound [Na+].NC(=O)N\N=C/1C(=O)C=C2N(C)C(S([O-])(=O)=O)CC2=C\1 HLFCZZKCHVSOAP-WXIWBVQFSA-M 0.000 description 1
- DVVRRDZBTZGGCT-WKSAPEMMSA-M sodium;[2-[(8s,9r,10s,11s,13s,14s,16r,17r)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] sulfate Chemical compound [Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COS([O-])(=O)=O)(O)[C@@]1(C)C[C@@H]2O DVVRRDZBTZGGCT-WKSAPEMMSA-M 0.000 description 1
- LTWZNVWFOGRESW-WDCKKOMHSA-M sodium;[2-[(8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] sulfate Chemical compound [Na+].O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COS([O-])(=O)=O)[C@@H]4[C@@H]3CCC2=C1 LTWZNVWFOGRESW-WDCKKOMHSA-M 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- YRALAIOMGQZKOW-UHFFFAOYSA-N sulfated caerulein Natural products C=1C=CC=CC=1CC(C(N)=O)NC(=O)C(CC(O)=O)NC(=O)C(CCSC)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(C(C)O)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)C(CCC(N)=O)NC(=O)C1NC(=O)CC1)CC1=CC=C(OS(O)(=O)=O)C=C1 YRALAIOMGQZKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
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- 235000019157 thiamine Nutrition 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 description 1
- 229960003873 thymostimulin Drugs 0.000 description 1
- 230000002916 thymostimulin Effects 0.000 description 1
- 229960004659 ticarcillin Drugs 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
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- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- FAPSXSAPXXJTOU-UHFFFAOYSA-L trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;dibromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C FAPSXSAPXXJTOU-UHFFFAOYSA-L 0.000 description 1
- 229960002655 tubocurarine chloride Drugs 0.000 description 1
- IESDGNYHXIOKRW-LEOABGAYSA-N tuftsin Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-LEOABGAYSA-N 0.000 description 1
- 229940035670 tuftsin Drugs 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
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- 238000005550 wet granulation Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C31/18—Polyhydroxylic acyclic alcohols
- C07C31/26—Hexahydroxylic alcohols
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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
- A61P3/06—Antihyperlipidemics
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Treatments For Attaching Organic Compounds To Fibrous Goods (AREA)
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Description
Oppfinnelsen angår en ny D-mannitol og dens fremstilling, samt faststoffsammensetning inneholdende D-mannitol. Mer spesifikt angår den D-mannitol som kan bli anvendt som en eksipient med ypperlig sammenpressbarhet innenfor fagfeltet for fremstilling av medikamenter og matprosesseirngsindustri, og en fremgangsmåte for å fremstille den. D-mannitol er ypperlig når det gjelder sikkerhet og kompatibilitet med fysiologisk aktive substanser. Siden den ikke er hygroskopisk og ikke beholder noe vesentlig fuktighet, har den høy verdi som en eksipient for formulering av særlig en fysiologisk aktiv substans med høy fuktighetssensitivitet til tabletter eller kapsler. På den annen side er D-mannitol dårlig når det gjelder bindbarhet når den er utsatt for sammenpressing, og ved siden av dens friksjon med en metallvegg er sterk. Disse manglene har en tendens til å forårsake stansefriksjon eller kapping ved sammenpressing, hvilket mislykkes i å gi tilstrekkelig hardhet til tablettene, og gir slitasje på veggen av en stanse og på sideoverflaten av et stempel, og gjør til og med ofte kjøring av tabletteringsmaskinen vanskelig. I lys av det foregående har anvendelse av D-mannitol som eksipient vært begrenset i meget begrensede doseringsformer slik som tyggbare tabletter. D-mannitol er krystallinsk pulver som har polymorfe former klassifisert i ct-form, B-form og 8-form ved røntgendiffraksjonsmønstre [Walter-Levy, L., Acad. Sc. Paris, t. 267 Series C, 1779 (1968)]. For forbedring av sammenpressbarhet av det krystallinske pulveret, har det generelt vært kjent, at krystaller som er finoppmalt for å øke bindingspunktene gir en bedre sammenpressbarhet. I det tilfellet med D-mannitol, vil mer oppmalt til fint pulver øke friksjon med metallveggen når den blir utsatt for sammenpressing, og involverer også problemer når det gjelder behandling slik som forstøving og senking av fluiditet.
I Journal of Pharmaceutical Sciences, 53 (2), 188-192 (1964) er det en rapport på en metode for å oppnå D-mannitol forbedret når det gjelder dens sammenpressbarhet, hvilken omfatter sammensmelting av D-mannitol, og umiddelbar avkjøling. Forbedringen når det gjelder sammenpressbarhet som fremkom i denne metoden er ikke den som tilstrekkelig tilfredsstiller kravene i formuleringsprosessen. Prosedyren er spesifikk slik at den er vanskelig å anvendé i en industriell produksjonsskala, hvilket ikke tilfredsstiller problemet fra et kostnadssynspunkt.
Et mål med oppfinnelsen er å skaffe tilveie D-mannitol ved en enkel prosedyre, som er ypperlig når det gjelder pulveregenskaper og dramatisk forbedret når det gjelder sammenpressbarhet.
Et annet mål med oppfinnelsen er å tilveiebringe en prosess for fremstilling av D-mannitol.
Et annet mål med foreliggende oppfinnelse er å skaffe tilveie en faststoffsammensetning som omfatter D-mannitol som en eksipient.
Disse mål såvel som andre mål og fordeler ved foreliggende oppfinnelse vil fremkomme tydelig for personer med kunnskap innenfor fagområdet ved følgende beskrivelse med referanse til etterfølgende tegninger. Fig. 1 er en graf som illustrerer hardhet av de sammenpressede produktene fremstilt i eksempel 1 og den til det sammenpressede produktet fremstilt i sammenligningseksempel 1 heretter. I fig. 1 viser åpne sirkler og åpne kvadrater hhv. komparativt sammenpressede produkter som anvender ubehandlede 5-form krystaller og B-form krystaller, mens fylte sirkler og fylte kvadrater viser hhv. resultatene som ble observert i det sammenpressede produktet fremstilt ved anvendelse av behandlede krystaller i eksempel 1 og sammenligningseksempel 1. Fig. 2 er scanningselektronmikroskopisk kilde av D-mannitol i foreliggende oppfinnelse fremstilt i eksempel 1.
Fig. 3 er scanningselektronmikroskopisk bilde av 5-form krystaller.
Fig. 4 er respektive pulver røntgendiffraksjonsmønstre av D-mannitol fra foreliggende oppfinnelse og 5-form og B-form mannitol. Fig. 5 er respektive hardheter av det sammenpressede produktet fremstilt i eksempel 2 og den fra det sammenpressede produktet fremstilt i sammenligningseksempel 2 i det etterfølgende. Fig. 6 er en graf som illustrerer respektiv hardhet av det sammenpressede produktet fra eksempel 3 og den til det sammenpressede produktet i sammenligningseksempel 3 i det etterfølgende. Fig. 7 er en graf som illustrerer respektiv styrke av det sammenpressede produktet fra eksempel 4 og den til det sammenpressede produktet fra sammenligningseksempel 4. Fig. 8 er en graf som illustrerer forhold av mengde av renset vann anvendt for behandling av 5-form krystallene med egenskapene til resulterende D-mannitol.
Under disse omstendigheter har foreliggende oppfinnere intensivt gjennomført studier for å etablere en fremgangsmåte for fremstilling av D-mannitol som er ypperlig når det gjelder pulveregenskaper og forbedret når det gjelder sammenpressbarhet, ved en enkel fremgangsmåte. Som et resultat har det blitt funnet at når 6-form krystaller blir brakt i kontakt med et vannoppløselig oppløsningsmiddel, blir de omdannet til B-formen ved kontaktgrenseflaten for å gi finkrystallinsk utfellinger. Dette fenomen har inspirert foreliggende oppfinnere til at D-mannitol som består av en aggregering av fine krystaller kunne bli oppnådd. Foreliggende oppfinnelse har blitt fullført ved oppfinnernes ytterligere intensive undersøkelser basert på denne antydning.
Ifølge foreliggende oppfinnelse blir det skaffet tilveie D-mannitol som har spesifikt overflateareal som ikke er mindre enn ca. 1 m<2>/g, særlig slik D-mannitol som omfatter en blanding av 5-form krystaller og B-form krystaller.
Et annet trekk skaffer foreliggende oppfinnelse tilveie en fremgangsmåte for fremstilling av D-mannitol som har et spesifikt overflateareal som er mindre enn ca. 1 m<2>/g som omfatter behandling av 5-form D-mannitol krystaller med et vann-oppløselig oppløsningsmiddel, etterfulgt av tørking.
I denne sammenheng er det foretrukket å anvende det vann-løselige oppløsningsmiddel i en mengde på ca. 3 til ca. 70 v/v% basert på vekt av 5-form D-mannitol krystallene.
Et annet trekk skaffer foreliggende oppfinnelse tilveie en faststoffsammensetning som omfatter D-mannitol som har et spesifikt overflateareal som ikke er mindre enn ca. 1 m<2>/g. Den faste sammensetningen i oppfinnelsen omfatter videre fortrinnsvis en farmakologisk aktiv komponent, f eks. en høy-fuktighets-sensitiv komponent. D-mannitol i foreliggende oppfinnelse er B-form krystallene alene eller en blanding derav med 5-form krystallene, som er et aggregat av D-mannitol krystaller hvis spesifikke overflateareal ikke er mindre enn ca. 1 m<2>/g, fortrinnsvis ikke mindre enn ca. 1,5 m<2>/g, normalt ca. 1,5 til ca. 4 m<2>/g.
Det spesifikke overflatearealet som her blir anvendt er det som er beregnet med BET metoden som har vid generell anvendelse.
Fra synspunktet med hensiktsmessighet ved utnyttelse som additiver eller eksipienter av farmasøytiske preparater eller matprodukter, er D-mannitol fortrinnsvis i den tilstand av granuler av krystallinsk aggregat særlig hvis gjennomsnittlig størrelse er ca. 0,05 til ca. 5,0 mm, mer å foretrekke ca. 0,08 til ca. 2,0 mm i diameter. Former for krystallinsk aggregat er imidlertid ikke spesifikt begrenset og en hvilken som helst form av krystallinsk aggregat som tilfredsstiller kravene, og f. eks. er nett-lignende eller plate-lignende er innbefattet i foreliggende oppfinnelse, så langt aggregatet har ovenfornevnte egenskaper.
oc-form, B-form og 8-form D-mannitol krystaller som her er beskrevet er definert i overensstemmelse med klassifikasjonen i polymorfe former av røntgendifrfaksjons-mønstre som er rapportert i Acad. Sc. Paris, t. 267 Serie C, 1779, (1968) av Walter-Levy, L. D-mannitol i foreliggende oppfinnelse kan bli fremstilt ved en fremgangsmåte som omfatter behandling av 5-form krystallene som benyttes som utgangsmateriale med et vannoppløselig løsningsmiddel og deretter tørking av det behandlede materialet, fortrinnsvis ved å utsette det for rask tørking for å sørge for omdanning av overflate eller innsiden av utgangskrystallene til fine B-formkrystaller. Fremgangsmåten omfatter mer spesifikt et trinn for fuktning av overflaten av S-form krystallene med et vannløselig oppløsningsmiddel som sørger for suksessiv omdanning av en del eller alle S-form krystallene reagert med oppløsningsmiddel til B-formen fra overflaten til innsiden, og et trinn med å tørke for å undertrykke vekst av resulterende B-form krystaller. Normalt eksisterer D-mannitol i foreliggende oppfinnelse som en blanding av 8-form krystaller av B-form krystaller. Forholdet av 8-form krystaller og B-form krystaller i blandingen er definert av ovenfornevnte omdanningstrinn av krystallform og krystallvoksetrinn. Den er imidlertid ikke spesifikt begrenset.
For behandling av 8-form krystallene med et vann-oppløselige løsningsmiddel, kan en hvilken som helst måte som fukter overflaten av de individuelle krystallene uten oppløsning fullstendig i vannoppløselig løsningsmiddel, f. eks. spraying av et vann-løselig oppløsningsmiddel på et tynt lag av 8-form krystallene eller risting under spraying eller drypping av et vann-løselig oppløsningsmiddel på 8-form krystallene, bli benyttet. I denne behandlingen kan andre komponenter eventuelt eksistere sammen så lenge overflaten av D-mannitol krystallene kan bli gjort fuktig. Som f.eks. beskrevet i de etterfølgende eksemplene, vil behandling av en del eller hele blandingen av et formulert sluttprodukt som inneholder D-mannitol med et vann-oppløselig løsemiddel også falle innenfor rekkevidden av oppfinnelsen.
Eksempler på vann-løselige oppløsningsmidler innbefatter renset vann, etanol, aceton eller en blanding av disse, og blandeforholdet er hensiktsmessig valgt avhengig av situasjonen. Blant disse blir renset vann, etanol og en blanding av disse fortrinnsvis benyttet.
Mengden av vann-løselig oppløsningsmiddel som skal bli anvendt blir hensiktsmessig valgt i henhold til den spesielle behandlingen av krystallene, det spesielle oppløsningsmiddel som skal bli anvendt eller lignende, normalt i området fra ca. 3% til ca. 70%, fortrinnsvis ca. 15% til ca. 40 vekt-% basert på vekt av utgangskrystallene. I det tilfellet man benytter en fremgangsmåte som omfatter tilsetning av det vann-løselige oppløsningsmidlet til utgangskrystallene og risting av blandingen, blir fortrinnsvis det vann-løselige oppløsningsmidlet tilsatt i en mengde fra ca. 5 v/v% eller mer i lys av diffusjonshastigheten av det vann-løselige oppløsningsmidlet. I tørketrinnet for å undertrykke vekst av finkrystallene som utvikles i ovenfor-beskrevne metode, er tiden som er nødvendig for tørking fortrinnsvis så kort som mulig. Rask tørking er derfor normalt foretrukket i mange tilfeller. På den annen side fortsetter omdanningen som er forårsaket av behandlingen med det vann-løselige oppløsningsmidlet inntil fullføring av omdanningen til B-formen. Tørking i fremgangsmåten i foreliggende oppfinnelse blir derfor bestemt avhengig av relasjon med omdanningshastigheten av krystallene, således er tørketiden ikke spesifikt begrenset. I det tilfellet med fremgangsmåten som omfatter blanding av utgangskrystallene med renset vann, er det derfor f.eks. foretrukket å fjerne det rensede vannet i løpet av 48 timer, fortrinnsvis 16 timer, mer å foretrekke 8 timer etter at krystaller og renset vann er homogent blandet. Tiden kan naturligvis variere med f.eks. behandlingsmetode, oppløsningsmiddel og tørkemetode som benyttes. Eksempler på tørkemetode innbefatter vakuumtørking, lufttørking, fluidisert sjikttørking, og dielektrisk høyfrekvenstørking og lignende, og blant disse er vakuumtørking foretrukket.
Den således oppnådde D-mannitol i foreliggende oppfinnelse har ovenfor-beskrevne spesifikke overflateareal og utviser en ypperlig sammenpressbarhet, og kan bli anvendt som en eksipient for direkte sammenpressing, våt-granulering eller tørr-granulering. Mannitol kan bli anvendt som en god eksipient innenfor fagfeltet farmasøytiske og matprodukter. Den er særlig nyttig for produksjon av en fast sammensetning som omfatter en farmakologisk aktiv komponent, et søtningsmiddel eller lignende.
Den faste sammensetningen i foreliggende oppfinnelse omfatter D-mannitol som har et spesifikt overflateareal som ikke er mindre enn ca. 1 m<2>/g. Sammensetningen i oppfinnelsen omfatter videre fortrinnsvis en farmakologisk aktiv komponent, et søtningsmiddel eller lignende. Sammensetningen kan inneholde en farmakologisk aktiv komponent, et søtningsmiddel eller lignende i en effektiv mengde. Sammensetningen i foreliggende oppfinnelse omfatter særlig fortrinnsvis en farmakologisk aktiv komponent.
Eksempler på farmakologisk aktiv komponent innbefatter fysiologisk aktive peptider, anti-tumormidler, antibiotika, antipyretiske midler, analgetiske midler, antiinflammatoriske midler, antihosteekspektoranter, bronkodilatorer, sedative midler, muskelrelakseringsmidler, antiepileptiske midler, antiulcermidler, antidepressive midler, antiallergiske midler, kardiotoniske midler, antiarrytmimidler, vasodilatorer, hypotensive diuretiske midler, antidiabetiske midler, antilipidemiske midler, antikoagulanter, hemostatiske midler, antituberkuløse midler, hormoner, narkotiske antagonister, benresorpsjonshemmende midler, osteogenesefremmende midler, angiogenesefremmende midler, angiogenesehemmende midler, vitaminer og lignende.
Eksempler på de fysiologisk aktive peptidene innbefatter LH-RH (luteiniserende hormonfirgjørende hormon) agonister [US-patenter 3.853.837, 4.008.209 og 3.972.859; britisk patent nr. 1.423.083; 78, 6509-6512 (1981)], LH-RH antagonister (US-patent nr. 4.086.219, 4.124.577, 4.253.997, 4.317.815 og 5.480.868), insulin, somatostatin, somatostatinderivater (sandostatin, US-patent nr. 4.087.390, 4.093.574, 4.100.117 og 4.253.998), veksthormoner, prolaktin, adrenocorticotropisk hormon (ACTH), ACTH derivater (f.eks. ebiratid, etc), melanocyt-stimulerende hormon (MSH), tyrotropin-frigjørende hormon (TRH) og dens derivater (JP-A 50-121273 og JP-A 52-116465), tyroid-stimulerende hormon (TSH), luteiniserende hormon (LH), follikelstimulerende hormon (FSH), vasopressin, vasopressinderivater [desmopressin (Nippon Naibunpi Gakkaishi, 54, 5, 676-691 (1978))], oksytocin, kalsitonin, paratyroidhormon (PTH), gulcagon, gastrin, sekretin, pankreozymin, kolecystokinin, angiotensin, human placentallaktogen, human korionisk gonadotropin (HCG), enkefalin, enkefalinderivater (US-patent nr. 4.277.394, EP-A 31567), endorfin, kyotorfin, interferoner (f.eks. IFN-a, B, y, etc.) interleukiner (f.eks. IL-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc), tuftsin, tymopoietin, tymosin, tymostimulin, tymisk humoral faktor (THF), blodtymisk faktor (FTS) og dens derivater (US-patent 4.229.438) og andre tymiske faktorer [Igaku no Ayumi, 125, 10, 835-843 (1983)], tumoraekrosefaktor (TNF), kolonistimulerende faktorer (CSF, GCSF, GMCSF, MCSF, etc), motilin, dynorfin, bombesin, neurotensin, kaerulein, bradykinin, urokinase, asparaginase, kallikrein, substans P, insulin-lignende vekstfaktorer (IGF-I, IGF-II), nervevekstfaktor (NGF), cellevekstfaktorer (EGF, TGF-a, TGF-B, PDGF, syreholdige FGF, basisk FGF, etc), osteogenesefaktor (BMP), neurotrofiske faktorer (NT-3, NT-4, CNTF, GDNF, BDNF, etc), blodkoagulerings-faktorer VIII og IX, lysozymklorid, polymyksin B, kolistin, gramicidin, bacitracin og erytropoietin (EPO), trombopoietin (TPO), polypeptider som har endotelantagonistisk aktivitet (EP-A 436189, 457195 og 496452; JP-A 3-94692, JP-A 3-130299) og lignende.
Eksempler på anti-tumormidler innbefatter blomycin, metotreksat, actinomycin D, mytomycin C, vinblasinsulfat, vincristinsulfat, daunorbicin, adriamycin, neokarzinostatin, cytosinarabinosid, fluorouracil, tetrahydrofuryl-5-fluorouracil, klestin, picibanil, lentinan, levamisol, bestatin, azimexon, glycyrrhizin, poly I:C, poly A:U, polylCLC og lignende.
Eksempler på antibiotiske midler omfatter gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracyklinhydroklorid, oksytetracyklinhydroksyklorid, rolitetracyklin, doksycyklinhydroklorid, ampicillin, piperacillin, ticarcillin, cefalotin, cefaloridin, cefotiam, cefsulodin, cefmenoksim, cefmetazol, cefazolin, cefotaksim, cefoperazon, ceftizoksim, moksalaktam, tienamycin, sulfazecin, azthreonam, ceftiam, heksetilhydroklorid, acetoksymetyl (+)-(5R, 6S)-6-[(R)-1 -hydroksyetyl] -7-okso-3 -(3 -pyirdyl)-4-tia-1 -azabicyklo [3.2.0]hept-2-ene-2-karbksylat og lignende.
Eksempler på antipyretiske midler, analgetiske midler og antiinflammatoriske midler innbefatter salicylsyre, sulpyrin, flufenaminsyre, diklofenak, indometicin, morfin, petidinhydroklorid, levorfanoltartrat, oksymorfon og lignende.
Eksempler på antihosteekspektoranter innbefatter efedrinhydroklorid, metylefedrin-hydroklorid, noscapinhydroklorid, codeinfosfat, dihydrocodeinfosfat, alloclamid-hydroklorid, clofedanolhydroklorid, picoperidaminhydroklorid, kloperastin, protokylolhydroklorid, isoproterenolhydroklorid, salbutamolsulfat, tertbutalinsulfat og lignende.
Eksempler på bronkodillatorer innbefatter fenylpropanolaminhydroklorid, teofyllin, salbutamolsulfat og lignende.
Eksempler på sedative midler innbefatter klorpromazin, proklorperazin, trifluorperazin, atropinsulfat, metylscopolaminbromid og lignende.
Eksempler på muskelavslappende midler innbefatter pridinolmetansulfonat, tubokurarinklorid, pankuroniumbromid og lignende.
Eksempler på antiepileptiske midler innbefatter fenytoin, etoksuksimid, acetazolamid-natrium, klordiazepoksid og lignende.
Eksempler på antiulcermidler innbefatter benzimidazolforbindelser (US-patenter 4.045.563, 4.255.431 og 4.472.409; EP-A 45200, 5129, 174726, 175464 og 208452; GB-A 2134523), metoklopramid, histidinhydroklorid og lignende.
Eksempler på antidepressive midler innbefatter imipramin, klomipramin, noksiptilin, fenelzinsulfat og lignende.
Eksemplar på antiallergiske midler innbefatter difenhydraminhydroklorid, klor-feniraminmaleat, tripelenaminhydroklorid, metdilazinhydroklorid, clemizolhydroklorid, difenylpyralinhydroklorid, metoksyfenaminhydroklorid og lignende.
Eksempler på kardiotone midler innbefatter trans-7t-oksokamfor, teofyllol, aminofyllin, etilefrinhydroklorid og lignende.
Eksempler på antiarrytmiske midler innbefatter propanolol, alprenolol, bufetolol, oksprenolol og lignende.
Eksempler på vasodilatorer innbefatter oksyfedrinhydroklorid, diltiazem, tolazolin-hydroklorid, heksobendin, bametansulfat og lignende.
Eksempler på hypotensive diuretiske midler innbefatter heksametoniumbromid, pentrinium, mecamylaminhydroklorid, ecarazinhydroklorid, clonidin og lignende.
Eksempler på antidiabetiske midler innbefatter insulinsensitivitetsforøkere (EP-A 749751), voglibos, miglitol, glymidinnatrium, glipizid, fenforminhydroklorid, buforminhydroklorid, metformin og lignende.
Eksempler på antilipidemiske midler innbefatter natrium 3R,5S-(+)-erytro-(E)-7-[4-(4-fluorfenyl)-2,6-diisopropyl-5 -metoksymetyl-pyrid-3 -yl] -3,5 -dihydroksy-hept-6-enoat, pravastatinnatrium, simvastatin, clinofibrat, clofibrat, simfibrat, benzfibrat og lignende.
Eksempler på antikoagulanter innbefatter heparinnatrium og lignende.
Eksempler på hemostatiske midler innbefatter tromboplastin, trombin, menadionnatirumbisulfit, acetomenafton, e-aminokaproinsyre, traneksaminsyre, karbazokromnatriumsulfonat, adrenokrommonoaminguanidinmetansulfonat og lignende.
Eksempler på antituberkulosemidler innbefatter isoniazid, etambutol, para-aminosalicyl-syre og lignende.
Eksempler på hormoner innbefatter prednisolon, prednisolonnatriumsulfat, deksametasonnatriumsulfat, betametasonnatriumfosfat, heksoestrolfosfat, heksoestrolacetat, metimazol og lignende.
Eksempler på narkotiske antagonister innbefatter levallorfantartrat, nalorfinhydroklorid, naloksonhydroklorid og lignende.
Eksempler på benresorpsjonshemmende midler innbefatter ipriflavon og lignende.
Eksempler på osteogenesefremmende midler innbefatter polypeptider slik som BMP, PTH, TGF-B, IGF-1 og lignende, (2R,4S)-(-)-N-[4-(dietoksyfosforylmetyl)fenyl]-l,2,4,5-tetrahydro-4-metyl-7,8-metylendioksy-5-okso-3-benzotiepin-2-karboksamid, 2-(3-piridyl)-etan-l,l,-difosfonsyre og lignende.
Eksempler på angiogenesehemmende midler innbefatter angiogenesehemmende steroider [Science, 221, 719 (1983)], fumagillin (EP-A 325199), fumagillolderivater (EP-A 357061, 359036, 386667 og 415294) og lignende.
Eksempler på vitaminer innbefatter cyanokobalamin, tiamin, askorbinsyre, pantotenisk syre og lignende.
De ovenfor-beskrevne farmakologiske aktive komponentene kan være i form av farmasøytisk akseptable salter. Eksempler på slike salter innbefatter salter med uorganiske syrer (f.eks. saltsyre, svovelsyre, salpetersyre, etc), organiske syrer (f.eks. karbonsyre, bikarbonsyre, ravsyre, eddiksyre, propionsyre, trifluoreddiksyre, etc), uorganiske faser (f.eks. alkalimetaller som natrium, kalium, etc. og jordalkalimetaller som kalsium, magnesium, etc.) og organiske baser (organiske aminer slik som trietylamin, etc. og basiske aminosyrer som arginin, etc).
Blant de ovenfor-beskrevne farmakologiske aktive komponentene er de som har høyest fuktighets-sensitivitet egnet til å vise endringer i sine egenskaper under produksjon av de farmasøytiske preparatene ved konvensjonell farmasøytisk teknikk og er vanskelig å behandle. Foreliggende oppfinnelse kan anvendes til slike fuktighetssensitive komponenter og tilveiebringer en ny metode for å produsere farmasøytiske preparater av slike høye fuktighets-sensitive farmakologiske aktive komponenter.
Begrepet "høy fuktighets-sensitiv komponent" menes en komponent som gjennomgår kjemiske endringer (dekomponering, farging og lignende) eller fysiologiske endringer (endring av krystallinsk form og lignende) som skyldes tilstedeværelse av vann.
De farmakologisk aktive komponentene er fortrinnsvis fysiologisk aktive peptider, antibiotika, bronkodilatorer, antilipidemiske midler og vitaminer. Det er mer å foretrekke at den farmakologiske aktive komponenten er antilipidemisk midler, særlig natrium 3R, 5S-(+)-erytro-(E)-7-[4-(4-fluorfenyl)-2,6-diisopropyl-5-metoksymetyl-pyrid-3-yl]-3,5-dihydroksy-hept-6-enoat.
Eksempler på søtningsstoffer innbefatter stivelsessukker, redusert maltose, sorbitol, sukrose, fruktpse, laktose, honning, xylitol, sakkarin, glycyrriza og dens ekstrakter, glycyrrhetisk syre, hydrangete, aspartam og lignende. Blant disse er aspartam som er en høyfuktighets-sensitiv komponent den foretrukkede.
I tillegg til ovenfor angitte D-mannitol og komponenter, kan faststoffsammensetningen i foreliggende oppfinnelse videre inneholde andre eksipienter, disintegratorer, bindemidler, glidemidler, smøremidler og lignende, som vanligvis benyttes for fremstilling av matprodukter eller medikamenter. Eksempler på slike eksipienter innbefatter laktose, stivelse, sukrose, krystallinsk cellulose, vannfri kalsiumhydrogen-fosfat og kalsiumkarbonat. Disintegratorene er f.eks. lav-substituert hydroksypropylmetylcellulose, karboksymetylcellulose, karboksymetylcellulosekalsium, karmellose, kloskarmelosenatrium, karboksymetylstivelsesnatrium, partiell pregeratinisert stivelse og krospovidon. Bindemidler er f.eks. metylcellulose, hydroksypropylcellulose, hydroksypropylmetylcellulose, karboksymetylcellulosenatrium, pregeneratinisert stivelse, acacia, agar, gelatin, tragakant, natriumalginat, polyvinylpyrrolidon og polyvinylalkohol. Glidemidlet er f.eks. hydratisert silisiumdioksid, lett vannfri kieselsyre syntetisk aluminiumsilikat, syntetisk hydrotalsitt, tørket aluminium-hydroksidgel, kaolin, kalsiumsilikat, magnesiummetasilikataluminat. Smøremidler er f.eks. magnesiumstearat, kalsiumstearat, stearinsyre, talk, natriumlaurylsulfat, hydrogenen vegetabilsk olje, mikrokrystallinsk voks, sukrosefettsyreester og polyetylenglykol.
Selv om faststoffsammensetningene i foreliggende oppfinnelse kan bli fremstilt ved i seg selv kjente teknikker, kan D-mannitol i foreliggende oppfinnelse benyttes i produksjonstrinnet i en form som er fremstilt i forveien, eller kan bli tilsatt i form av utgangskrystaller for å tillate at de blir omdannet til den ønskede krystallformen under produksjonsprosessen i de farmasøytiske preparatene og matproduktene.
Siden D-mannitol i foreliggende oppfinnelse, som har et øket bindingspunkt som skyldes mikrokrystallisering av primære partikler, mens den beholder de iboende kjemiske og biologiske egenskapene, har ypperlig kompabilitet og sammenpressbarhet, er den bemerkelsesverdig nyttig som en eksipient. Ifølge fremgangsmåten i foreliggende oppfinnelse, kan D-mannitol bli fremstilt hensiktsmessig og sikkert. Foreliggende oppfinnelse bidrar således i stor grad til design av ny farmasøytiske preparater og matprodukter og utvikling av farmasøytisk fremstilling og matefremstillingstenikker.
Følgende sammenligningseksempler og eksempler illustrerer videre foreliggende oppfinnelse, men de begrenser ikke rekkevidden av foreliggende oppfinnelse.
I sammenligningseksemplene og eksemplene ble B-form og 8-form D-mannitol krystaller fremstilt ved hovedsakelig samme måte som beskrevet i MICROSCOPE, 18, 279-285
(1970).
Sammenligningseksempel 1
Til 100 g av B-form D-mannitolkrystaller ble det tilsatt 20 g renset vann. Blandingen ble omrørt i en morter i 3 min. for å fukte krystallene jevnt, hvilke ble utsatt for vakuumtørking (40°C, 16 timer), etterfulgt av pulverisering gjennom en sikt av nr. 16 mesh. Partiklene som ble oppnådd på denne måten (spesifikt overflateareal: 0,5 m<2>/g) ble utsatt for sammenpressing under følgende betingelser.
Sammenpressingsmaskin: Autograf (Shimadz Seisakusho Ltd.)
Sammenpressingshastighet: 10 mm/min.
Stempel: 10 mm<l>, flat
Vekt: 400 mg
Sammenligningseksempel 2
I en ristegranulator (Powrex, Vertical Granulator VG10 type) ble 1500 g av B-form D-mannitolkrystaller fuktet jevnt med 375 g renset vann (200 rpm, 2 minutter), som ble gjenstand for vakuumtørking (40°C, 16 timer), etterfulgt av oppmaling i en kraftovn (Showa Kagaku, P-3 type stempelstørrelse: 1,5 mm§). Pulveret som ble oppnådd på denne måten (spesifikt overflateareal: 0,5 m<2>/g; heretter kalt "B-formkrystaller AG) ble blandet som i følgende formel og var gjenstand for tablettisering under følgende betingelser.
Formel:
Tabletteringsmaskin: Correct 19 AWC (Kikusui Seisakusho)
Tabletteirngstrykk: 1200-2400 kg/cm<2>
Rotasjonsfrekvens: 30 rpm
Stempel: 8,0 mm<f), flat-side skråkant
Vekt: 180 mg
Sammenligningseksempel 3
I en ristegranulator (Powrex, Vertical Granulator VG10 type) ble en blanding av 1267,2 g av B-form D-mannitolkrystaller og 316,8 g fenylpropanolaminhydroklorid fuktet jevnt med 240 g renset vann (200 rpm, 2 minutter), som ble gjenstand for vakuumtørking (40°C, 16 timer), etterfulgt av oppmaling i en kraftovn (Showa Kagaku, P-3 type stempelstørrelse: 1,5 mm(}>). En blanding av 792,0 g av det således oppnådde pulveret og 8,0 g magnesiumstearat ble utsatt for tablettering under følgende betingelser.
Tabletteringsmaskin: Correct 19 AWC (Kikusui Seisakusho)
Tabletteringstrykk: 100-3000 kg/cm<2>
Rotasjonsfrekvens: 30 rpm
Stempel: 8,0 mm(J), flat-overflate skråkant
Vekt: 180 mg/
Sammenligningseksempel 4
I en ristegranulator (Powrex, Vertical Granulator VG10 type) ble 1500 g av B-form D-mannitolkrystailer fuktet jevnt med 375 g renset vann (200 rpm, 2 minutter), som ble gjenstand for vakuumtørking (40°C, 16 timer), etterfulgt av oppmaling i en kraftovn (Showa Kagaku, P-3 type stempelstørrelse: 1,5 mmij)). B-formkrystaller AG (spesifikt overflateareal: 0,5 m<2>/g) ble blandet som i følgende formel og var gjenstand for tørrgranulering. Slagg som ble oppnådd ble oppmalt i kraftoppmaleren (Showa Kagaku, P-3 type, stempelstørrelse: 2,0 mm^).
Formel:
Maskin: Rullekompaktor (FREUND, Model-mini)
Rotasjonsfrekvens: 30 rpm
Kraft-tilførselshastighet: 20 rpm
Sammenpressingstrykk: 50 kg/cm<2>
Tykkelse på flak: ca. 2,0 mm
Eksempel 1
Til 100 g av 8-form D-mannitolkrystaller ble tilsatt 20 g renset vann. Blandingen ble omrørt i en morter i 3 minutter for å flikte krystallene jevnt, og disse var gjenstand for vakuumtørking (40°C, 16 timer), etterfulgt av pulverisering gjennom en sikt på 16 mesh. Pulveret oppnådd på denne måten (spesifikt overflateareal: 1,9 m<2>/g) var gjenstand for sammenpressingstøping under samme betingelser som i sammenligningseksempel 1. På den annen side, som sammenligningspressede produkter, ble de sammenpressede produktene fremstilt respektivt ved å anvende ubehandlede 5-form D-mannitol krystaller (spesifikt overflateareal: 0,5 m<2>/g) og B-form D-mannitol krystaller (spesifikt overflateareal: 0,5 m<2>/g) på vesentlig samme måte. Hardheten i de sammenpressede produktene som således ble oppnådd og den til det sammenpressede produktet i sammenligningseksempel 1 ble bestemt med et instrument som måler tablettbruddstyrke som et resultat ble ingen forskjell i hardhet gjenkjent, under de ovenfor-beskrevne sammenpressingsbetingelser, blant de tre sammenpressede produktene som anvender ubehandlet 5-formkrystaller, ubehandlet B-formkrystaller og behandlede B-formkrystaller i sammenligningseksempel 1. Hardheten av det sammenpressede produktet fremstilt i dette eksempel 1 ble funnet å være bemerkelsesverdig høy sammenlignet med det sammenpressede produktet fremstilt ved å anvende ubehandlede 5-formkrystaller eller behandlede B-formkrystaller (fig. 1). D-mannitol fra eksempel 1 var ved observasjon under scanningselektronmikroskop, ulikt utgangskrystallene (fig. 3), porøse partikler som besto av fin-krystallinske aggregater av D-mannitol (fig. 2), hvis pulverrøntgendifrfaksjonspektrum ble målt og bekreftet overgang av S-form til B-form (fig. 4).
Eksempel 2
I en ristegranulator (Powrex, Vertical Granulator VG10 type) ble en blanding av 1500 g av B-form D-mannitolkrystallene fuktet jevnt med 375 g renset vann (200 rpm, 2 minutter), som ble gjenstand for vakuumtørking (40°C, 16 timer), etterfulgt av oppmaling i en oppmalingskvern (Showa Kagaku, P-3 type stempelstørrelse: 1,5 mm(j)). Pulveret som ble oppnådd på denne måten (spesifikt overflateareal: 0,5 m<2>/g; heretter kalt "B-formkrystaller AG) ble blandet som i følgende formel og var gjenstand for tablettisering. Hardheten i det sammenpressede produktet som ble oppnådd på denne måten og den i det sammenpressede produktet i sammenligningseksempel 2 ble bestemt ved et instrument som måler tablettbruddstyrke (Toyama Sangyo). Resultatene viser at det sammenpressede produktet i dette eksempel 2 viste bemerkelsesverdig god sammenpressbarhet og ga tilstrekkelig hardhet med lav tabletteringstrykk, mens det sammenpressede produktet i sammenligningseksempel 2 viste dårlig sammenpressbarhet og tildekking forekommer ved et tablettrykk på 1800 kg/cm<2> eller mer uten å gi tilfredsstillende tabletter (fig. 5).
Formel:
Tabletteringsmaskin: Correct 19 AWC (Kikusui Seisakusho)
Tabletteringstrykk: 600-1800 kg/cm<2>
Rotasjonsfrekvens: 30 rpm
Stempel: 8,0 mm(j), flat-flate skråkant
Vekt: 180 mg
Eksempel 3
I en ristegranulator (Powrex, Vertical Granulator VG10 type) ble en blanding av 1267,2 g av B-form D-mannitolkrystaller og 316,8 g fenylpropanolaminhydroklorid fuktet jevnt med 240 g renset vann (200 rpm, 2 minutter), som ble gjenstand for vakuumtørking (40°C, 16 timer), etterfulgt av oppmaling i en kraftkvern (Showa Kagaku, P-3 type stempelstørrelse: 1,5 mm(t>). En blanding av 792,0 g av det således oppnådde pulveret og 8,0 g magnesiumstearat ble utsatt for tablettering under følgende betingelser. Hardheten i det sammenpressede produktet ble bestemt ved et instrument som måler tablettbruddstyrke (Toyama Sangyo). Resultatene viser at det sammenpressede produktet i dette eksempel 3 viste bemerkelsesverdig god sammenpressbarhet og ga tilstrekkelig hardhet, mens det sammenpressede produktet i sammenligningseksempel 3 som ble fremstilt ved å anvende B-form D-mannitolkrystaller viste dårlig sammenpressbarhet og tildekking forekommer ved et tablettrykk på 2000 kg/cm<2> eller mer uten å gi tilfredsstillende tabletter (fig. 6).
Tabletteringsmaskin: Correct 19 AWC (Kikusui Seisakusho)
Tabletteirngstrykk: 1000-3000 kg/cm<2>
Rotasjonsfrekvens: 30 rpm
Stempel: 8,0 mm<|>, flat-overflate skråkant
Vekt: 180 mg
Eksempel 4
I en ristegranulator (Powrex, Vertical Granulator VG 10 type) ble 1500 g av B-form D-mannitolkrystaller fuktet jevnt med 375 g renset vann (200 rpm, 2 minutter), som ble gjenstand for vakuumtørking (40°C, 16 timer), etterfulgt av oppmaling i en kraftkvern (Showa Kagaku, P-3 type, stempelstørrelse: 1,5 mm<t>). B-formkrystaller AG som ble oppnådd på denne måten (spesifikt overflateareal: 1,9 m<2>/g) ble blandet som i følgende formel og var gjenstand for tørrgranulering under samme betingelser som i sammenligningseksempel 4. Slagg som ble oppnådd ble oppmalt i kraftkvern (Showa Kagaku, P-3 type, stempelstørrelse: 2,0 mm(|)). Styrken på granulene ble bestemt med et instrument som måler granulær styrke (Okada Seiko, Grano), og resultatene er vist i (fig. 7), fra hvilken gjennomsnittsgranulærstyrke til begge produktene er beregnet (n = 30; 1,0-2,0 mm) for å finne at gjennomsnittlig granulær styrke til granulene nevnt i eksempel
4 var 601,7 g, mens til granulene i sammenligningseksempel 4 var 292,0 g.
Det er tydelig fra resultatene at formelen i dette eksempel 4 som anvender 8-formkrystaller AG ga harde granuler som inneholder lite mikropulver og som viste ypperlige egenskaper for fylling i kapsler. På den annen side siden styrken i granulene oppnådd med formelen i sammenligningseksempel 4 ved å anvende B-formkrystaller i AG ikke var tilstrekkelig, var innkapsling av dem vanskelig.
Formel:
Eksempel 5
Til ristende granulatorer (Powrex, Vertical Granulator VG10 type) hver inneholdende 1000 g av 8-form D-mannitolkrystaller, 50, 100, 150, 200, 250 og 300 g renset vann (5-30 v/v% basert på vekt av mannitol) ble respektivt tilsatt en blokk. De respektive blandingene ble ristet (2 min., 200 rpm), etterfulgt av vakuumtørking (40°C, 16 timer). Hvert tørkede materiale ble oppmalt i en kraftkvern (Showa Kagaku, P-3 type stempelstørrelse: 1,5 mm<j>). Det således oppnådde pulveret (spesifikke overflatearealer: 1,0, 1,4, 1,7, 1,9, 3,5 og 2,7 m<2>/g) var gjenstand for tablettering under følgende betingelser. Hardheten i det sammenpressede produktet ble bestemt ved et instrument som måler tablettbruddstyrke (Toyama Sangyo). Spesifikt overflateareal av pulveret ble målt ved BET-meotden. Resultatene viste at volumet av vannet som ble behandlet for behandling ga en påvirkning på det spesifikke overflatearealet av produktet oppnådd ved behandling av krystaller for tilsvarende å påvirke hardheten av det sammenpressede produktet (fig. 8). I fig. 8 vises tallverdier i parenteser % ved vekt av renset vann anvendt relativt til vekt av 5-form D-mannitolkrystaller.
Tabletteringsmaskin: Correct 19 AWC (Kikusui Seisakusho)
Tabletteringstrykk: 2000 kg/cm<2>
Rotasjonsrfekvens: 30 rpm
Stempel: 8,0 mmfy, flat-overflate skråkant
Vekt: 180 mg
Claims (7)
1. D-mannitol, karakterisert ved at den har et spesifikt overflateareal som ikke er mindre enn ca. 1 m<2>/g.
2. D-mannitol ifølge krav 1, karakterisert ved at den er en blanding av 5-formkrystaller og B-formkrystaller.
3.
Fremgangsmåte for fremstilling av D-mannitol som har et spesifikt overflateareal som ikke er mindre enn ca. 1 m<2>/g, karakterisert ved at den omfatter behandling av 5-form D-mannitolkrystaller med et vann-løselig oppløsningsmiddel, etterfulgt av tørking.
4.
Fremgangsmåte ifølge krav 3, karakterisert ved at det vann-løselige oppløsningsmiddel ble anvendt i en mengde fra ca. 3 til ca. 70 v/v% basert på vekt av S-form D-mannitolkrystaller.
5.
Faststoffsammensetning, karakterisert ved at den omfatter D-mannitol som har et spesifikt overflateareal som ikke er mindre enn ca. 1 m2/g.
6.
Faststoffsammensetning ifølge krav 5, karakterisert v e d at den videre omfatter en farmakologisk aktiv komponent.
7.
Faststoffsammensetning ifølge krav 6, karakterisert v e d at den farmakologisk aktive komponenten er en meget fuktighets-sensitiv komponent.
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JP9440196 | 1996-04-16 | ||
PCT/JP1997/001286 WO1997038960A1 (en) | 1996-04-16 | 1997-04-14 | D-mannitol and its preparation |
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NO20012249A NO20012249D0 (no) | 1996-04-16 | 2001-05-07 | Faststoffsammensetning inneholdende D-mannitol og cerivastatin samt anvendelse av faststoffsammensetning forfremstilling av farmasöytisk preparat |
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DE10008506A1 (de) * | 2000-02-24 | 2001-09-13 | Bayer Ag | Verfahren zur Herstellung von pharmazeutischen Darreichungsformen |
FR2807034B1 (fr) † | 2000-03-29 | 2002-06-14 | Roquette Freres | Mannitol pulverulent et son procede de fabrication |
JPWO2002024167A1 (ja) * | 2000-09-19 | 2004-01-29 | 第一製薬株式会社 | 医薬組成物 |
US6855333B1 (en) | 2000-10-03 | 2005-02-15 | Mutual Pharmaceutical Co., Inc. | Stabilization of solid thyroid drug formulations |
US6979462B1 (en) | 2000-10-03 | 2005-12-27 | Mutual Pharmaceutical Co., Inc. | Stabilization of solid drug formulations |
DE10161402A1 (de) * | 2001-12-13 | 2003-06-18 | Merck Patent Gmbh | Verfahren zur Herstellung von direkt tablettierbarem beta-Mannit |
US7462232B2 (en) * | 2002-05-14 | 2008-12-09 | Fmc Corporation | Microcrystalline cellulose compositions |
US8163797B2 (en) * | 2003-12-31 | 2012-04-24 | Actavis Elizabeth Llc | Method of treating with stable pravastatin formulation |
US7879382B2 (en) * | 2005-09-30 | 2011-02-01 | Fmc Corporation | Stabilizers and compositions and products comprising same |
US8486450B2 (en) | 2005-12-28 | 2013-07-16 | Takeda Pharmaceutical Company Limited | Method of producing solid preparation disintegrating in the oral cavity |
BRPI0708108B1 (pt) | 2006-02-20 | 2021-12-14 | Chugai Seiyaku Kabushiki Kaisha | Composição farmacêutica compreendendo fosfato de oseltamivir |
US8932629B2 (en) * | 2006-10-27 | 2015-01-13 | Fmc Corporation | Co-processed microcrystalline cellulose and sugar alcohol as an excipient for tablet formulations |
RU2478375C2 (ru) | 2007-03-13 | 2013-04-10 | ДАЙНИППОН СУМИТОМО ФАРМА Ко., ЛТД. | Распадающаяся во рту таблетка |
CA2687813C (en) * | 2007-05-22 | 2015-07-07 | Ssci, Inc. | Preparation of mannitol modification iii |
DE102007052070A1 (de) | 2007-10-30 | 2009-05-07 | Tiefenbacher Pharmachemikalien Alfred E. Tiefenbacher Gmbh & Co. Kg | Candesartancilexetil |
EP2651397A2 (de) | 2010-12-17 | 2013-10-23 | Merck Patent GmbH | Verfahren zur herstellung von direkt tablettierbarem -mannit |
WO2013052118A1 (en) | 2011-10-05 | 2013-04-11 | Fmc Corporation | Stabilizer composition of co-attrited microcrystalline cellulose and carboxymethylcellulose, method for making, and uses |
JP6188030B2 (ja) | 2011-10-05 | 2017-08-30 | エフ エム シー コーポレーションFmc Corporation | 微結晶セルロースおよびカルボキシメチルセルロースの安定化剤組成物、該組成物の製造方法並びに食品製品 |
PL2787837T3 (pl) | 2011-12-09 | 2017-09-29 | Fmc Corporation | Współścierana kompozycja stabilizatora |
CN106535661B (zh) * | 2014-07-21 | 2020-08-04 | 罗盖特公司 | 用于通过直接压缩进行压片的糖组合物 |
IT201900002857A1 (it) | 2019-02-27 | 2020-08-27 | Ntc S R L | Procedimento di riempimento di contenitori con una polvere |
CN113116843A (zh) * | 2021-05-11 | 2021-07-16 | 福建海西新药创制有限公司 | 一种含有缬沙坦的药物组合物及其制备方法 |
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FR2571046B1 (fr) | 1984-10-03 | 1987-10-16 | Roquette Freres | Procede de preparation de mannitol granulaire directement compressible |
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US5177080A (en) | 1990-12-14 | 1993-01-05 | Bayer Aktiengesellschaft | Substituted pyridyl-dihydroxy-heptenoic acid and its salts |
HU9203780D0 (en) * | 1991-12-12 | 1993-03-29 | Sandoz Ag | Stabilized pharmaceutical products of hmg-coa reductase inhibitor and method for producing them |
FR2710637B1 (fr) | 1993-09-28 | 1995-12-08 | Roquette Freres | Mannitol pulvérulent de friabilité modérée et son procédé de préparation. |
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US6235947B1 (en) * | 1997-04-14 | 2001-05-22 | Takeda Chemical Industries, Ltd. | D-mannitol and its preparation |
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