WO2019234763A1 - Lincomycin sustained release tablets 1000mg - Google Patents
Lincomycin sustained release tablets 1000mg Download PDFInfo
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- WO2019234763A1 WO2019234763A1 PCT/IN2019/050434 IN2019050434W WO2019234763A1 WO 2019234763 A1 WO2019234763 A1 WO 2019234763A1 IN 2019050434 W IN2019050434 W IN 2019050434W WO 2019234763 A1 WO2019234763 A1 WO 2019234763A1
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- Prior art keywords
- lincomycin
- sustained release
- release composition
- hpmc
- released
- Prior art date
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- 229960005287 lincomycin Drugs 0.000 title claims abstract description 74
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 title claims abstract description 74
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 239000007939 sustained release tablet Substances 0.000 title abstract description 18
- 239000000203 mixture Substances 0.000 claims description 35
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 34
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 33
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 27
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 27
- 238000013268 sustained release Methods 0.000 claims description 22
- 239000012730 sustained-release form Substances 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 14
- 239000011248 coating agent Substances 0.000 claims description 13
- 238000000576 coating method Methods 0.000 claims description 13
- 229920001577 copolymer Polymers 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 13
- 239000008187 granular material Substances 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 11
- 239000003086 colorant Substances 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 10
- 239000000314 lubricant Substances 0.000 claims description 10
- 239000011159 matrix material Substances 0.000 claims description 10
- 239000004014 plasticizer Substances 0.000 claims description 10
- 239000003826 tablet Substances 0.000 claims description 9
- 229920000642 polymer Polymers 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 230000000181 anti-adherent effect Effects 0.000 claims description 7
- 239000003911 antiadherent Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 229940117837 methacrylic acid - methyl methacrylate copolymer (1:2) Drugs 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 5
- DZSDDKNXMARQMJ-AVXYAQEDSA-N (2S,4R)-4-ethyl-N-[(1R,2R)-2-hydroxy-1-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methylpyrrolidine-2-carboxamide Chemical compound CN1C[C@H](CC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 DZSDDKNXMARQMJ-AVXYAQEDSA-N 0.000 claims description 4
- CWPMAVJRTHPUNS-UHFFFAOYSA-N Lincomycin B Natural products CCC1CC(NC(=O)C(C(C)O)C2OC(SC)C(O)C(O)C2O)N(C)C1 CWPMAVJRTHPUNS-UHFFFAOYSA-N 0.000 claims description 4
- DZSDDKNXMARQMJ-UHFFFAOYSA-N N-Desmethyllincomycin Natural products CN1CC(CC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 DZSDDKNXMARQMJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007891 compressed tablet Substances 0.000 claims description 4
- 238000007906 compression Methods 0.000 claims description 4
- 230000006835 compression Effects 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
- 230000001050 lubricating effect Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000007873 sieving Methods 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920001688 coating polymer Polymers 0.000 claims description 3
- 229960005191 ferric oxide Drugs 0.000 claims description 3
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical group O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000796 flavoring agent Substances 0.000 claims description 3
- 235000019634 flavors Nutrition 0.000 claims description 3
- -1 glidants Substances 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- POUMFISTNHIPTI-BOMBIWCESA-N hydron;(2s,4r)-n-[(1r,2r)-2-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide;chloride Chemical compound Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 POUMFISTNHIPTI-BOMBIWCESA-N 0.000 description 18
- 229960001595 lincomycin hydrochloride Drugs 0.000 description 18
- 229940079593 drug Drugs 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 210000002966 serum Anatomy 0.000 description 11
- 230000036470 plasma concentration Effects 0.000 description 7
- 238000003556 assay Methods 0.000 description 5
- 230000003907 kidney function Effects 0.000 description 5
- 230000002459 sustained effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000007922 dissolution test Methods 0.000 description 4
- 230000003908 liver function Effects 0.000 description 4
- 239000007916 tablet composition Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 210000000941 bile Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000005033 polyvinylidene chloride Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 241000295644 Staphylococcaceae Species 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
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- 230000001580 bacterial effect Effects 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 239000000599 controlled substance Substances 0.000 description 2
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- 239000002552 dosage form Substances 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
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- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- XOIYZMDJFLKIEI-UHFFFAOYSA-N (hydroxysulfonimidoyl)oxybenzene Chemical compound NS(=O)(=O)OC1=CC=CC=C1 XOIYZMDJFLKIEI-UHFFFAOYSA-N 0.000 description 1
- XGBFWQUQYQIFLB-MTTMTQIXSA-N 23312-56-3 Chemical compound OS(O)(=O)=O.O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O XGBFWQUQYQIFLB-MTTMTQIXSA-N 0.000 description 1
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 101100126329 Mus musculus Islr2 gene Proteins 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 241000187399 Streptomyces lincolnensis Species 0.000 description 1
- NVNQOUOFMWKNLY-AVENPWRCSA-N [(2R,3R,4S,5R,6R)-4,5-dihydroxy-6-[(1R,2R)-2-hydroxy-1-[[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical compound CCC[C@@H]1C[C@H](N(C)C1)C(=O)N[C@H]([C@@H](C)O)[C@H]1O[C@H](SC)[C@H](OP(O)(O)=O)[C@@H](O)[C@H]1O NVNQOUOFMWKNLY-AVENPWRCSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940033683 lincocin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 241001446247 uncultured actinomycete Species 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 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
- 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
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
Definitions
- the invention provides sustained release tablets of lincomycin.
- the sustained release tablets of lincomycin Hydrochloride comprise lincomycin in an amount of lOOOmg for once a day administration.
- the invention provides sustained release tablets of lincomycin.
- the sustained release tablets of lincomycin Hydrochloride comprise lincomycin in an amount of lOOOmg for once a day administration.
- the combination of High viscosity grade hydroxypropyl methylcellulose 10000 cps and 200000 cps is used in a ratio of 1 : 1.1 to 1 : 1.3 to effectively control the delivery of the highly soluble lincomycin over period of 20 to 24 hrs.
- the anionic copolymer according to the invention is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2).
- the anionic copolymer is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2); the lubricant is magnesium stearate, the plasticizer is Polyethylene Glycol and the colorant is Ferric Oxide Red.
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- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention discloses lincomycin sustained release tablets. More particularly, the invention discloses sustained release tablets of lincomycin 1000mg for once a day administration.
Description
“LINCOMYCIN SUSTAINED RELEASE TABLETS lOOOmg”
Technical filed:
The present invention relates to lincomycin sustained release tablets. More particularly, the invention relates to sustained release tablets of lincomycin lOOOmg for once a day administration.
Background and prior art:
Lincomycin Hydrochloride is a lincosamide antibiotic originally identified in actinomycete Streptomyces lincolnensis with activity against gram-positive cocci and anaerobic bacteria, known from l960s. Lincomycin hydrochloride is white crystalline powder and freely soluble in water.
The lincomycin hydrochloride is chemically known as Methyl 6,8-dideoxy-6-(l- methyl-trans-4-propyl-L-2-pyrolidinecarboxamido)-l-thio-D-erythro-a-D-galacto- octopyranoside monohydrochloride monohydrate, shown below as formula I.
Formula I
Lincomycin indicated for serious infections due to susceptible strains of streptococci, pneumococci, and staphylococci. Lincomycin is also effective against other organisms including actinomycetes, mycoplasma, and some species of Plasmodium.
Lincomycin inhibits protein synthesis in susceptible bacteria by binding to the 50 S subunits of bacterial ribosomes and prevents peptide bond formation. It is usually considered as bacteriostatic but may be bactericidal in high concentrations or when used against highly susceptible organisms.
Lincomycin is well absorbed in gastro intestinal tract when administered orally. However, food significantly delays and decreases absorption, the mean peak plasma level from a dose given immediately after a meal being only about half the fasting levels.
Lincomycin distributes widely and rapidly to most fluids and tissues except cerebrospinal fluid (CSF); high concentrations in bone, bile, and urine are reported. Like clindamycin. Lincomycin is metabolized in the liver and excreted in the bile. About 40% of an oral dose can be recovered from the feces. Less than 5% of an oral dose appears in the urine over 24 h, but up to 60% after intravenous administration, mostly in the first 4 h.
The recommended daily dose by WHO is about l .8g for oral as well as parenteral administration in a divided doses of 500mg for 2 to 4 times based on the severity of the infection. The peak serum concentration was observed within 2 to 4 hrs upon oral administration. The biological half-life of lincomycin after administration in a person with normal renal function is 5.4 ± 1.0 h. The serum half-life of lincomycin may be prolonged in patients with severe impairment of renal function, for example 10 to 20 hrs, compared to patients with normal renal function. In patients with abnormal hepatic function, serum half-life may be twofold longer than in patients with normal hepatic function. Haemodialysis and peritoneal dialysis are not effective in removing lincomycin from the serum. Tissue level studies indicate that bile is an important route of excretion.
It was further reported that the protein binding of the lincomycin decreases with increased plasma concentrations.
Lincomycin is available with brand name(s) such as Lincocin; Lineorex, Linx etc. as a 5Q0mg capsule administered every 6 to 8 hrs.
There is very less literature available on lincomycin, its analogs, its salts & compositions.
US3304229 discloses pharmaceutical preparation which comprises novel pharmaceutical salts of lincomycin selected from the group consisting of lincomycin phenylsulfamate and lincomycin n-phenyl-n-alkyl-sulfamate in an amount of 100 to about 1000 mg, dispersed in a pharmaceutical earner.
US3539689 discloses compositions comprise 7-halo-lincomycin in an amount of 15-500 mg along with pharmaceutical carrier for oral and parenteral administration.
US3642987 discloses Lincomycin and tetracycline composition with ranges of lincomycin 5-95 parts (50-1000 mg) to tetracycline 95-5 parts (50-1000 mg)
US 3509256 disclose compositions comprising lincomycin-2-phosphate.
CN104095871A describes veterinary' injection containing lincomycin hydrochloride and spectinomycin sulphate.
Lincomycin is conventionally administered as 500mg capsules in the form of immediate release dosage form with peak serum concentration within 2 to 4 hrs upon oral administration. The rapid and wide distribution of this drug makes it the best choice for the treatment of infections arising out of streptococci, pneumococci, and staphylococci bacterial species.
The biggest disadvantage of the conventional immediate release formulation as mentioned above lies in the biological half-life of the lincomycin and its presence in the body over a longer period. As described above, the biological half-life of
lincomycin after administration in a person with normal renal function is 5.4 ± 1.0 h. In patients with abnormal hepatic function, serum half-life may be twofold longer than in patients with normal hepatic function.
It has been observed by the present inventors that the conventional immediate release dosage form of Lincomycin Hydrochloride has few limitations. For example, administering 500 mg capsule every 6 or 8 hourly would amount to dose dumping leading to increased plasma concentration due to the longer biological half-life and also due to hepatic metabolism of the lincomycin, even in a person with normal renal function.
Additional reported disadvantage is that the decreased protein binding of the lincomycin with increased plasma concentrations, leads to lesser absorption and higher excretion of the drug in addition to development of bacterial resistance. However, none of the prior arts or any research groups have ever tried to address these issues by providing a suitable solution so as to increase the effectiveness of lincomycin and patient compliance with safety.
Therefore, there remains a need in the art to provide sustained release tablet of lincomycin that will take care of issues with multiple dosing and improved protein binding with constant serum concentrations.
Accordingly, the objective of the present invention is to provide sustained release lincomycin tablets of lOOOmg that will control the release of the lincomycin over a period of 20 to 24 hrs and can maintain constant serum concentrations thereby improved therapeutic effect.
Summary of the invention:
In accordance with the above objective, the invention provides sustained release tablets of lincomycin. In an aspect, the sustained release tablets of lincomycin
Hydrochloride comprise lincomycin in an amount of lOOOmg for once a day administration.
According to the invention, the sustained/controlled drug delivery of Lincomycin Hydrochloride helps in maintenance of constant plasma drug concentration and retards the release rate of drug thereby extending the duration of action. The sustained release tablets of lincomycin provide patient compliance by reducing the multiple dosing, see-saw fluctuations and maintain constant serum plasma concentration by providing sustained delivery of the drug for up 20 to 24 hrs thereby exerts desired therapeutic effect.
Accordingly, the present invention provides sustained release composition which comprises;
a) a slow dissolving matrix consisting of,
i) Lincomycin in an amount of 60 to 70% by weight;
ii) Combination of Hydroxypropyl methyl cellulose 100000 Cps and Hydroxypropyl methyl cellulose 200000 Cps as rate controlling polymer in an amount of 10 to 20% by weight;
iii) Microcrystalline cellulose as diluent in an amount of 10 to 15% by weight; iv) Polyvinyl pyrrolidone as binder in an amount of 0.5 to 1% by weight; b) anionic copolymers as coating polymer in an amount of 1 to 1.5%; and c) one or more pharmaceutical carriers or excipients.
The combination of high viscosity grade Hydroxypropyl methyl cellulose, according to the invention is in the ratio of 1 : 1.1 to 1 : 1.3.
The anionic copolymer according to the invention is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2), used for coating of the tablets.
The concentration of lincomycin is lOOOmg in the sustained release composition, meant for once a day administration.
The pharmaceutical carriers or excipients may be selected from the group consisting of lubricants, diluents, glidants, anti-adherents, colors, flavours, plasticizers etc.
The sustained release composition according to the invention wherein the composition exhibits dissolution profile which is characterized by not more than 20% of the lincomycin released within zero to two hours; 10 % - 40% of the lincomycin released within zero to six hours; 35 % to 65% of the lincomycin released within zero to ten hours; 60 % to 85% of the lincomycin released within zero to fourteen hours; and not less than 80% of the lincomycin released within zero to twenty hours.
The composition has Lincomycin B impurity in not more than 5.0%, indicating the long term stability of the composition.
In another aspect, the invention provides a process for preparation of sustained release composition wherein the process comprising the steps of;
a) Sifting and mixing lincomycin, High viscosity grade HPMCs and Microcrystalline Cellulose;
b) Preparing binder solution by dissolving Polyvinyl Pyrrolidone in IP A;
c) Granulating the mixture of step a) with the binder solution of step b) to obtain granules followed by drying and sieving the granules;
d) Lubricating the granules of step c) by adding the lubricants, glidants and anti adherents followed by compression to obtain compressed tablets; and e) Preparing the coating solution by dissolving anionic copolymer, plasticizer, colorants and coating the tablets of step d) with the coating solution.
The combination of High viscosity grade HPMCs as used in the process of the present invention is the combination of HPMC 100000 CPs and 200000CPs; the anionic copolymer is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2); the lubricant is magnesium stearate, the plasticizer is Polyethylene Glycol and the colorant is Ferric Oxide Red.
Detailed description:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Accordingly, the invention provides sustained release tablets of lincomycin. In an aspect, the sustained release tablets of lincomycin Hydrochloride comprise lincomycin in an amount of lOOOmg for once a day administration.
According to the invention, the sustained/controlled drug delivery of Lincomycin Hydrochloride helps in maintenance of constant plasma drug concentration and retards the release rate of drug thereby extending the duration of action.
The sustained release tablets of lincomycin provide patient compliance by reducing the multiple dosing, see-saw fluctuations and maintain constant serum plasma concentration by providing sustained delivery of the drug for up 20 to 24 hrs thereby exerts desired therapeutic effect.
For the development of sustained delivery of the highly soluble lincomycin hydrochloride for upto 20 to 24 hrs, a proper polymer matrix is needed to be prepared from which the drug release occurs by polymer swelling, polymer erosion, drug dissolution/diffusion mechanism. The present inventors have tried different polymers which include carbopol, high viscosity grades of HPMC and the combinations thereof.
In line with the above, in one embodiment, the matrix formulation was prepared with carbopol as shown in example 1. However, this formulation failed to achieve desired sustained release as shown in analysis report of example 1.
In another embodiment, the matrix formulation was prepared with HPMC. HPMC (hydroxy propyl methyl cellulose), available in various grades, is routinely used in
the development of immediate and controlled released drug delivery. In accordance with this embodiment, the present inventors have attempted the preparation of sustained release matrix using high viscosity grade HPMC 100000 cps as shown in example 2. However, HPMC 100000 cps grade is failed to provide desired sustained release of lincomycin as shown in example 2, instead this matrix release the drug as burst release.
Therefore, to circumvent the variability of drug release and to improve the consistency and sustainability of lincomycin drug release, in another embodiment, the matrix was prepared with the combination of HPMC lOOOOcps and HPMC 20000cps in 1 : 1 ratio as depicted in example 3. Although this matrix exhibits relatively better release characteristics, however, failed to provide desired sustained release of lincomycin as shown in example 3.
All the above experiments (examples 1, example 2 and example 3) have failed the required dissolution test, i.e., the release of the active shall not more be than 20% of Label claim at the end of 2nd hr.
However, to the applicant’s surprise a modification in the ratio of both the high viscosity HPMCs results in desired sustained release and even the release was observed to be last up to 20 to 24 hrs (example 4 and another 2 reproducible batch as shown example 5 and example 6).
Accordingly, in a preferred embodiment, the combination of High viscosity grade hydroxypropyl methylcellulose 10000 cps and 200000 cps is used in a ratio of 1 : 1.1 to 1 : 1.3 to effectively control the delivery of the highly soluble lincomycin over period of 20 to 24 hrs.
In one preferred embodiment, the ratio of hydroxypropyl methylcellulose 10000 cps and hydroxypropyl methylcellulose 200000 cps is used in a ratio of 1 : 1.25.
Accordingly, the present invention provides sustained release composition which comprises;
a) a slow dissolving matrix consisting of
i) Lincomycin in an amount of 60 to 70% by weight;
ii) Combination of High viscosity grade HPMCs as rate controlling polymer in an amount of 10 to 20% by weight;
iii) Microcrystalline cellulose as diluent in an amount of 10 to 15% by weight; iv) Polyvinyl pyrrolidone as binder in an amount of 0.5 to 1% by weight; b) anionic copolymers as coating polymer in an amount of 1 to 1.5%; and c) one or more pharmaceutical carriers or excipients.
The anionic copolymer according to the invention is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2).
The concentration of lincomycin is lOOOmg in the sustained release composition, for once a day administration.
The pharmaceutical carriers or excipients may be selected from the group consisting of lubricants, diluents, glidants, anti-adherents, colors, flavours, plasticizers etc.
The sustained release composition according to the invention (as per the examples 4 to 6) wherein the composition exhibits dissolution profile which is characterized by not more than 20% of the lincomycin released within zero to two hours; 10 % - 40% of the lincomycin released within zero to six hours; 35 % to 65% of the lincomycin released within zero to ten hours; 60 % to 85% of the lincomycin released within zero to fourteen hours; and not less than 80% of the lincomycin released within zero to twenty hours.
It can be reasonably concluded based on the consistent release profile, as demonstrated in the present invention that the sustained release tablets of
lincomycin reduces see-saw fluctuations and can maintain constant serum plasma concentration thereby exerts desired therapeutic effect.
The composition is further characterized by having Lincomycin B impurity in not more than 5.0%, indicating good stability and shelf-life of the composition.
In another aspect, the invention provides a process for preparation of sustained release composition wherein the process comprising the steps of;
a) Sifting and mixing lincomycin; High viscosity grade HPMCs and Microcrystalline Cellulose;
b) Preparing binder solution by dissolving Polyvinyl Pyrrolidone in IP A;
c) Granulating the mixture of step a) with the binder solution of step b) to obtain granules followed by drying and sieving the granules;
d) Lubricating the granules of step c) by adding the lubricants, glidants and anti adherents followed by compression to obtain compressed tablets; and e) Preparing the coating solution by dissolving anionic copolymer, plasticizer, colorants and coating the tablets of step d) with the coating solution.
The High viscosity hydroxypropyl methylcellulose (HPMC) used as rate controlling polymer in the process of the invention, is the combination of HPMC 100000 CPs and HPMC 200000CPs in a ratio of 1 : 1 to 1 : 1.3; more preferably in a ratio of 1 : 1.25.
The anionic copolymer is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2); the lubricant is magnesium stearate, the plasticizer is Polyethylene Glycol and the colorant is Ferric Oxide Red.
The process of the present invention is simple and easier to scale up for industrial production of lincomycin sustained release tablets. The process of the present invention is cost effective as it does not require costly equipment and is easier for industrial scale up.
In yet another embodiment, the invention provides long term stability data conducted under accelerated conditions at 40°C (±2 °C),75% RH (± 5% RH) of the coated tablets along with its dissolution profile, as depicted in examples 4 to 6. According to assay, the coated tablets of the invention exhibit long term stability and consistent release profile even after 3 months. After 3 months stability studies of these tablets show lincomycin B impurity substantially the same and within the acceptable limits i.e., not more than 5%.
The following examples (example 4 to 6), which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples
Example 1
Lincomycin hydrochloride lOOOmg tablet formulation with Carbopol
Q.s = Quantity Sufficient
* Actual quantity of Lincomycin Hydrochloride may be varied on the Water and Assay content.
# The final quantity of active to be compensated with diluent.
Release and content characteristics of example 1
Conclusion: Product fails as per specification in dissolution test
Example 2
Lincomycin hydrochloride lOOOmg tablet formulation with HPMC 100000 cps
Q.s = Quantity Sufficient
* Actual quantity of Lincomycin Hydrochloride may be varied on the Water and Assay content.
# The final quantity of active to be compensated with diluent.
Release and content characteristics of example 2
Conclusion: Product fails as per specification in dissolution test
Example 3
Lincomycin hydrochloride lOOOmg tablet formulation with HPMC 100000 cps and 20000CPS in 1:1 ratio
Q.s = Quantity Sufficient
* Actual quantity of Lincomycin Hydrochloride may be varied on the Water and Assay content.
# The final quantity of active to be compensated with diluent.
Release and content characteristics of example 3
Example 4
Lincomycin hydrochloride lOOOmg tablet formulation
Q.s = Quantity Sufficient
* Actual quantity of Lincomycin Hydrochloride may be varied on the Water and Assay content.
# The final quantity of active to be compensated with diluent.
Note : Two more reproducible batches are prepared as per example 4 by considering the same as final formulation and subjected them to stability studies, as shown in examples 5 & 6.
Procedure:
a) Sifting and mixing lincomycin; Hydroxypropyl Methylcellulose 10000CPS and 200000CPS; Microcrystalline Cellulose;
b) Preparing binder solution by dissolving Polyvinyl Pyrrolidone in IP A;
c) Granulating the mixture of step a) with the binder solution of step b) to obtain granules followed by drying and sieving the granules;
d) Lubricating the granules of step c) by adding the lubricants, glidants and anti adherents followed by compression to obtain compressed tablets; and e) Preparing the coating solution by dissolving anionic copolymer, plasticizer, colorants and coating the tablets of step d) with the coating solution.
Release and content characteristics of example 4
Stability Data of the Example 4
Product Name: LINCOMYCIN SUSTAINED RELEASE TABLETS 1000 mg Pack: Blister of lOTablets (PVC-PVDC)
Storage Condition: Accelerated Data [40°C (±2 °C),75% RH (± 5% RH) ]
Example 5
Initial and Stability Data of reproducible batch as Example 4
Product Name: LINCOMYCIN SUSTAINED RELEASE TABLETS 1000 mg Pack: Blister of lOTablets (PVC-PVDC)
Storage Condition: Accelerated Data [40°C (±2 °C),75% RH (± 5% RH) ]
Example 6
Initial and Stability Data of reproducible batch as Example 4
Product Name: LINCOMYCIN SUSTAINED RELEASE TABLETS 1000 mg Pack: Blister of lOTablets (PVC-PVDC)
Storage Condition: Accelerated Data [40°C (±2 °C),75% RH (± 5% RH) ]
Claims
1. A sustained release composition of lincomycin comprising;
a) a slow dissolving matrix consisting of,
i) Lincomycin in an amount of 60 to 70% by weight;
ii) Combination of High viscosity grade hydroxypropyl methylcellulose (HPMC) 100000 CPS and 200000 CPS as rate controlling polymer in an amount of 10 to 20% by weight;
iii) Microcrystalline cellulose as diluent in an amount of 10 to 15% by weight;
iv) Polyvinyl pyrrolidone as binder in an amount of 0.5 to 1% by weight; b) anionic copolymers as coating polymer in an amount of 1 to 1.5%; and c) one or more pharmaceutical carriers or excipients.
2. The sustained release composition as claimed in claim 1, wherein the combination of high viscosity grade HPMC 100000 CPSand HPMC 200000 CPS is in a ratio of 1 : 1.1 to 1 : 1.3.
3. The sustained release composition as claimed in claim 1, wherein the anionic copolymer is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2).
4. The sustained release composition as claimed in claim 1, wherein the pharmaceutical carriers or excipients are selected from the group consisting of lubricants, diluents, glidants, anti-adherents, colors, flavours, plasticizers etc.
5. The sustained release composition as claimed in claim 1, wherein the concentration of lincomycin is lOOOmg.
6. The sustained release composition as claimed in claim 1, wherein the composition exhibits dissolution release profile which is characterized by not more than 20% of the lincomycin released within zero to two hours; 10 % - 40% of the lincomycin released within zero to six hours; 35 % to 65% of the lincomycin released within zero to ten hours; 60 % to 85% of the lincomycin released within zero to fourteen hours; and not less than 80% of the lincomycin released within zero to twenty hours.
7. The sustained release composition as claimed in claim 1, wherein the composition has Lincomycin B impurity in not more than 5.0%.
8. A process for preparation of sustained release composition as claimed in claim 1, wherein the process comprising the steps of;
a) Sifting and mixing lincomycin; High viscosity grade HPMCs and Microcrystalline Cellulose;
b) Preparing binder solution by dissolving Polyvinyl Pyrrolidone in IP A; c) Granulating the mixture of step a) with the binder solution of step b) to obtain granules followed by drying and sieving the granules;
d) Lubricating the granules of step c) by adding the lubricants, glidants and anti-adherents followed by compression to obtain compressed tablets; and e) Preparing the coating solution by dissolving anionic copolymer, plasticizer, colorants and coating the tablets of step d) with the coating solution.
9. The process as claimed in claim 8, wherein, the High viscosity grade HPMC is a combination of HPMC 100000 CPs and 200000CPs in a ratio of 1 : 1 to 1 : 1.3.
10. The process as claimed in claim 8, wherein, the anionic copolymer is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2).
11. The process as claimed in claim 8, wherein, the lubricant is magnesium stearate, the plasticizer is Polyethylene Glycol and the colorant is Ferric Oxide Red.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201821021166 | 2018-06-06 | ||
| IN201821021166 | 2018-06-06 |
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| WO2019234763A1 true WO2019234763A1 (en) | 2019-12-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2019/050434 WO2019234763A1 (en) | 2018-06-06 | 2019-06-06 | Lincomycin sustained release tablets 1000mg |
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| Country | Link |
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| WO (1) | WO2019234763A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200301139A (en) * | 2001-12-20 | 2003-07-01 | Pharmacia Corp | Zero-order sustained release dosage forms and method of making same |
| JP3893058B2 (en) * | 1999-09-30 | 2007-03-14 | ペンウェスト ファーマシューティカルズ カンパニー | Sustained release matrix system for highly soluble drugs |
-
2019
- 2019-06-06 WO PCT/IN2019/050434 patent/WO2019234763A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3893058B2 (en) * | 1999-09-30 | 2007-03-14 | ペンウェスト ファーマシューティカルズ カンパニー | Sustained release matrix system for highly soluble drugs |
| TW200301139A (en) * | 2001-12-20 | 2003-07-01 | Pharmacia Corp | Zero-order sustained release dosage forms and method of making same |
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