WO2005046651A1 - Liquid filled capsules of doxycycline - Google Patents
Liquid filled capsules of doxycycline Download PDFInfo
- Publication number
- WO2005046651A1 WO2005046651A1 PCT/IB2004/003718 IB2004003718W WO2005046651A1 WO 2005046651 A1 WO2005046651 A1 WO 2005046651A1 IB 2004003718 W IB2004003718 W IB 2004003718W WO 2005046651 A1 WO2005046651 A1 WO 2005046651A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carrier
- doxycycline
- liquid filled
- triacetin
- stable liquid
- Prior art date
Links
- 229960003722 doxycycline Drugs 0.000 title claims abstract description 56
- 239000002775 capsule Substances 0.000 title claims abstract description 53
- 239000007788 liquid Substances 0.000 title claims abstract description 47
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 title claims abstract 10
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 60
- 239000001087 glyceryl triacetate Substances 0.000 claims description 30
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 30
- 229960002622 triacetin Drugs 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000005456 glyceride group Chemical group 0.000 claims description 19
- 239000003921 oil Substances 0.000 claims description 19
- 235000019198 oils Nutrition 0.000 claims description 19
- IIRDTKBZINWQAW-UHFFFAOYSA-N hexaethylene glycol Chemical class OCCOCCOCCOCCOCCOCCO IIRDTKBZINWQAW-UHFFFAOYSA-N 0.000 claims description 16
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 12
- 239000008158 vegetable oil Substances 0.000 claims description 12
- 239000007903 gelatin capsule Substances 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 3
- 244000068988 Glycine max Species 0.000 claims description 2
- 235000010469 Glycine max Nutrition 0.000 claims description 2
- 239000008365 aqueous carrier Substances 0.000 claims description 2
- 235000005687 corn oil Nutrition 0.000 claims description 2
- 239000002285 corn oil Substances 0.000 claims description 2
- 239000012738 dissolution medium Substances 0.000 claims description 2
- 239000000084 colloidal system Substances 0.000 claims 1
- 239000008240 homogeneous mixture Substances 0.000 claims 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 48
- 239000000203 mixture Substances 0.000 description 12
- 238000011282 treatment Methods 0.000 description 7
- 208000035143 Bacterial infection Diseases 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 6
- 208000022362 bacterial infectious disease Diseases 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 239000008273 gelatin Substances 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 235000011852 gelatine desserts Nutrition 0.000 description 6
- 239000007970 homogeneous dispersion Substances 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 4
- PTNZGHXUZDHMIQ-UHFFFAOYSA-N 4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C)C(C(O)C3C(C(O)=C(C(N)=O)C(=O)C3N(C)C)(O)C3=O)C3=C(O)C2=C1O PTNZGHXUZDHMIQ-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical group OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 229960004082 doxycycline hydrochloride Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 230000036269 ulceration Effects 0.000 description 3
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010070818 Oesophageal irritation Diseases 0.000 description 2
- 206010030201 Oesophageal ulcer Diseases 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- HALQELOKLVRWRI-VDBOFHIQSA-N doxycycline hyclate Chemical compound O.[Cl-].[Cl-].CCO.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H]([NH+](C)C)[C@@H]1[C@H]2O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H]([NH+](C)C)[C@@H]1[C@H]2O HALQELOKLVRWRI-VDBOFHIQSA-N 0.000 description 2
- 229960001172 doxycycline hyclate Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000020937 fasting conditions Nutrition 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229940102015 monodox Drugs 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 239000008347 soybean phospholipid Substances 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical group O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GJPGCACMCURAKH-YQCFNCLSSA-L chembl2364574 Chemical compound [Ca+2].O=C1C2=C([O-])C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O.O=C1C2=C([O-])C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O GJPGCACMCURAKH-YQCFNCLSSA-L 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960003788 doxycycline calcium Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- -1 propylene glycol ethers Chemical class 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000004094 surface-active agent Substances 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
- 229940124597 therapeutic agent Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K31/65—Tetracyclines
Definitions
- the present invention relates to stable liquid filled capsule of Doxycycline and the process of preparation thereof.
- Doxycycline is a broad spectrum antibiotic synthetically derived from oxytetracycline and is available as doxycycline nionohydrate; doxycycline hyclate; doxycycline hydrochloride hemiethanolate hemihydrate; and doxycycline calcium for oral administration. It is also available as doxycycline hyclate for intravenous use as well as coated pellets.
- Doxycycline has a high degree of lipid solubility and low aqueous solubility i.e. it is hydrophobic in nature. Tablet containing doxycycline hydrochloride tends very easily to stick to the mucosa in the esophagus causing irritation and ulceration.
- U.S. Patent No. 4,693,997 relates to a complex of careageenan and 10-70% by weight of said complex of doxycycline, calculated as doxycycline hydrochloride, which comprises reacting in solution carrgeenan or a salt thereof with doxycycline or and salt thereof to thereby provide said complex.
- U.S. Patent No. 6,294,192 discloses a capsule for oral administration comprising a hydrophobic therapeutic agent and a carrier comprising atleast one hydrophilic surfactant selected from a group consisting of hydrophilic non-ionic surfactant, hydrophilic ionic surfactants and combination thereof and a solubilizer selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a non-aqueous base as a carrier.
- a stable bioequivalent liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from polyglycohzed glycerides, Triacetin or Vegetable oils.
- the dispersibility of the carrier can further be improved by addition of Soyalecithin.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from Polyglycohzed glycerides, such as Com oil PEG-6 Esters (marketed by Gattefosse as Labrafil® M 2125 CS and Labrafil® M 1944 CS).
- a carrier selected from Polyglycohzed glycerides, such as Com oil PEG-6 Esters (marketed by Gattefosse as Labrafil® M 2125 CS and Labrafil® M 1944 CS).
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Triacetin as a carrier.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from vegetable oils such as Miglyol or Soyabean oil.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Com oil PEG-6 Esters and Triacetin as a carrier.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Com oil PEG-6 Esters and Miglylol as a carrier.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Triacetin and Miglylol as a carrier.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from Polyglycohzed glycerides such as Com oil PEG-6 Esters, wherein the ratio of doxycycline to Com oil PEG-6 Esters is in the range of 1 :0.5 to 1:5 and more particularly in the range of 1 : 1 to 1:2.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Triacetin as a carrier wherein the ratio of doxycycline to triacetin is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1:1 to 1:2.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Miglyol as a carrier wherein the ratio of doxycycline to Miglyol is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1:1 to 1:2.
- Li another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Com oil PEG-6 Esters, and Triacetin as carrier wherein their ratio is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1 :1 to 1 :2.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Com oil PEG-6 Esters, and Miglyol as carrier wherein their ratio is in the range of 1 :0.5 to 1:5 and most preferably in the range of 1 : 1 to 1 :2.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Triacetin and Miglyol as carrier wherein their ratio is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1:1 to 1:2.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Polyglycohzed glycerides such as Com oil PEG-6 Esters as a carrier for the treatment of bacterial infections.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and triacetin as a canier for the treatment of bacterial infections.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Miglylol as a carrier for the treatment of bacterial infections.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Corn oil PEG-6 Esters and triacetin as carrier for the treatment of bacterial infections.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Com oil PEG-6 Esters and Miglyol as carrier for the treatment of bacterial infections.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Triacetin and Miglyol as carrier for the treatment of bacterial infections.
- a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a canier selected from Polyglycohzed glycerides, Triacetin or Vegetable oils, wherein the capsule is a soft gelatin capsule or a hard gelatin capsule.
- a stable liquid filled capsule comprising doxycycline and a non-aqueous carrier selected from Polyglycohzed glyceride and/or Triacetin and/or Miglyol having dissolution of at least 70% in 60 min as measured using USP 24 Type 2 paddle type apparatus at 75 rpm, in a dissolution medium constituted by 0.1N HC1.
- capsules containing an active amount of doxycycline in few particular carrier quickly displays the desired activity without oesophageal irritation and ulceration.
- the use of wax bases as carrier led to product that is not bioequivalent, and hydrophilic bases resulted into change in coloration when subjected to 40/75%RH for 5 days. It was found that doxycycline in combination with certain non- aqueous bases remains stable and results in a bioequivalent dosage form.
- the tenn "Liquid filled” refers to the ingredients, which are liquid when filled in the capsule. This liquid can later turn into semisolid or remain as a liquid when the capsule is sealed.
- stable liquid filled softgelatin capsule comprising doxycycline is prepared by rotary die process.
- the fill liquid may be prepared by mixing Doxycycline and the carrier alone or in combination in the ratio of 1 : 1. This mixture is passed through a colloidal mill to form a homogeneous dispersion. The remaining quantity of carrier is added and mixed with the homogeneous dispersion.
- the fill formulation is encapsulated into one-piece gelatin sheath or shell that includes a plasticizer to control the softness and flexibility of the sheath, water, and optionally, other additives, such as flavorants, colorants, opacifiers, etc.
- the softgel capsules are produced in a known manner with a rotary die process in which a molten mass of a gelatin sheath formulation is fed from a reservoir onto drums to form two spaced sheets or ribbons of gelatin in a semi-molten state. These ribbons are fed around rollers and brought together at a convergent angle into the nip of a pair of roller dies that include opposed die cavities. A fill formulation to be encapsulated is fed into the wedge-shaped joinder of the ribbons.
- the gelatin ribbons are continuously conveyed between the dies, with portions of the fill formulation being trapped between the sheets inside the die cavities.
- the sheets are then pressed together, and severed around each die so that opposed edges of the sheets flow together to form a continuous gelatin sheath around the entrapped medicament.
- the part of the gelatin sheet that is severed from the segments forming the capsules is then collected for recycling, and the soft capsules are dried.
- the sheath plasticizer preferably is sorbitol, sorbitol special (a mixture of sorbitol and sorbitan), maltitol, glycerin or a mixture thereof
- the sheath formulations may also contain other ingredients, such as taste modifiers, coloring agents, and moisture retaining agents.
- Various FD&C coloring agents may be used to impart the desired color to the capsule.
- stable liquid filled hard gelatin capsule comprising doxycycline and a carrier is prepared by mixing doxycycline and the a part of carrier alone or in combination. This mixture is passed through a colloidal mill to form a homogeneous dispersion. The remaining quantity of carrier is added and mixed with the homogeneous dispersion. The resulting dispersion is then filled into hard gelatin capsules.
- Doxycycline and Com oil PEG-6 Esters or Triacetin in the ratio of 1 : 1 alone or in combination are mixed.
- step 1 The ingredients of step 1 are passed through a colloidal mill to fonn a homogenous dispersion.
- step 3 The dispersion of step 3 is then incorporated in soft gelatin capsules of suitable size.
- Table 2 EXAMPLE 4 - 5
- Doxycycline, Soyalecithin and Triacetin or Miglyol in the ratio of 1 : 1 alone or in combination are mixed.
- step 1 The ingredients of step 1 are passed through a colloidal mill to form a homogenous dispersion.
- step 3 The remaining quantity of Triacetin or Miglyol are mixed to the homogeneous dispersion of step 2. 4. The dispersion of step 3 is then incorporated in hard gelatin capsules of suitable size.
- the soft gelatin capsules demonstrated comparable extent of absorption when compared to the reference Monodox.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to stable liquid filled capsule of Doxycycline and the process of preparation thereof.
Description
LIQUID FILLED CAPSULES OF DOXYCYCLINE
Field of the Invention
The present invention relates to stable liquid filled capsule of Doxycycline and the process of preparation thereof. Background of the Invention
Doxycycline is a broad spectrum antibiotic synthetically derived from oxytetracycline and is available as doxycycline nionohydrate; doxycycline hyclate; doxycycline hydrochloride hemiethanolate hemihydrate; and doxycycline calcium for oral administration. It is also available as doxycycline hyclate for intravenous use as well as coated pellets.
Doxycycline has a high degree of lipid solubility and low aqueous solubility i.e. it is hydrophobic in nature. Tablet containing doxycycline hydrochloride tends very easily to stick to the mucosa in the esophagus causing irritation and ulceration.
U.S. Patent No. 4,693,997 relates to a complex of careageenan and 10-70% by weight of said complex of doxycycline, calculated as doxycycline hydrochloride, which comprises reacting in solution carrgeenan or a salt thereof with doxycycline or and salt thereof to thereby provide said complex.
U.S. Patent No. 6,294,192 discloses a capsule for oral administration comprising a hydrophobic therapeutic agent and a carrier comprising atleast one hydrophilic surfactant selected from a group consisting of hydrophilic non-ionic surfactant, hydrophilic ionic surfactants and combination thereof and a solubilizer selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof.
The above given references show that doxycycline is either administered as a complex or in combination with various carriers, thus resulting in a reduction of esophageal irritation and ulceration.
Summary of the Invention
Hence in one aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a non-aqueous base as a carrier. In another aspect it provides a stable bioequivalent liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from polyglycohzed glycerides, Triacetin or Vegetable oils.
When two carriers with different HLB values are used in combination the dispersibility of the carrier can further be improved by addition of Soyalecithin.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from Polyglycohzed glycerides, such as Com oil PEG-6 Esters (marketed by Gattefosse as Labrafil® M 2125 CS and Labrafil® M 1944 CS).
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Triacetin as a carrier. In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from vegetable oils such as Miglyol or Soyabean oil.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Com oil PEG-6 Esters and Triacetin as a carrier.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Com oil PEG-6 Esters and Miglylol as a carrier.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Triacetin and Miglylol as a carrier.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from Polyglycohzed glycerides such as Com oil PEG-6 Esters, wherein the ratio of doxycycline to Com oil PEG-6 Esters is in the range of 1 :0.5 to 1:5 and more particularly in the range of 1 : 1 to 1:2.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Triacetin as a carrier wherein the ratio of doxycycline to triacetin is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1:1 to 1:2. In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Miglyol as a carrier wherein the ratio of doxycycline to Miglyol is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1:1 to 1:2.
Li another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Com oil PEG-6 Esters, and Triacetin as carrier wherein their ratio is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1 :1 to 1 :2.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Com oil PEG-6 Esters, and Miglyol as carrier wherein their ratio is in the range of 1 :0.5 to 1:5 and most preferably in the range of 1 : 1 to 1 :2.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Triacetin and Miglyol as carrier wherein their ratio is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1:1 to 1:2.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Polyglycohzed glycerides such as Com oil PEG-6 Esters as a carrier for the treatment of bacterial infections.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and triacetin as a canier for the treatment of bacterial infections.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Miglylol as a carrier for the treatment of bacterial infections.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Corn oil PEG-6 Esters and triacetin as carrier for the treatment of bacterial infections.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Com oil PEG-6 Esters and Miglyol as carrier for the treatment of bacterial infections. In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Triacetin and Miglyol as carrier for the treatment of bacterial infections.
In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a canier selected from Polyglycohzed glycerides, Triacetin or Vegetable oils, wherein the capsule is a soft gelatin capsule or a hard gelatin capsule.
In another aspect it provides a stable liquid filled capsule comprising doxycycline and a non-aqueous carrier selected from Polyglycohzed glyceride and/or Triacetin and/or Miglyol having dissolution of at least 70% in 60 min as measured using USP 24 Type 2 paddle type apparatus at 75 rpm, in a dissolution medium constituted by 0.1N HC1.
Detailed Description of the invention
In the present invention we have found that capsules containing an active amount of doxycycline in few particular carrier quickly displays the desired activity without
oesophageal irritation and ulceration. The use of wax bases as carrier led to product that is not bioequivalent, and hydrophilic bases resulted into change in coloration when subjected to 40/75%RH for 5 days. It was found that doxycycline in combination with certain non- aqueous bases remains stable and results in a bioequivalent dosage form. The tenn "Liquid filled" refers to the ingredients, which are liquid when filled in the capsule. This liquid can later turn into semisolid or remain as a liquid when the capsule is sealed.
In one of the embodiments stable liquid filled softgelatin capsule comprising doxycycline is prepared by rotary die process. The fill liquid may be prepared by mixing Doxycycline and the carrier alone or in combination in the ratio of 1 : 1. This mixture is passed through a colloidal mill to form a homogeneous dispersion. The remaining quantity of carrier is added and mixed with the homogeneous dispersion.
The fill formulation is encapsulated into one-piece gelatin sheath or shell that includes a plasticizer to control the softness and flexibility of the sheath, water, and optionally, other additives, such as flavorants, colorants, opacifiers, etc. The softgel capsules are produced in a known manner with a rotary die process in which a molten mass of a gelatin sheath formulation is fed from a reservoir onto drums to form two spaced sheets or ribbons of gelatin in a semi-molten state. These ribbons are fed around rollers and brought together at a convergent angle into the nip of a pair of roller dies that include opposed die cavities. A fill formulation to be encapsulated is fed into the wedge-shaped joinder of the ribbons.
The gelatin ribbons are continuously conveyed between the dies, with portions of the fill formulation being trapped between the sheets inside the die cavities. The sheets are then pressed together, and severed around each die so that opposed edges of the sheets flow together to form a continuous gelatin sheath around the entrapped medicament. The part of the gelatin sheet that is severed from the segments forming the capsules is then collected for recycling, and the soft capsules are dried.
The sheath plasticizer preferably is sorbitol, sorbitol special (a mixture of sorbitol and sorbitan), maltitol, glycerin or a mixture thereof
The sheath formulations may also contain other ingredients, such as taste modifiers, coloring agents, and moisture retaining agents. Various FD&C coloring agents may be used to impart the desired color to the capsule.
In another embodiment stable liquid filled hard gelatin capsule comprising doxycycline and a carrier is prepared by mixing doxycycline and the a part of carrier alone or in combination. This mixture is passed through a colloidal mill to form a homogeneous dispersion. The remaining quantity of carrier is added and mixed with the homogeneous dispersion. The resulting dispersion is then filled into hard gelatin capsules.
The invention is further illustrated by the following examples, which is for illustrative purpose only and should not be considered as limiting the scope of the invention in any way.
Table 1: EXAMPLE 1 - 3
PROCEDURE:
1. Doxycycline and Com oil PEG-6 Esters or Triacetin in the ratio of 1 : 1 alone or in combination are mixed.
2. The ingredients of step 1 are passed through a colloidal mill to fonn a homogenous dispersion.
3. The remaining quantity of Com oil PEG-6 Esters or Triacetin are mixed to the homogeneous dispersion of step 2.
4. The dispersion of step 3 is then incorporated in soft gelatin capsules of suitable size.
Table 2: EXAMPLE 4 - 5
1. Doxycycline, Soyalecithin and Triacetin or Miglyol in the ratio of 1 : 1 alone or in combination are mixed.
2. The ingredients of step 1 are passed through a colloidal mill to form a homogenous dispersion.
3. The remaining quantity of Triacetin or Miglyol are mixed to the homogeneous dispersion of step 2. 4. The dispersion of step 3 is then incorporated in hard gelatin capsules of suitable size.
In vitro dissolution study
In vitro release of doxycycline from capsules as per composition of Example 1-4 was studied in 900 ml, 0.1 N HCl, (pH-1.2), using USP apparatus - II, at 75 rpm. The results are listed in Table 3. Table 3: In vitro release of doxycycline from capsules
In vivo performance of doxycycline softgelatin capsules prepared as per the composition of Example 1 were evaluated with respect to the Monodox in 12 healthy male volunteers under fasting condition. The study protocol followed was randomized treatments, single dose crossover bioavailability study on Doxycycline 100 mg soft gelatin capsules under fasting condition with a wash out period of at least 10 days. Blood samples were collected at appropriate time intervals over a period of 96 hours and doxycycline content analyzed using a validated HPLC with UV detector method. Pharmacokinetic parameters Cmax (Maximum plasma concentration), AUC0-t (Area under the plasma concentration vs time curve from 0 hours to the time of last sample collected) and AUC0-a (Area under the plasma concentration vs. time curve from 0 hours to infinity) were calculated from the data obtained. The results of the study are given in Table 4.
Table 4: Comparative pharmacokinetic data
While there has been shown and described what are the prefened embodiments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the fonnulations and process can be made without departing from the scope of the invention as it is defined by the appended claims.
Claims
1. A stable liquid filled capsule comprising doxycycline and a non-aqueous carrier selected from Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil having a dissolution of at least 70% in 60 min as measured using USP 24 Type 2 paddle type apparatus at 75 rpm, in a dissolution medium constituted by 0.1N HCl.
2. The stable liquid filled capsule according to Claim 1 wherein the ratio of doxycycline to the Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil is in the range of 1:0.5 to 1:5.
3. The stable liquid filled capsule according to Claim 2 wherein the ratio of doxycycline to the Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil is in the range of 1 : 1 to 1:2.
4. The stable liquid filled capsule according to Claim 1 wherein the carrier is selected from Polyglycohzed glyceride such as Com oil PEG-6 Esters.
5. The stable liquid filled capsule according to claim 4 wherein carrier is Com oil PEG- 6 Esters.
6. The stable liquid filled capsule according to Claim 1 wherein the carrier is Triacetin.
7. The stable liquid filled capsule according to Claim 1 wherein the carrier is selected from vegetable oils such as Miglyol or Soyabean oil.
8. The stable liquid filled capsule according to Claim 7 wherein the carrier is Miglyol.
9. The stable liquid filled capsule according to claim 1 wherein carrier is a combination of Com oil PEG-6 Esters and Triacetin.
10. The stable liquid filled capsule according to claim 1 wherein carrier is a combination of Com oil PEG-6 Esters and Miglyol.
11. The stable liquid filled capsule according to claim 1 wherein carrier is a combination of Triacetin and Miglyol.
12. The stable liquid filled capsule according to claim 1 wherein it is either a softgelatin or hard gelatin capsule.
13. A process for preparation of a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil as a carrier by mixing doxycycline and a part of carrier; then passing through a colloid mill to form a homogeneous mixture, to which the remaining quantity of carrier is added and finally filled into capsules.
14. The process according to claim 13 wherein the ratio of doxycycline to the Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil is in the range of 1 : 0.5 to 1:5.
15. The process according to claim 14 wherein the ratio of doxycycline to the Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil is in the range of 1 : 1 to 1 :2.
16. The process according to claim 13 wherein carrier is selected from Polyglycohzed glycerides such as Corn oil PEG-6 Esters.
17. The process according to claim 13 wherein the carrier is Triacetin.
18. The process according to claim 13 wherein the carrier is selected from Vegetable oils such as Miglyol.
19. The process according to claim 13 wherein carrier is a combination of Com oil PEG- 6 Esters and Triacetin.
20. The process according to claim 13 wherein carrier is a combination of Com oil PEG- 6 Esters and Miglyol.
21. The process according to claim 13 wherein carrier is a combination of Triacetin and Miglyol.
22. A stable bioequivalent liquid filled softgelatin capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil as a carrier as described and illustrated herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1395/DEL/2003 | 2003-11-12 | ||
| IN1395DE2003 | 2003-11-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005046651A1 true WO2005046651A1 (en) | 2005-05-26 |
Family
ID=34586956
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2004/003718 WO2005046651A1 (en) | 2003-11-12 | 2004-11-12 | Liquid filled capsules of doxycycline |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2005046651A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007087416A3 (en) * | 2006-01-24 | 2007-09-20 | Paratek Pharaceuticals Inc | Methods of increasing oral bioavailability of tetracyclines |
| EP1902706A1 (en) * | 2006-09-25 | 2008-03-26 | Divasa-Farmavic, S.A. | Stable pharmaceutical compositions of tetracyclines in solution, method for obtaining them and their uses |
| CN102213723A (en) * | 2010-04-02 | 2011-10-12 | 北京库尔科技有限公司 | Doxycycline detection kit and preparation method thereof |
| US9119793B1 (en) | 2011-06-28 | 2015-09-01 | Medicis Pharmaceutical Corporation | Gastroretentive dosage forms for doxycycline |
| WO2015200444A1 (en) * | 2014-06-24 | 2015-12-30 | Saudi Arabian Oil Company | Encapsulation of an acid precursor for oil field applications |
| US10842802B2 (en) | 2013-03-15 | 2020-11-24 | Medicis Pharmaceutical Corporation | Controlled release pharmaceutical dosage forms |
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| WO1998056360A2 (en) * | 1997-06-11 | 1998-12-17 | The Procter & Gamble Company | Film-coated tablet for improved upper gastrointestinal tract safety |
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| WO1982004191A1 (en) * | 1981-06-01 | 1982-12-09 | Marttila Esko Veikko | Tablets which do not damage the oesophagus |
| US4693997A (en) * | 1982-03-12 | 1987-09-15 | Kabivitrum Ab | Novel pharmaceutical composition |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007087416A3 (en) * | 2006-01-24 | 2007-09-20 | Paratek Pharaceuticals Inc | Methods of increasing oral bioavailability of tetracyclines |
| EP2298324A1 (en) * | 2006-01-24 | 2011-03-23 | Paratek Pharmaceuticals, Inc. | Methods of increasing oral bioavailability of tetracyclines |
| AU2007208214B2 (en) * | 2006-01-24 | 2013-02-14 | Paratek Pharmaceuticals, Inc. | Methods of increasing oral bioavailability of tetracyclines |
| US9078811B2 (en) | 2006-01-24 | 2015-07-14 | Paratek Pharmaceuticals, Inc. | Methods of increasing oral bioavailability of tetracyclines |
| EP1902706A1 (en) * | 2006-09-25 | 2008-03-26 | Divasa-Farmavic, S.A. | Stable pharmaceutical compositions of tetracyclines in solution, method for obtaining them and their uses |
| CN102213723A (en) * | 2010-04-02 | 2011-10-12 | 北京库尔科技有限公司 | Doxycycline detection kit and preparation method thereof |
| US9119793B1 (en) | 2011-06-28 | 2015-09-01 | Medicis Pharmaceutical Corporation | Gastroretentive dosage forms for doxycycline |
| US10842802B2 (en) | 2013-03-15 | 2020-11-24 | Medicis Pharmaceutical Corporation | Controlled release pharmaceutical dosage forms |
| WO2015200444A1 (en) * | 2014-06-24 | 2015-12-30 | Saudi Arabian Oil Company | Encapsulation of an acid precursor for oil field applications |
| US9796919B2 (en) | 2014-06-24 | 2017-10-24 | Saudi Arabian Oil Company | Encapsulation of an acid precursor for oil field applications |
| US10093851B2 (en) | 2014-06-24 | 2018-10-09 | Saudi Arabian Oil Company | Encapsulation of an acid precursor for oil field applications |
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