WO2005025564A1 - Oral pharmaceutical formulations of rofecoxib - Google Patents
Oral pharmaceutical formulations of rofecoxib Download PDFInfo
- Publication number
- WO2005025564A1 WO2005025564A1 PCT/TR2004/000039 TR2004000039W WO2005025564A1 WO 2005025564 A1 WO2005025564 A1 WO 2005025564A1 TR 2004000039 W TR2004000039 W TR 2004000039W WO 2005025564 A1 WO2005025564 A1 WO 2005025564A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- rofecoxib
- pharmaceutical formulations
- oral pharmaceutical
- active substance
- new oral
- Prior art date
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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
- A61K9/2022—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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
-
- 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
Abstract
This innovation deals with the newly developed preparation method of new pharmaceutical dosage forms that contain the active substance rofecoxib and that are orally administrated. Owing to the development of this formulation, the dissolution properties and the in vivo characteristics of rofecoxib have been improved.
Description
DESCRIPTION
NEW ORAL PHARMACEUTICAL FORMULATIONS OF ROFECOXIB
This innovation presents the new method developed to prepare new pharmaceutical dosage forms that contain the active ingredient rofecoxib and that are orally administrated.
The patents number US5474995, WO9500501 and WO95187999 define the active ingredient rofecoxib (4-[4-(methylsulfonyl) phenyl]- 3- phenyl- 2(5H)- furanone) used to treat the pathological diseases mediated by the cyclooxygenase-2 (cox-2) as well as the other 3,4 double substituted furanone derivatives that are inliibitors of cox-2. The structure of the rofecoxib molecule is as represented below:
C17H1 O4S Rofecoxib is a NSAID. In the pre-clinical studies done on laboratory animals, rofecoxib has been proved to have analgesic, antipyretic, and anti-inflammatory properties. Rofecoxib shows these properties by selectively inhibiting the cox-2 enzyme, principally responsible for the inflammation. These are two known isoforms of the enzyme cyclooxygenase. During the inflammation process, cyclooxygenase is inductible and the selective inhibition of this enzyme reduces pain, fever and inflammation. In this case, the influence mechanism is thought to be the inhibition of the prostaglandin synthesis. On the other hand, since the enzyme cox-2 is responsible for the cytoprotective activity, its inhibition is not a desirable situation. The NSAI drugs suc aspirin, naproxen, and etodolac being not selective; they can present serious side effects for the gastro-intestinal system.
Among the NSAID, the drugs that selectively inhibit cox-2 enzyme have been widely used those last years and demonstrated successful clinical results. The selective inhibitors of the enzyme cox-2 are more protective regarding the gastrointestinal system than the other NSAI drugs, consequently they turned out to become more appropriate choices for the diseases that necessitate long lasting treatment such as rheumatoid arthritis and osteoarthritis.
When orally administrated, in the treatment dosage the bioavailability of rofecoxib is 93%. Given this high oral bioavailability, tablets and suspension forms have been developed. After the once dosing of the original product Vioxx, the value of the peak plasma concentration is (Cmax) 215±90 ng/ml. The time needed to reach this value can differ from one individual to another. It was determined that the value Tmax varies between 2 and 9 hours. The Cmax value calculated during in vivo studies of our formulation was 238+112 ng/ml. Rofecoxib is slightly soluble in methanol and isopropyl acetate, very slightly soluble in ethanol, practically insoluble in octanol and insoluble in water.
In the patent number US5474995 the compositions including rofecoxib are described as curative for the following pains and diseases: - Rheumatoid inflammation, - Violent lumbago, back and neck pain, - Dysmenorrhea, - Toothache, headache, - Sprains and strains, - Muscle and tendon aches, - Joint inflammations, - Degenerative j oint diseases, - Gout, spondilitis, bursitis, - Burns, - Fever and inflammations resulting from the chirurgical and dental operations/injuries.
A lot of pharmaceutical dosage forms have been described, among which is included the active ingredient rofecoxib. The document referenced as WO0217923
and WO03035080 are describing the topical pharmaceutical compositions of the active ingredients responsible for the selective inhibition of cox-2 enzyme. The patent number WO02067894 explains the formulations of the oral tablet that rapidly dissolves in the mouth and that is specially prepared for the persons having difficulties in swallowing the tablet forms.
The patent number WO03013473 presents the preparation of pharmaceutical forms orally appropriate for the compositions that are slightly soluble in water. The patent WO03035063 describes the formulations of the cox-2 enzyme selective inhibitors that are parenterally convenient and that are used to treat the pain and inflammation related to the cox-2 enzyme activity.
The patent number WO9744028 describes the once-daily oral dosage forms that are used to cure diseases mediated by cox-2. It also presents the description of the product Vioxx that contains the active ingredient rofecoxib and which is the property of Merck Inc. The oral dosage forms that contain the active ingredient 4-[4-(meth.ylsulfonyl) phenyl]- 3- phenyl- 2(5H)- furanone (rofecoxib) is marketed as tablet forms of 12,5 mg, 25 mg, and 50 mg and as suspension form of 12.5 mg/5 ml and 25 mg/5 ml. The daily dosage is variable according to the indications of the product and the acuteness of the disease. The innovation that is the subject of our patent, utilizes active ingredient in an appropriate dosage and inert excipients that are pharmacologically convenient. During the preparation of the tablet forms, the following materials are used: - Polyvinyl pyrrolidone K30 (PVP K30) as binding agent, - Sodium lauryl sulfate as wetting agent, _ Lactose monohydrate and microcrystalline cellulose pH 102 as filling material, - Croscarmellose sodium (Ac-Di-Sol) as disintegrant, - And magnesium stearate as lubricant.
Because of the bad fluidity of the active ingredient and the poor dissolution properties of rofecoxib, this newly developed formulation is prepared v th the wet granulation method by using appropriate excipients. In the wet granulation phase, water solution PVP K30 is used as a binder.
PVP K30 is a synthetic polymer that can be used in the granulation process. Thanks to its polarity, PVP K30 proved to have positive impacts regarding dissolution when it was used for the granulation of slightly soluble active ingredients. Wet granulation is generally performed with water and or alcoholic solution of this polymer. Besides, granulation can also be done with its powder form after being added to the mixture.
Lactose monohydrate and Avicel pH 102 are the filling materials used in the oral formulation of rofecoxib. Lactose monohydrate is a filling material often used in wet granulations.
Owing to its fluidity and compressibility, Avicel pH102 is a filling material that is frequently chosen in the formulations. Furthermore the formulation also benefits from its disintegrant property. This disintegrant specificity via the porous structure of its particles results in a water penetration. The anionic surfactant that is used in the new formulation results in an increase of the solubility of rofecoxib in tablet form.
The use of the super disintegrant croscarmellose sodium (Ac-di-sol) in the formulation ensures distribution of the tablet in a short time. Ac-di-sol can be added either to the internal phase or to the external phase. Magnesium stearate has been used as lubricant; therefore the tablets can be compressed without adhering to the tablet punch face.
Since rofecoxib is not soluble in water, a wetting agent was used to increase the solubility of the ingredient. In this innovation, contrarily to the original product, sodium lauryl sulfate and PVP K30 were used. In this formulation the quantity of sodium lauryl sulfate used is in proportion of the tablet weight is between 1 and 5 %, preferably 3 % and that of the PVP K30 is in proportion of the tablet weight is between 0.5 and 5 %, preferably 1 %. These uses provided superior specificities to the formulation in terms of dissolution and in vivo properties. The addition of these excipients to the formulation enhanced the solubility of the active ingredient rofecoxib. In the comparative dissolution studies made between the reference product and the formulation subject of this innovation, the dissolution values of the new formulation
4 SUBSTITUTE SHEET (RUI± ΛJ
turned to be better (Table 1).
In the in vivo evaluations too, Cmax and AUC values of our new formulation are better than those of the reference product (Table 2).
Table 1 Comparative dissolution values of the rofecoxib 25 mg tablet.
Table 2 Cmax and AUCoo values of Rofecoxib 25 mg/ Vioxx 25 mg, the bio-equivalence studies performed on healthy test subjects, the number of test subjects is 24.
The tablets prepared with the binder PVP K30 were examined from a friability perspective: the obtained result is 0.55 % of friability. In the international pharmacopoeias this value is defined as maximum 1%. A.s for the reference product the friability result obtained was 0.8 %. The use of the binder PVP K30, as we did in our formulation instead of hydroxypropyl methylcellulose as in the reference product, provided a superior characteristic to our formulation.
SAMPLES
The samples below presented aim at showing the characteristics of the formulation and at delimiting the scope of this patent.
Sample 1: Rofecoxib tablet 25 mg prepared with the wet granulation technique. The tablets were prepared according to the values presented in the table 3 Table 3
Rofecoxib, sodium lauryl sulfate and Ac-di-sol for 50%, yellow ferric oxide for approximately 10% and lactose monohydrate are mixed in the powder-mixing pan. The water solution of PVP K30 is prepared in a ratio of 10%. The powder mixture that has been prepared is transferred to the mixer. The wet granulation is performed with the PVP 30 solution prepared in advance. The paste is then riddled through a sieve. The granules are dried in an oven and then sifted in to the powder-mixing pan. The magnesium stearate is sifted, poured into the mixing pan and mixed. After what the tablets are pressed in the press machine.
Table 4
Rofecoxib and Ac-di-sol for 5O%, yellow ferric oxide for approximately 10% and lactose monohydrate are mixed in the powder-mixing pan. The water solution of PVP K30 is prepared in a ratio of 10%. In this solution, Poloxamer 407 is diluted. The powder mixture that has been prepared is transferred to the mixer. The wet granulation is performed with the PVP K30 solution prepared in advance. The paste is then riddled through a sieve. The granules are dried in an oven and then sifted in to the powder-mixing pan. The magnesium stearate is sifted, poured into the mixing pan and mixed. After what the tablets are pressed in the press machine.
Claims
1. This document includes the new oral pharmaceutical formulations to treat the diseases mediated by the cyclooxygenase-2, that are appropriate for an oral administration and that contains the active substance 4-[4-(methylsulfonyl) phenyl]- 3- phenyl- 2(5H)- furanone) (rofecoxib).
2. As defined in claim 1, these new oral pharmaceutical formulations contain the active substance rofecoxib and are characterized by being a composition including between 1 mg and 200 mg of active ingredient rofecoxib, preferably 25 mg or 50 mg.
3. As defined in claim 1, these new oral pharmaceutical formulations contain the active substance rofecoxib and are characterized by also including surfactant, filling materials, disintegrant, coloring and lubricant (gliding) substances.
4. As defined in claim 3, these new oral pharmaceutical formulations include the active substance rofecoxib and are characterized by containing surfactant that can be anionic, cationic or non-ionic.
5. As defined in claim 4, the surfactant is preferably anionic.
6. As defined in claim 5, the surfactant is preferably sodium lauryl sulfate. In the formulation, the quantity of sodium lauryl sulfate used is in proportion of the tablet weight: between 1 and 5 %, preferably 3 %.
7. As defined in claim 3, these new oral pharmaceutical formulations include the active substance rofecoxib and are characterized by preferably containing polyvinyl pyrrolidone as binding agent.
8. As defined in claim 7, the binding agent polyvinyl pyrrolidone used in the formulation is PVP K30. In the formulation, the quantity of PVP used is in proportion of the tablet weight: between 0.5 and 5%, preferably 1%.
9. As defined in claim 3, these new oral pharmaceutical formulations include the active substance rofecoxib and are characterized by the use of preferably lactose monohydrate and microcrystalline cellulose as filling material.
10. As defined in claim 3, these new oral pharmaceutical formulations include the active substance rofecoxib and are characterized by the use of preferably croscarmellose sodium as disintegrant substance.
11. As defined in claim 3, these new oral pharmaceutical formulations of rofecoxib are characterized by the use of preferably red and/or yellow ferric oxide as coloring material.
12. As defined in claim 3, these new oral pharmaceutical formulations of rofecoxib are characterized by the use of preferably magnesium stearate as lubricant.
13. The pharmaceutical formulations as defined in claim 1, are characterized by the following dissolution value: minimum 80 % of dissolution at 15 min after the dosing, preferably superior to 85 %.
14. These new oral pharmaceutical formulations that are prepared as defined in claim 1, include the active substance rofecoxib and are characterized by their availability in capsule form, preferably in tablet form.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TR2003/01552A TR200301552A1 (en) | 2003-09-18 | 2003-09-18 | Novel oral pharmacological formulations of rofecoxib. |
TR2003/01552 | 2003-09-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005025564A1 true WO2005025564A1 (en) | 2005-03-24 |
Family
ID=34311481
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/TR2004/000039 WO2005025564A1 (en) | 2003-09-18 | 2004-09-16 | Oral pharmaceutical formulations of rofecoxib |
Country Status (2)
Country | Link |
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TR (1) | TR200301552A1 (en) |
WO (1) | WO2005025564A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10945992B1 (en) | 2019-11-13 | 2021-03-16 | Tremeau Pharmaceuticals, Inc. | Dosage forms of rofecoxib and related methods |
US11559509B2 (en) | 2018-11-21 | 2023-01-24 | Tremeau Pharmaceuticals, Inc. | Purified forms of rofecoxib, methods of manufacture and use |
US11858909B2 (en) | 2021-04-09 | 2024-01-02 | Tremeau Pharmaceuticals, Inc. | Deuterated etoricoxib, methods of manufacture, and use thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997044028A1 (en) * | 1996-05-17 | 1997-11-27 | Merck & Co., Inc. | Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases |
WO2001041760A2 (en) * | 1999-12-08 | 2001-06-14 | Pharmacia Corporation | Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect |
WO2002067894A2 (en) * | 2001-02-27 | 2002-09-06 | Ranbaxy Laboratories Limited | Fast dissolving tablets of cyclooxygenase-2 enzyme inhibitors |
WO2003013473A1 (en) * | 2001-08-06 | 2003-02-20 | Pharmacia Corporation | Stabilized oral suspension formulation |
WO2003086343A2 (en) * | 2002-04-05 | 2003-10-23 | Cadila Healthcare Limited | Fast disintegrating oral dosage forms |
-
2003
- 2003-09-18 TR TR2003/01552A patent/TR200301552A1/en unknown
-
2004
- 2004-09-16 WO PCT/TR2004/000039 patent/WO2005025564A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997044028A1 (en) * | 1996-05-17 | 1997-11-27 | Merck & Co., Inc. | Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases |
WO2001041760A2 (en) * | 1999-12-08 | 2001-06-14 | Pharmacia Corporation | Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect |
WO2002067894A2 (en) * | 2001-02-27 | 2002-09-06 | Ranbaxy Laboratories Limited | Fast dissolving tablets of cyclooxygenase-2 enzyme inhibitors |
WO2003013473A1 (en) * | 2001-08-06 | 2003-02-20 | Pharmacia Corporation | Stabilized oral suspension formulation |
WO2003086343A2 (en) * | 2002-04-05 | 2003-10-23 | Cadila Healthcare Limited | Fast disintegrating oral dosage forms |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11559509B2 (en) | 2018-11-21 | 2023-01-24 | Tremeau Pharmaceuticals, Inc. | Purified forms of rofecoxib, methods of manufacture and use |
US11576890B2 (en) | 2018-11-21 | 2023-02-14 | Tremeau Pharmaceuticals, Inc. | Purified forms of rofecoxib, methods of manufacture and use |
US11617735B2 (en) | 2018-11-21 | 2023-04-04 | Tremeau Pharmaceuticals, Inc. | Purified forms of rofecoxib, methods of manufacture and use |
US11872206B2 (en) | 2018-11-21 | 2024-01-16 | Tremeau Pharmaceuticals, Inc. | Purified forms of rofecoxib, methods of manufacture and use |
US10945992B1 (en) | 2019-11-13 | 2021-03-16 | Tremeau Pharmaceuticals, Inc. | Dosage forms of rofecoxib and related methods |
CN115605197A (en) * | 2019-11-13 | 2023-01-13 | 特默罗制药股份有限公司(Us) | Novel dosage forms of rofecoxib and related methods |
US11858909B2 (en) | 2021-04-09 | 2024-01-02 | Tremeau Pharmaceuticals, Inc. | Deuterated etoricoxib, methods of manufacture, and use thereof |
Also Published As
Publication number | Publication date |
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TR200301552A1 (en) | 2005-10-21 |
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