EP1370244A1 - Novel tablets and capsules and a process for its preparation - Google Patents

Novel tablets and capsules and a process for its preparation

Info

Publication number
EP1370244A1
EP1370244A1 EP02702234A EP02702234A EP1370244A1 EP 1370244 A1 EP1370244 A1 EP 1370244A1 EP 02702234 A EP02702234 A EP 02702234A EP 02702234 A EP02702234 A EP 02702234A EP 1370244 A1 EP1370244 A1 EP 1370244A1
Authority
EP
European Patent Office
Prior art keywords
tablet
weight
capsule
active ingredient
microcrystalline cellulose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02702234A
Other languages
German (de)
French (fr)
Inventor
Thyge Borup Hjorth
Breian Knudsen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Research Foundation
Original Assignee
Novo Nordisk AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP1370244A1 publication Critical patent/EP1370244A1/en
Withdrawn legal-status Critical Current

Links

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
    • A61K9/2009—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • Novel tablets and capsules and a process for its preparation Novel tablets and capsules and a process for its preparation.
  • the present invention relates to novel tablets and capsules with relatively low amounts of the active ingredient.
  • the present invention further relates to tablets and capsules comprising as the active ingredient (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salt thereof.
  • (2S)(-)-3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid in the following (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid) and pharmaceutically ac- ceptable salts thereof has been found useful in the treatment of type 2 diabetes acting as an insulin sensitizer as disclosed in eg PCT Publication WO 99/19313, WO 00/50414 and WO 00/63192, which are incorporated herein by reference.
  • compositions containing (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid as active ingredient or a pharmaceutically acceptable salt thereof are described in WO01/74363.
  • One object of the present invention is to provide tablets and capsules having improved homogeneity.
  • Another object of the present invention is to provide tablets and capsules having improved homogeneity with respect to the content of active ingredient. Another object of the present invention is to provide tablets and capsules having improved homogeneity with respect to the distribution of active ingredient.
  • Another object of the present invention is to provide tablets and capsules having a low content of active ingredient.
  • a still further object of the present invention is to provide tablets and capsules being supe- rior to the known art.
  • a tablet or capsule wherein the content of active ingredient in the tablet or capsule is between about 3 % (weight/weight) and about 0.001 % (weight/weight) can be prepared with improved homogenous distribution of the active ingredient if microcrystalline cellulose and silicon dioxide are used as some of the starting materials.
  • a tablet or capsule wherein the content of active ingredient in the tablet or capsule is not more than about 2 % (weight/weight) can be prepared with improved homogenous distribution of the active ingredient if microcrystalline cellulose and silicon dioxide are used as some of the starting materials.
  • any sort of microcrystalline cellulose can be used for the preparation of the tablets and capsules according to the present invention.
  • the microcrystalline cellulose used for the preparation of the tablets and capsules according to the present invention has a bulk density above 0.35 g/ml.
  • the microcrystalline cellulose used for the preparation of the tablets and capsules according to the present invention has a particle size above about 50 micrometer.
  • a tablet or capsule according to the present invention comprises preferably microcrystalline cellulose in an amount of at least 20 %, more preferred of at least 30 % and even more preferred of at least 40 % (weight/weight) and most preferred in an amount of at least 45% (weight/weight).
  • the tablet or capsule according to the invention comprises microcrystalline cellulose in amounts ranging from 20% to 80% (weight/weight) , amounts from 30% to 70% are preferred while amounts from 40% to 60% are even more preferred and amounts ranging from 45% to 55% are especially preferred.
  • any sort of silicone dioxide can be used for the preparation of the tablets and cap- sules according to the present invention.
  • the silicone dioxide used for the preparation of the tablets and capsules according to the present invention has a particle size from about 1 namometer to about 100 micrometer.
  • a tablet or capsule according to the present invention comprises preferably an amount of silicone dioxide in the range from 0.1 to 5 %, preferably in the range from 0.2% to 3%, even more preferred in the range from 0.5% to 1 ,5% (weight/weight).
  • the tablet or capsule further comprises mannitol.
  • the tablet or capsule comprises mannitol in an amount of at least 20%, preferably at least 30% an even more pre- ferred at lest 40% (weight/weight) and most preferred in an amount of at least 45%
  • the tablet or capsule comprises mannitol in amounts ranging from 20% to 80% (weight/weight) , amounts from 30% to 70%) are preferred while amounts from 40% to 60% are even more preferred and amounts ranging from 45% to 55% are especially preferred.
  • the tablet or capsule comprises mannitol and microcrystalline cellulose in proportions between 2:8 and 8:2, preferably between 3:5 and 5:3, more preferred between 4:6 and 6:4, and even more preferred between 45:55 and 55:45.
  • the tablet or capsule comprises talc in the range from 0.1 to 10 % (weight/weight).
  • the tablet or capsule comprises micro- crystalline cellulose in an amount ranging from 45% to 55% and silicon dioxide in an amount from 0,5%) to 1 ,5%(weight/weight).
  • the tablet or capsule comprises: (i) an active ingredient selected from the group consisting of (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2- ethoxypropanoic acid, pharmaceutically acceptable salt, ester, metabolite, hydrate, solvate, polymorph, and pro-drug form thereof, (ii) microcrystalline cellulose; and (iii) silicon dioxide, wherein the amount of said active ingredient is between about 0.01% and about 2,0% (weight/weight); the amount of said microcrystalline cellulose is between about 40% and about 50%) (weight/weight); and the amount of said silicone dioxide is between about 0.8% and about 1.2% (weight/weight).
  • an active ingredient selected from the group consisting of (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2- ethoxypropanoic acid, pharmaceutically acceptable salt, ester, metabolite, hydrate, solvate, polymorph, and pro-d
  • Non-limiting examples of a formulation according to invention include the following (expressed as % weight/ total weight of each ingredient):
  • the tablets or capsules are prepared using one of the commercial products marketed under the designations ProSolv HD 90, Pro- Solv SMCC 50, and ProSolv SMCC 90 by the firm PenWest, each of which contain both microcrystalline cellulose and silicon dioxide.
  • the tablets or capsules have a relative standard deviation (RSD) for the content of active ingredient in the tablet or capsule which is not more than about 4%.
  • RSD relative standard deviation
  • the RSD value is not more than about 3 %, more preferred the RSD value is not more than about 2,5 %, and even more preferred the RSD value is not more than about 2 %, especially preferred the RSD value is not more than about 1 ,5 %, and even more preferred the RSD value is not more than about 1 %.
  • the relative standard deviation (RSD) for the content of active ingredient in the tablets of the present invention can be determined as described in the United States Pharmacopeia (USP 24) 2000, chapter 905 using the test for Uniformity of Dosage Units, ⁇ 905>, USP XV.
  • the bulk and tapped density can be determined as described in method BTD-8, Handbook of Pharmaceutical Excipients, 2nd ed., 1994. Particle size distribution can be determined by Sieve analysis using US standard sieves.
  • the tablets and capsules according to the present invention can be prepared in a manner known perse. More specifically, the tablets and capsules may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19 th edition, 1995. According to a preferred feature of the present invention, the tablet or capsule ac- cording to the present invention are prepared by direct compression. Direct compression has the advantage that it is possible to first mix all the ingredients which are to be present in the final tablet or capsule and then to subject the mixture to direct compression.
  • the active ingredient present in the tablets and capsules of the present invention can be any pharmaceutical such as analgesics and anti-inflammatory agents, anthelminthics, anti- arrhythmic agents, antibacterial agents, anticoaglants, antidepressants, antidiabetic agents, antiepileptics, antifungal agents, antigout agents, antihypertensive agents, antimalarials, an- timigraine gents, antimuscarinic agents, antineoplastic agents, immunosuppressants, anti- protozoal agents, antithyroid agents, antiviral agents, anxiolytic sedatives, hypnotics, neuro- leptics, beta-adrenoceptor blocking agents, calcium regulating agents, cardiac inotropic agents, chelating agents, antidotes, antagonists, corticosteroids, diuretics, dopaminergic an- tiparkinsonian agents, gastro-intestinal agents, anaesthetics, hormones, lipid regulating agents, , anti
  • An example of a specific medicaments is (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid and pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts forming part of this invention include salts such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts, aluminium salts.
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulplionates, benzoates, salicy- lates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketogluta- rates and the like.
  • Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • the present invention also encompasses esters, metabolites, hydrates, solvates, poly- morphs, and pro-drug forms of (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
  • (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine is used in the present invention.
  • Another example of a specific medicament is 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2- quinazolinyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione and pharmaceutically acceptable salts thereof as active ingredient as described in PCT Publication WO 97/41097.
  • the present invention also encompasses esters, metabolites, hydrates, solvates, polymorphs, and pro- drug forms of 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl- methyl]thiazolidine-2,4-dione.
  • suitable carriers present in the tablets and capsules according to the present invention are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, mannitol, sorbitol, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the tablets and capsules may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the tablets and capsules of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the tablets and capsules can be sterilized and mixed, if desired, with auxiliary agents, emul- sifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • the tablets and capsules of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of various diseases as mentioned above.
  • mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the exact dosage of the tablets and capsules will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the powder mixture is compressed into tablets on a tabletting machine.
  • the tablet weight is EXAMPLE 6
  • the powder mixture is compressed into tablets on a tabletting machine.
  • the tablet weight is EXAMPLE 8
  • the powder mixture is compressed into tablets on a tabletting machine.
  • the tablet weight is 110 mg.
  • the powder mixture is compressed into tablets on a tabletting machine.
  • the tablet weight is 110 mg.

Abstract

Tablets and capsules wherein the content of active ingredient in the tablet or capsule is not more than about 3 % (weight/weight) can be prepared if microcrystalline cellulose and silicon dioxide are used as some of the starting materials.

Description

Novel tablets and capsules and a process for its preparation.
FIELD OF THE INVENTION
The present invention relates to novel tablets and capsules with relatively low amounts of the active ingredient. The present invention further relates to tablets and capsules comprising as the active ingredient (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
In US patent 5,948,438 and US patent 6,106,865 oral solid dosage forms comprising micro- crystalline cellulose and a compressibility augmenting agent such as silicon dioxide are described.
(2S)(-)-3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid (in the following (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid) and pharmaceutically ac- ceptable salts thereof has been found useful in the treatment of type 2 diabetes acting as an insulin sensitizer as disclosed in eg PCT Publication WO 99/19313, WO 00/50414 and WO 00/63192, which are incorporated herein by reference. Pharmaceutical compositions containing (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid as active ingredient or a pharmaceutically acceptable salt thereof are described in WO01/74363.
One object of the present invention is to provide tablets and capsules having improved homogeneity.
Another object of the present invention is to provide tablets and capsules having improved homogeneity with respect to the content of active ingredient. Another object of the present invention is to provide tablets and capsules having improved homogeneity with respect to the distribution of active ingredient.
Another object of the present invention is to provide tablets and capsules having a low content of active ingredient. A still further object of the present invention is to provide tablets and capsules being supe- rior to the known art. SUMMARY OF THE INVENTION
It has now been found that a tablet or capsule wherein the content of active ingredient in the tablet or capsule is between about 3 % (weight/weight) and about 0.001 % (weight/weight) can be prepared with improved homogenous distribution of the active ingredient if microcrystalline cellulose and silicon dioxide are used as some of the starting materials. Surprisingly, it has now been found that a tablet or capsule wherein the content of active ingredient in the tablet or capsule is not more than about 2 % (weight/weight) can be prepared with improved homogenous distribution of the active ingredient if microcrystalline cellulose and silicon dioxide are used as some of the starting materials. Using these starting materials, it is even possible to prepare tablets and capsules wherein the content of active ingredient in the tablet or capsule is not more than about 1 %, not more than about 0.5 %, not more than about 0.05 %, not more than about 0.01 %, and even not more than about 0.005 % (weight/weight).
It is a further object of the present invention to provide a tablet or capsule with improved homogenous distribution which comprises microcrystalline cellulose and silicon dioxide and (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically ac- ceptable salt thereof.
MORE DETAILED DESCRIPTION OF THE PRESENT INVENTION
Generally, any sort of microcrystalline cellulose can be used for the preparation of the tablets and capsules according to the present invention. However, it is preferred that the microcrystalline cellulose used for the preparation of the tablets and capsules according to the present invention has a bulk density above 0.35 g/ml. Furthermore, it is preferred that the microcrystalline cellulose used for the preparation of the tablets and capsules according to the present invention has a particle size above about 50 micrometer. A tablet or capsule according to the present invention comprises preferably microcrystalline cellulose in an amount of at least 20 %, more preferred of at least 30 % and even more preferred of at least 40 % (weight/weight) and most preferred in an amount of at least 45% (weight/weight). For example, the tablet or capsule according to the invention comprises microcrystalline cellulose in amounts ranging from 20% to 80% (weight/weight) , amounts from 30% to 70% are preferred while amounts from 40% to 60% are even more preferred and amounts ranging from 45% to 55% are especially preferred.
Similarly, any sort of silicone dioxide can be used for the preparation of the tablets and cap- sules according to the present invention. However, it is preferred that the silicone dioxide used for the preparation of the tablets and capsules according to the present invention has a particle size from about 1 namometer to about 100 micrometer. A tablet or capsule according to the present invention comprises preferably an amount of silicone dioxide in the range from 0.1 to 5 %, preferably in the range from 0.2% to 3%, even more preferred in the range from 0.5% to 1 ,5% (weight/weight).
In another embodiment according to the present invention, the tablet or capsule further comprises mannitol. In a preferred embodiment according to the invention, the tablet or capsule comprises mannitol in an amount of at least 20%, preferably at least 30% an even more pre- ferred at lest 40% (weight/weight) and most preferred in an amount of at least 45%
(weight/weight). In preferred embodiments of the invention, the tablet or capsule comprises mannitol in amounts ranging from 20% to 80% (weight/weight) , amounts from 30% to 70%) are preferred while amounts from 40% to 60% are even more preferred and amounts ranging from 45% to 55% are especially preferred.
In another embodiment of the present invention, the tablet or capsule comprises mannitol and microcrystalline cellulose in proportions between 2:8 and 8:2, preferably between 3:5 and 5:3, more preferred between 4:6 and 6:4, and even more preferred between 45:55 and 55:45.
In another embodiment of the present invention, the tablet or capsule comprises talc in the range from 0.1 to 10 % (weight/weight).
In a further preferred embodiment of the invention, the tablet or capsule comprises micro- crystalline cellulose in an amount ranging from 45% to 55% and silicon dioxide in an amount from 0,5%) to 1 ,5%(weight/weight).
In another embodiment of the invention, the tablet or capsule comprises: (i) an active ingredient selected from the group consisting of (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2- ethoxypropanoic acid, pharmaceutically acceptable salt, ester, metabolite, hydrate, solvate, polymorph, and pro-drug form thereof, (ii) microcrystalline cellulose; and (iii) silicon dioxide, wherein the amount of said active ingredient is between about 0.01% and about 2,0% (weight/weight); the amount of said microcrystalline cellulose is between about 40% and about 50%) (weight/weight); and the amount of said silicone dioxide is between about 0.8% and about 1.2% (weight/weight).
Non-limiting examples of a formulation according to invention include the following (expressed as % weight/ total weight of each ingredient):
Active ingredient 1%
Microcrystalline cellulose 97.8-98.2%
Silicon dioxide 0.8-1.2%
Active ingredient 1 %
Microcrystalline cellulose 47%
Silicon dioxide 1%
Mannitol 47%
Talc 4%
Active ingredient 1%
Microcrystalline cellulose 45.2%
Silicon dioxide 0.8%
Mannitol 49%
Talc 4%
Active ingredient 0.5%
Microcrystalline cellulose 98.3-98.7%
Silicon dioxide 0.8-1.2%
Active ingredient 2%
Microcrystalline cellulose 96.8-97.2%
Silicon dioxide 0.8-1.2%
Active ingredient 0.2% Microcrystalline cellulose 98.6-99.0%
Silicon dioxide 0.8-1.2
Active ingredient 2% Microcrystalline cellulose 46.5%
Silicon dioxide 1%
Mannitol 46.5%
Talc 4
In a preferred embodiment of the present invention, the tablets or capsules are prepared using one of the commercial products marketed under the designations ProSolv HD 90, Pro- Solv SMCC 50, and ProSolv SMCC 90 by the firm PenWest, each of which contain both microcrystalline cellulose and silicon dioxide.
In one aspect of the present invention, the tablets or capsules have a relative standard deviation (RSD) for the content of active ingredient in the tablet or capsule which is not more than about 4%. Preferably, the RSD value is not more than about 3 %, more preferred the RSD value is not more than about 2,5 %, and even more preferred the RSD value is not more than about 2 %, especially preferred the RSD value is not more than about 1 ,5 %, and even more preferred the RSD value is not more than about 1 %.
The relative standard deviation (RSD) for the content of active ingredient in the tablets of the present invention can be determined as described in the United States Pharmacopeia (USP 24) 2000, chapter 905 using the test for Uniformity of Dosage Units, <905>, USP XV.
The bulk and tapped density can be determined as described in method BTD-8, Handbook of Pharmaceutical Excipients, 2nd ed., 1994. Particle size distribution can be determined by Sieve analysis using US standard sieves.
The tablets and capsules according to the present invention can be prepared in a manner known perse. More specifically, the tablets and capsules may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19th edition, 1995. According to a preferred feature of the present invention, the tablet or capsule ac- cording to the present invention are prepared by direct compression. Direct compression has the advantage that it is possible to first mix all the ingredients which are to be present in the final tablet or capsule and then to subject the mixture to direct compression.
The active ingredient present in the tablets and capsules of the present invention can be any pharmaceutical such as analgesics and anti-inflammatory agents, anthelminthics, anti- arrhythmic agents, antibacterial agents, anticoaglants, antidepressants, antidiabetic agents, antiepileptics, antifungal agents, antigout agents, antihypertensive agents, antimalarials, an- timigraine gents, antimuscarinic agents, antineoplastic agents, immunosuppressants, anti- protozoal agents, antithyroid agents, antiviral agents, anxiolytic sedatives, hypnotics, neuro- leptics, beta-adrenoceptor blocking agents, calcium regulating agents, cardiac inotropic agents, chelating agents, antidotes, antagonists, corticosteroids, diuretics, dopaminergic an- tiparkinsonian agents, gastro-intestinal agents, anaesthetics, hormones, lipid regulating agents, , anti-angina agents, vitamins, anti-asthma agents, skeletal muscle relaxants, stimulants, anoretics, sympatomimetics, thrombolytic agents, and vasodilators.
An example of a specific medicaments is (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts forming part of this invention include salts such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts, aluminium salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulplionates, benzoates, salicy- lates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketogluta- rates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
The present invention also encompasses esters, metabolites, hydrates, solvates, poly- morphs, and pro-drug forms of (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
In a preferred embodiment, (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine is used in the present invention. Another example of a specific medicament is 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2- quinazolinyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione and pharmaceutically acceptable salts thereof as active ingredient as described in PCT Publication WO 97/41097. The present invention also encompasses esters, metabolites, hydrates, solvates, polymorphs, and pro- drug forms of 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl- methyl]thiazolidine-2,4-dione.
Examples of suitable carriers present in the tablets and capsules according to the present invention are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, mannitol, sorbitol, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The tablets and capsules may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The tablets and capsules of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The tablets and capsules can be sterilized and mixed, if desired, with auxiliary agents, emul- sifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
The tablets and capsules of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of various diseases as mentioned above. Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
The exact dosage of the tablets and capsules will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
The present invention will further be illustrated with the following non-exhaustive examples.
EXAMPLE 1
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 1423g Mannitol 1423g
Magnesium stearate 30g
Talc 120g
Manufacture: (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
The results from test for content uniformity according to USP gave the following results: Mean content of (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in each tablet: 0.0973mg RSD: 1.17%
EXAMPLE 2
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g Microcrystalline cellulose with 2% silicon dioxide 2846g
Magnesium stearate 30g
Talc 120g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. The rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
The results from test for content uniformity according to USP gave the following results: Mean content of (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in each tablet: 0.103mg
RSD: 1.85%
EXAMPLE 3
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 1708 g
Mannitol 1138 g
Magnesium stearate 30g
Talc 120 g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is con- tinued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes.
The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg. EXAMPLE 4
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 1138 g Mannitol 1708 g
Magnesium stearate 30g
Talc 120 g
Manufacture: (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
EXAMPLE 5
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 1897 g
Mannitol 949 g
Magnesium stearate 30g
Talc 120 g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide ismixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is con- tinued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes.
The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is EXAMPLE 6
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 949 g Mannitol 1897 g
Magnesium stearate 30g
Talc 120 g
Manufacture: (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
EXAMPLE 7
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 407 g
Mannitol 2439 g
Magnesium stearate 30g
Talc 120 g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is con- tinued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes.
The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is EXAMPLE 8
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 2439 g Mannitol 407 g
Magnesium stearate 30g
Talc 120 g
Manufacture: (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
EXAMPLE 9
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose 90 g
Lactose, monohydrate 2885
Silica, colloidal anhydrous 6 g
Magnesium stearate 15 g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 90 g of microcrystalline cellulose is mixed in a drum mixer for 5 minutes. Lactose and silica is added and mixing is continued for 10 minutes. Magnesium stearate is added and mixed for further 5 minutes.
The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg. EXAMPLE 10
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 19.30g
Microcrystalline cellulose with 2% silicon dioxide 1693 g Mannitol 1138 g
Magnesium stearate 30g
Talc 120 g
Manufacture: (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture are compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
EXAMPLE 11
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 1.930g
Microcrystalline cellulose with 2% silicon dioxide 950 g
Mannitol 1898 g
Magnesium stearate 30g
Talc 120 g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is con- tinued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes.
The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.

Claims

1. A tablet or capsule containing microcrystalline cellulose and silicon dioxide and active ingredient in an amount between about 3 % and about 0.001 % (weight/ weight).
2. A tablet or capsule, according to claim 1 , wherein the content of active ingredient is not more than about 2 % (weight/weight).
3. A tablet or capsule, according to claim 1 , wherein the content of active ingredient is not more than about 1 %( weight/weight).
4. A tablet or capsule, according to any one of the preceding claims, wherein the content of active ingredient is not more than about 0.5 %( weight/weight).
5. A tablet or capsule, according to any one of the preceding claims, wherein the content of active ingredient is not more than about 0.05 %( weight/weight).
6. A tablet or capsule, according to any one of the preceding claims, wherein the content of active ingredient is not more than about 0.01 % (weight/weight).
7. A tablet or capsule, according to any one of the preceding claims, wherein the content of active ingredient is not more than about 0.005 %( weight/weight).
8. A tablet or capsule, according to any one of the preceding claims, wherein the active in- gredient is (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salt thereof.
9. A tablet or capsule, according to any one of the preceding claims, wherein the active ingredient is (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt
10. A tablet or capsule, according to any one of the preceding claims, which further comprises mannitol.
11. A tablet or capsule according to any one of the preceding claims comprising mannitol and microcrystalline cellulose in proportions between 2:8 and 8:2, preferably between 3:5 an 5:3, even more preferred between 4:6 and 6:4, and most preferred between 45:55 and 55:45.
12. A tablet or capsule according to any one of the preceding claims comprising silicon dioxide in the range from 0.1 to 5 %, preferably in the range from 0.2% to 3%, and even more preferred in the range from 0.5% to 1 ,5% (weight/weight).
13. A tablet or capsule according to any one of the preceding claims comprising microcrystalline cellulose in an amount ranging from 45% to 55% and silicon dioxid in an amount ranging from 0,5% to 1 ,5% (weight/weight).
14. A tablet or capsule, according to any one of the preceding claims, wherein the microcrystalline cellulose has a bulk density above 0.35 g/ml.
15. A tablet or capsule according to any one of the preceding claims, wherein the microcrystalline cellulose has a particle size above about 50 micrometer.
16. A tablet or capsule according to any one of the preceding claims, wherein the silicone dioxide has a particle size from about 1 namometer to about 100 micrometer.
17. A tablet or capsule according to any one of the preceding claims containing ProSolv HD 90, ProSolv SMCC 50, and ProSolv SMCC 90 (from PenWest).
18. A tablet or capsule according to any one of the preceding claims for which the relative standard deviation (RSD) for the content of active ingredient in the tablet or capsule is not more than about 4%.
19. A tablet or capsule according to any one of the preceding claim for which the RSD value is not more than about 3 %.
20. A tablet or capsule according to any one of the preceding claims for which the RSD value is not more than about 2,5 %.
21. A tablet or capsule according to any one of the preceding claims for which the RSD value is not more than about 2 %.
22. A tablet or capsule according to any one of the preceding claims for which the RSD value is not more than about 1 ,5 %.
23. A tablet or capsule according to any one of the preceding claims for which the RSD value is not more than about 1 %.
24. A process for preparing a tablet or capsule according to any one of the preceding claims which process is characterized in that the tablets or capsules are prepared by direct compression.
25. A tablet or capsule which comprises microcrystalline cellulose and silicon dioxide and wherein the active ingredient is (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2- ethoxypropanoic acid or a pharmaceutically acceptable salt thereof.
26. A tablet or capsule comprising: (i) an active ingredient selected from the group consist- ing of (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid, pharmaceutically acceptable salt, ester, metabolite, hydrate, solvate, polymorph, and pro-drug form thereof.; (ii) microcrystalline cellulose; and (iii) silicon dioxide, wherein the amount of said active ingredient is between about 0.01 % and about 2,0% (weight/weight); the amount of said microcrystalline cellulose is between about 40% and about 50% (weight/weight); and the amount of said silicone dioxide is between about 0.8% and about 1.2%
(weight/weight).
EP02702234A 2001-03-12 2002-03-12 Novel tablets and capsules and a process for its preparation Withdrawn EP1370244A1 (en)

Applications Claiming Priority (3)

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DK200100413 2001-03-12
DKPA200100413 2001-03-12
PCT/DK2002/000163 WO2002072069A1 (en) 2001-03-12 2002-03-12 Novel tablets and capsules and a process for its preparation

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JP2007506649A (en) * 2003-06-27 2007-03-22 ドクター レディーズ リサーチ ファンデーション Composition comprising balaglitazone and a further antidiabetic compound
EP3185900A4 (en) 2014-08-25 2018-05-02 Aimmune Therapeutics, Inc. Egg protein formulations and methods of manufacture thereof

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AU5957480A (en) * 1979-07-26 1981-01-29 American Cyanamid Company Diethyl carbamazine resinate
IL110376A (en) * 1993-08-02 1998-08-16 Bristol Myers Squibb Co Pharmaceutical compositions containing ifetroban salts and methods for the preparation thereof
WO1996030016A2 (en) * 1995-03-28 1996-10-03 Janssen Pharmaceutica N.V. Low dose ridogrel formulations and their use for the treatment of inflammatory bowel diseases
TWI249526B (en) * 1998-03-13 2006-02-21 Aventis Pharma Inc Novel processes for the preparation of (R)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
AU2001244098A1 (en) * 2000-04-04 2001-10-15 Novo-Nordisk A/S Pharmaceutical composition containing 3-(4(2-phenoxazin-10-yl)ethoxy)phenyl)-2-ethoxy propanoicacid
US6855333B1 (en) * 2000-10-03 2005-02-15 Mutual Pharmaceutical Co., Inc. Stabilization of solid thyroid drug formulations

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Title
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