EP2804594A1 - Formulations comprising diclofenac as the active agent - Google Patents

Formulations comprising diclofenac as the active agent

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Publication number
EP2804594A1
EP2804594A1 EP13720143.0A EP13720143A EP2804594A1 EP 2804594 A1 EP2804594 A1 EP 2804594A1 EP 13720143 A EP13720143 A EP 13720143A EP 2804594 A1 EP2804594 A1 EP 2804594A1
Authority
EP
European Patent Office
Prior art keywords
formulation
diclofenac
range
agent
effervescent
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Withdrawn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
EP13720143.0A
Other languages
German (de)
French (fr)
Inventor
Mahmut Bilgic
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.)
Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP2804594A1 publication Critical patent/EP2804594A1/en
Withdrawn legal-status Critical Current

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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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention has analgesic, anti-inflammatory and antipyretic activity and relates to pharmaceutical formulations comprising diclofenac that shall be used in the treatment of mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
  • Diclofenac was first disclosed in the application numbered US3558690.
  • Diclofenac and/or its pharmaceutically acceptable salts are analgesic, anti-inflammatory and anti-rheumatic drugs belonging to the group of non-steroidal anti-inflammatory drugs (NSAID).
  • NSAID non-steroidal anti-inflammatory drugs
  • Diclofenac is available in the forms of 25 mg and 50 mg dragee; 75 mg/3ml ampoule; 1%,2% and 3% gel; 100 mg capsule; 0.1% eye drop; 50 mg and 100 mg suppository; 75 mg and 100 mg sustained release tablet; 25 mg, 50 mg and 100 mg enterically coated tablet and 100 mg retard tablet on the market.
  • Diclofenac is a hygroscopic molecule and thus its water solubility is quite low. Therefore, it is observed that effervescent formulations comprising diclofenac disperse slowly when they contact with water and the active agent does not dissolve sufficiently owing to these characteristics of the active agent diclofenac. Due to this, sufficient amount of the active agent cannot be absorbed; the required bioavailability cannot be obtained. Consequently, an effective treatment cannot be provided. In other aspect, it is required that the solutions obtained by dissolving the formulations comprising diclofenac in water should have a pH value in water in the range of 4,1-5 according to the specifications.
  • the effervescent formulations comprising diclofenac comprise at least two buffering agents having acidic and basic characteristics along with effervescent acid and effervescent base and the ratio of the acidic buffering agent to the basic buffering agent is in the range of 70: 1 to 10: 1; they have high water solubility, bioavailability and therapeutic activity and they do not cause any stomach disturbances since the solution obtained during use of said formulations is in optimal pH range for the stomach.
  • the present invention relates to pharmaceutical formulations comprising diclofenac.
  • diclofenac effervescent formulations which comprise at least two buffering agents having acidic and basic characteristics along with effervescent acid and effervescent base and wherein the ratio of the acidic buffering agent to the basic buffering agent is in the range of 70:1 to 10:1, have high water solubility, bioavailability and therapeutic activity.
  • the inventors have seen that since the solution obtained during use of said formulations is in optimal pH range for the stomach, it does not cause stomach disturbances and an effective treatment is obtained.
  • the first aspect of the present invention is that the effervescent formulations comprising diclofenac comprise at least two acidic and basic buffering agents along with effervescent acid and effervescent base and the ratio of the acidic buffering agent to the basic buffering agent is in the range of 70:1 to 10: 1.
  • said formulation comprises diclofenac in the range of 0.1-10%, preferably in the range of 0.5-8%, more preferably in the range of 1- 5 % as the active agent.
  • Diclofenac comprised in the pharmaceutical formulations of the present invention is in the form of its pharmaceutically acceptable organic and inorganic salts, hydrates, solvates, esters, enantiomers, racemates or combinations thereof in terms of chemical structure; in free form, crystalline, amorphous forms or combinations thereof in terms of polymorphic structure.
  • the particle size of diclofenac active agent is another parameter affecting on the dissolution and bioavailability of the formulation.
  • the inventors have found that in the case that diclofenac used as active agent has average particle size in the range of 1-100 ⁇ , preferably 3-60 ⁇ ⁇ , more preferably 5-40 ⁇ , the obtained effervescent formulation dissolves rapidly and thus a high bioavailability is obtained.
  • the present invention relates to the pharmaceutical formulations wherein diclofenac which is used as active agent has average particle size in the range of 1-100 ⁇ , preferably 3-60 ⁇ , more preferably 5-40 ⁇ .
  • the present invention relates to the pharmaceutical formulations wherein the ratio of di 0 value of diclofenac to d 90 value of diclofenac is in the range of 1 : 1 to 1 :100, preferably in the range of 1 : 10 to 1 :75, and more preferably in the range of 1 :20 to 1 :60.
  • d 10 value used herein signifies that 10% of the said substance by volume has a particle size below the value stated with di 0 .
  • d 90 value used herein signifies that 90% of the said substance by volume has a particle size below the value stated with d 90.
  • the formulations of the present invention comprising diclofenac are in the form of effervescent tablet, granule or powder, preferably in effervescent tablet form.
  • the effervescent acid comprised in the formulation comprising diclofenac according to the present invention is less than 60%, preferably in the range of 10-59%, more preferably in the range of 20-40%.
  • the effervescent base in the formulation comprising diclofenac according to the present invention is more than 15%, preferably in the range of 15.1-58%, more preferably in the range of 20-55%
  • the effervescent acid in the formulation of the present invention can be selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid and monosodium citrate or a combination thereof.
  • citric acid or monosodium citrate is used as the effervescent acid.
  • the effervescent base in the pharmaceutical formulations of the present invention can be selected from a group comprising sodium bicarbonate, sodium citrate dihydrate, sodium hydroxide or combinations thereof.
  • preferably sodium bicarbonate is used as the effervescent base.
  • the ratio of the basic buffering agent to the acidic buffering agent is in the range of 60.T to 20: 1, more preferably in the range of 55:l to 30:l .
  • the basic buffering agent can be selected from a group comprising potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium citrate dihydrate, sodium hydroxide or a combination thereof.
  • sodium carbonate is used as the basic buffering agent in the formulations of the present invention.
  • the acidic buffering agent used in the pharmaceutical formulations of the present invention can be selected from a group comprising sodium citrate, sodium acetate, dibasic sodium phosphate, tribasic sodium phosphate, monobasic sodium phosphate, sodium acid pyrophosphate and sodium acid sulphate or a combination thereof.
  • sodium citrate more preferably its sodium citrate dihydrate form is used as the acidic buffering agent in the formulations of the present invention.
  • the ratio of sodium carbonate: sodium citrate dihydrate is in the range of 70: 1 to 10:1, preferably in the range of 60: 1 to 20: 1, more preferably in the range of 55: 1 to 30: 1.
  • the inventors have also seen that the weight ratio of diclofenac active agent to buffering agents has an influence on the dissolution and homogeneity of the formulation. They have observed that when the ratio of diclofenac to the combination of the buffering agents is in the range of 1 : 10 to 9: 10, preferably 2:10 to 6: 10 by weight, homogeneous and rapidly dispersible effervescent formulations have been provided.
  • the present invention relates to the effervescent formulations wherein the ratio of diclofenac active agent to the combination of the buffering agents is in the range of 1 : 10 to 9:10, preferably 2:10 to 6: 10 by weight.
  • the formulations of the present invention can comprise at least one pharmaceutically acceptable excipient along with diclofenac, effervescent acid, effervescent base, basic buffering agent and acidic buffering agent.
  • the pharmaceutically acceptable excipients that can be used in the formulations of the present invention can be selected from lubricant, sweetener and/or taste regulating agent, wetting agent, filling agent, binder, solvent or combinations thereof.
  • composition comprising two different sweeteners is used as the sweetener and/or taste regulating agent.
  • the sweeteners used in the formulations of the present invention can be selected from a group comprising acesulfame potassium, aspartame, fructose, maltitol, xylitol, saccharine, sodium cyclamate, sucralose, sucrose.
  • the sweetener composition used as the sweetener and/or taste regulating agent is preferably composed of sodium cyclamate and aspartame.
  • the lubricant used in the formulations of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, adipic acid, potassium benzoate, sodium benzoate.
  • the wetting agent used in the formulations of the present invention can be selected from a group comprising benzalkonium chloride, poloxamer, docusate sodium, polyoxyethylene alkyl ester, sodium lauryl sulphate or combinations thereof.
  • the filling agent used in the formulations of the present invention can be selected from a group comprising D-manntiol, xylitol, microcrystalline cellulose, crospovidone, dibasic calcium phosphate anhydrous, lactose, starch, maltose, dextrin, maltodextrin, magnesium carbonate, talc and combinations thereof.
  • the binder used in the formulations of the present invention can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, methyl cellulose and povidone.
  • the solvent used in the formulations of the present invention can be selected from a group comprising sorbitol, propylene glycol, methanol, ethanol, isopropyl alcohol, mannitol, ethylene glycol, butyl alcohol, penthanol or combinations thereof.
  • the effervescent formulations comprising diclofenac of the present invention can optionally comprise a second active agent in addition to diclofenac.
  • the second active agent that can be used along with diclofenac in the formulations of the present invention can be selected from analgesic, antipyretic, myorelaxant, non-steroidal antiinflammatory, prostaglandin analogue, gastric proton pump inhibitor (PPI), opiate agonist agents or combinations thereof.
  • PPI gastric proton pump inhibitor
  • the diclofenac effervescent formulations of the present invention can preferably comprise an opiate agonist, more preferably codeine as the second active agent in addition to diclofenac.
  • the diclofenac effervescent formulations of the present invention can preferably comprise a myorelaxant, more preferably thiocolchicoside as the second active agent in addition to diclofenac.
  • the diclofenac effervescent formulations of the present invention can preferably comprise a prostaglandin analogue, more preferably misoprostol as the second active agent in addition to diclofenac.
  • the diclofenac effervescent formulations of the present invention can preferably comprise a gastric proton pump inhibitor (PPI), more preferably rabeprazole as the second active agent in addition to diclofenac.
  • PPI gastric proton pump inhibitor
  • the effervescent formulation comprising diclofenac which is prepared according to the production method of the present invention can comprise diclofenac in the range of 0.1-10%, effervescent acid in the range of 10-59%, effervescent base in the range of 15.1-58%, binder in the range of 0.01-3%, lubricant in the range of 1-10%, sweetener and/or taste regulating agent in the range of 0.2-5%, filling agent in the range of 2-15%, acidic buffering agent in the range of 0.05-2%, basic buffering agent in the range of 1-10%, wetting agent in the range of 0.01-2%, solvent in the range of 0.05-4% and flavouring agent in the range of 0.2-3% in proportion to total weight of unit amount.
  • Preparation of the pharmaceutical formulations of the present invention can be performed by a process which is composed of the steps of:
  • the pharmaceutical formulation of the present invention has analgesic, anti-inflammatory and antipyretic activity and it can be used in the treatment of the diseases such as mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
  • EXAMPLE 1 Formulation and process for preparation of effervescent tablet comprising diclofenac
  • Diclofenac, the effervescent acid and the effervescent base are mixed to obtain the formulation that shall be used in the present invention.
  • the 1 st mixture is obtained by granulating said mixture with a granulation solution obtained by dissolving the wetting agent and the binder in the solvent and water.
  • the effervescent acid and the sweetener are mixed and said mixture is granulated with the granulation solution obtained by dissolving the acidic buffering agent in water.
  • the 2 nd mixture is obtained by adding the effervescent base, the basic buffering agent and the lubricant into the granules obtained.
  • EXAMPLE 2 Formulation and process for preparation of effervescent tablet comprising diclofenac and codeine
  • Diclofenac, codeine, the effervescent acid and the effervescent base are mixed to obtain the formulation that shall be used in the present invention.
  • the 1 st mixture is obtained by granulating said mixture with the granulation solution obtained by dissolving the wetting agent and the binder in the solvent and water.
  • the effervescent acid and the sweetener are mixed and said mixture is granulated with the granulation solution obtained by dissolving the acidic buffering agent in water.
  • the 2 nd mixture is obtained by adding the effervescent base, the basic buffering agent and the lubricant into the granules obtained.
  • the 1 st mixture, the 2 nd mixture, the filling agent and the flavouring agent are mixed and the final mixture obtained is compressed in tablet form.

Abstract

The present invention has analgesic, anti-inflammatory, and antipyretic activity and relates to effervescent formulations comprising diclofenac that shall be used in the treatment of mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.

Description

FORMULATIONS COMPRISING DICLOFENAC AS THE ACTIVE AGENT
The present invention has analgesic, anti-inflammatory and antipyretic activity and relates to pharmaceutical formulations comprising diclofenac that shall be used in the treatment of mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
Diclofenac was first disclosed in the application numbered US3558690. Diclofenac and/or its pharmaceutically acceptable salts are analgesic, anti-inflammatory and anti-rheumatic drugs belonging to the group of non-steroidal anti-inflammatory drugs (NSAID).
Diclofenac is available in the forms of 25 mg and 50 mg dragee; 75 mg/3ml ampoule; 1%,2% and 3% gel; 100 mg capsule; 0.1% eye drop; 50 mg and 100 mg suppository; 75 mg and 100 mg sustained release tablet; 25 mg, 50 mg and 100 mg enterically coated tablet and 100 mg retard tablet on the market.
Diclofenac is a hygroscopic molecule and thus its water solubility is quite low. Therefore, it is observed that effervescent formulations comprising diclofenac disperse slowly when they contact with water and the active agent does not dissolve sufficiently owing to these characteristics of the active agent diclofenac. Due to this, sufficient amount of the active agent cannot be absorbed; the required bioavailability cannot be obtained. Consequently, an effective treatment cannot be provided. In other aspect, it is required that the solutions obtained by dissolving the formulations comprising diclofenac in water should have a pH value in water in the range of 4,1-5 according to the specifications. However, since pH value is over 5 in the solutions obtained by putting the formulations comprising diclofenac into water during their use in effervescent tablet form, they may cause possible stomach disturbances. In line with the problems mentioned in the prior art, there is need to produce new solutions in order to develop effervescent formulations comprising diclofenac which have high absorption and bioavailability and high therapeutic effect and which can dissolve easily during use and do not cause any disturbances in stomach.
The inventors have surprisingly observed that in the case that the effervescent formulations comprising diclofenac comprise at least two buffering agents having acidic and basic characteristics along with effervescent acid and effervescent base and the ratio of the acidic buffering agent to the basic buffering agent is in the range of 70: 1 to 10: 1; they have high water solubility, bioavailability and therapeutic activity and they do not cause any stomach disturbances since the solution obtained during use of said formulations is in optimal pH range for the stomach. Description of the Invention
The present invention relates to pharmaceutical formulations comprising diclofenac. As a result of the studies they conducted in line with this requirement, the inventors have observed that diclofenac effervescent formulations which comprise at least two buffering agents having acidic and basic characteristics along with effervescent acid and effervescent base and wherein the ratio of the acidic buffering agent to the basic buffering agent is in the range of 70:1 to 10:1, have high water solubility, bioavailability and therapeutic activity. In addition, the inventors have seen that since the solution obtained during use of said formulations is in optimal pH range for the stomach, it does not cause stomach disturbances and an effective treatment is obtained. According to this, the first aspect of the present invention is that the effervescent formulations comprising diclofenac comprise at least two acidic and basic buffering agents along with effervescent acid and effervescent base and the ratio of the acidic buffering agent to the basic buffering agent is in the range of 70:1 to 10: 1.
In one preferred embodiment of the present invention, said formulation comprises diclofenac in the range of 0.1-10%, preferably in the range of 0.5-8%, more preferably in the range of 1- 5 % as the active agent.
Diclofenac comprised in the pharmaceutical formulations of the present invention is in the form of its pharmaceutically acceptable organic and inorganic salts, hydrates, solvates, esters, enantiomers, racemates or combinations thereof in terms of chemical structure; in free form, crystalline, amorphous forms or combinations thereof in terms of polymorphic structure. It is known that the particle size of diclofenac active agent is another parameter affecting on the dissolution and bioavailability of the formulation. The inventors have found that in the case that diclofenac used as active agent has average particle size in the range of 1-100 μιη, preferably 3-60 μιη, more preferably 5-40 μπι, the obtained effervescent formulation dissolves rapidly and thus a high bioavailability is obtained.
In another aspect, the present invention relates to the pharmaceutical formulations wherein diclofenac which is used as active agent has average particle size in the range of 1-100 μηι, preferably 3-60 μπι, more preferably 5-40 μιη.
Moreover, in the studies the inventors conducted in order to develop the solubility of active agent and dissolution rate of the effervescent formulations, they have found that dlO and d90 values of the active agent are also important parameters for developing solubility and dissolution.
In another aspect, the present invention relates to the pharmaceutical formulations wherein the ratio of di0 value of diclofenac to d90 value of diclofenac is in the range of 1 : 1 to 1 :100, preferably in the range of 1 : 10 to 1 :75, and more preferably in the range of 1 :20 to 1 :60.
The term d10 value used herein signifies that 10% of the said substance by volume has a particle size below the value stated with di0.
The term d90 value used herein signifies that 90% of the said substance by volume has a particle size below the value stated with d90. The formulations of the present invention comprising diclofenac are in the form of effervescent tablet, granule or powder, preferably in effervescent tablet form.
The effervescent acid comprised in the formulation comprising diclofenac according to the present invention is less than 60%, preferably in the range of 10-59%, more preferably in the range of 20-40%. The effervescent base in the formulation comprising diclofenac according to the present invention is more than 15%, preferably in the range of 15.1-58%, more preferably in the range of 20-55% The effervescent acid in the formulation of the present invention can be selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid and monosodium citrate or a combination thereof.
In the formulations of the present invention, preferably citric acid or monosodium citrate is used as the effervescent acid.
The effervescent base in the pharmaceutical formulations of the present invention can be selected from a group comprising sodium bicarbonate, sodium citrate dihydrate, sodium hydroxide or combinations thereof.
In the formulations of the present invention, preferably sodium bicarbonate is used as the effervescent base.
In the pharmaceutical formulations of the present invention, the ratio of the basic buffering agent to the acidic buffering agent is in the range of 60.T to 20: 1, more preferably in the range of 55:l to 30:l .
In the formulations according to the present invention, the basic buffering agent can be selected from a group comprising potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium citrate dihydrate, sodium hydroxide or a combination thereof.
Preferably, sodium carbonate is used as the basic buffering agent in the formulations of the present invention. The acidic buffering agent used in the pharmaceutical formulations of the present invention can be selected from a group comprising sodium citrate, sodium acetate, dibasic sodium phosphate, tribasic sodium phosphate, monobasic sodium phosphate, sodium acid pyrophosphate and sodium acid sulphate or a combination thereof.
Preferably sodium citrate, more preferably its sodium citrate dihydrate form is used as the acidic buffering agent in the formulations of the present invention.
In the pharmaceutical formulations of the present invention, the ratio of sodium carbonate: sodium citrate dihydrate is in the range of 70: 1 to 10:1, preferably in the range of 60: 1 to 20: 1, more preferably in the range of 55: 1 to 30: 1. The inventors have also seen that the weight ratio of diclofenac active agent to buffering agents has an influence on the dissolution and homogeneity of the formulation. They have observed that when the ratio of diclofenac to the combination of the buffering agents is in the range of 1 : 10 to 9: 10, preferably 2:10 to 6: 10 by weight, homogeneous and rapidly dispersible effervescent formulations have been provided.
In another aspect, the present invention relates to the effervescent formulations wherein the ratio of diclofenac active agent to the combination of the buffering agents is in the range of 1 : 10 to 9:10, preferably 2:10 to 6: 10 by weight.
The formulations of the present invention can comprise at least one pharmaceutically acceptable excipient along with diclofenac, effervescent acid, effervescent base, basic buffering agent and acidic buffering agent.
The pharmaceutically acceptable excipients that can be used in the formulations of the present invention can be selected from lubricant, sweetener and/or taste regulating agent, wetting agent, filling agent, binder, solvent or combinations thereof. The patients feel disturbed since the solution obtained by dissolving the effervescent formulations comprising the active agent diclofenac known with its bad taste in water has an unpleasant, bad taste and therefore the effervescent forms obtained by formulating these formulations cause difficulty of use. As a result of the studies they conducted in line with this requirement, the inventors have seen that use of a composition comprising two different sweeteners as the sweetener and/or taste regulating agent removes this problem to a great extent.
According to this, another characteristic feature of the present invention is that a composition comprising two different sweeteners is used as the sweetener and/or taste regulating agent.
The sweeteners used in the formulations of the present invention can be selected from a group comprising acesulfame potassium, aspartame, fructose, maltitol, xylitol, saccharine, sodium cyclamate, sucralose, sucrose.
In the formulations of the present invention, the sweetener composition used as the sweetener and/or taste regulating agent is preferably composed of sodium cyclamate and aspartame. The lubricant used in the formulations of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, adipic acid, potassium benzoate, sodium benzoate.
The wetting agent used in the formulations of the present invention can be selected from a group comprising benzalkonium chloride, poloxamer, docusate sodium, polyoxyethylene alkyl ester, sodium lauryl sulphate or combinations thereof.
The filling agent used in the formulations of the present invention can be selected from a group comprising D-manntiol, xylitol, microcrystalline cellulose, crospovidone, dibasic calcium phosphate anhydrous, lactose, starch, maltose, dextrin, maltodextrin, magnesium carbonate, talc and combinations thereof.
The binder used in the formulations of the present invention can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, methyl cellulose and povidone. The solvent used in the formulations of the present invention can be selected from a group comprising sorbitol, propylene glycol, methanol, ethanol, isopropyl alcohol, mannitol, ethylene glycol, butyl alcohol, penthanol or combinations thereof.
The effervescent formulations comprising diclofenac of the present invention can optionally comprise a second active agent in addition to diclofenac. The second active agent that can be used along with diclofenac in the formulations of the present invention can be selected from analgesic, antipyretic, myorelaxant, non-steroidal antiinflammatory, prostaglandin analogue, gastric proton pump inhibitor (PPI), opiate agonist agents or combinations thereof.
Optionally, the diclofenac effervescent formulations of the present invention can preferably comprise an opiate agonist, more preferably codeine as the second active agent in addition to diclofenac.
Optionally, the diclofenac effervescent formulations of the present invention can preferably comprise a myorelaxant, more preferably thiocolchicoside as the second active agent in addition to diclofenac. Optionally, the diclofenac effervescent formulations of the present invention can preferably comprise a prostaglandin analogue, more preferably misoprostol as the second active agent in addition to diclofenac.
Optionally, the diclofenac effervescent formulations of the present invention can preferably comprise a gastric proton pump inhibitor (PPI), more preferably rabeprazole as the second active agent in addition to diclofenac.
The effervescent formulation comprising diclofenac which is prepared according to the production method of the present invention can comprise diclofenac in the range of 0.1-10%, effervescent acid in the range of 10-59%, effervescent base in the range of 15.1-58%, binder in the range of 0.01-3%, lubricant in the range of 1-10%, sweetener and/or taste regulating agent in the range of 0.2-5%, filling agent in the range of 2-15%, acidic buffering agent in the range of 0.05-2%, basic buffering agent in the range of 1-10%, wetting agent in the range of 0.01-2%, solvent in the range of 0.05-4% and flavouring agent in the range of 0.2-3% in proportion to total weight of unit amount. Preparation of the pharmaceutical formulations of the present invention can be performed by a process which is composed of the steps of:
• Granulating diclofenac, the effervescent acid and the effervescent base with a granulation solution comprising at least one excipient and obtaining the 1st mixture,
• Mixing the effervescent acid and the sweetener and granulating the mixture with a granulation solution comprising the acidic buffering agent and obtaining the 2nd mixture by adding the effervescent base, the basic buffering agent and at least one excipient into the granules obtained,
• Obtaining the final mixture by mixing the 1st mixture, the 2nd mixture and at least one excipient and compressing them in tablet form. The pharmaceutical formulation of the present invention has analgesic, anti-inflammatory and antipyretic activity and it can be used in the treatment of the diseases such as mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache. EXAMPLE 1 : Formulation and process for preparation of effervescent tablet comprising diclofenac
Diclofenac, the effervescent acid and the effervescent base are mixed to obtain the formulation that shall be used in the present invention. The 1st mixture is obtained by granulating said mixture with a granulation solution obtained by dissolving the wetting agent and the binder in the solvent and water. The effervescent acid and the sweetener are mixed and said mixture is granulated with the granulation solution obtained by dissolving the acidic buffering agent in water. The 2nd mixture is obtained by adding the effervescent base, the basic buffering agent and the lubricant into the granules obtained. Finally, the 1st mixture, the 2nd mixture, the filling agent and the flavouring agent are mixed and the final mixture obtained is compressed in tablet form. EXAMPLE 2: Formulation and process for preparation of effervescent tablet comprising diclofenac and codeine
Diclofenac, codeine, the effervescent acid and the effervescent base are mixed to obtain the formulation that shall be used in the present invention. The 1st mixture is obtained by granulating said mixture with the granulation solution obtained by dissolving the wetting agent and the binder in the solvent and water. The effervescent acid and the sweetener are mixed and said mixture is granulated with the granulation solution obtained by dissolving the acidic buffering agent in water. The 2nd mixture is obtained by adding the effervescent base, the basic buffering agent and the lubricant into the granules obtained. Finally, the 1st mixture, the 2nd mixture, the filling agent and the flavouring agent are mixed and the final mixture obtained is compressed in tablet form.

Claims

1. Effervescent formulations comprising diclofenac, characterized in that
- said formulations comprise at least two buffering agents having acidic and basic characteristics along with effervescent acid and effervescent base and
- the ratio of the basic buffering agent to the acidic buffering agent is in the range of
70: 1 to 10: 1.
2. The formulation according to claim 1, characterized in that said formulation comprises diclofenac in the range of 0.1-10% as the active agent.
3. The formulation according to claims 1-2, characterized in that said formulation is in the form of effervescent tablet, granule or powder.
4. The formulation according to claim 3, characterized in that said formulation is in effervescent tablet form.
5. The formulation according to any preceding claims, characterized in that the effervescent acid comprised in said formulation is less than 60% by weight.
6. The formulation according to claim 5, characterized in that the effervescent acid comprised in said formulation is in the range of 10-59% by weight.
7. The formulation according to any preceding claims, characterized in that the effervescent base comprised in said formulation is more than 15% by weight.
8. The formulation according to claim 7, characterized in that the effervescent base comprised in said formulation is in the range of 15.1 - 8% by weight.
9. The formulation according to any preceding claims, characterized in that citric acid or monosodium citrate is used as the effervescent acid in said formulation.
10. The formulation according to claim 9, characterized in that sodium bicarbonate is used as the effervescent base in said formulation.
1 1. The formulation according to any preceding claims, characterized in that the ratio of the basic buffering agent to the acidic buffering agent comprised in said formulation is in the range of 60: 1 to 20:1.
12. The formulation according to claim 1 1, characterized in that the ratio of the basic buffering agent to the acidic buffering agent comprised in said formulation is in the range of 55:1 to 30:1.
13. The pharmaceutical formulation according to the preceding claims wherein the ratio of diclofenac active agent to the combination of the buffering agents is in the range of 1 : 10 to 9:10.
14. The pharmaceutical formulation according to claim 13 wherein the ratio of diclofenac active agent to the combination of the buffering agents is in the range of 2:10 to 6:10.
15. The formulation according to any preceding claims, characterized in that sodium carbonate is used as the basic buffering agent in said formulation.
16. The formulation according to any preceding claims, characterized in that sodium citrate is used as the acidic buffering agent in said formulation.
17. The formulation according to claim 16, characterized in that sodium citrate dihydrate is used as the acidic buffering agent in said formulation.
18. The formulation according to any preceding claims, characterized in that the ratio of sodium carbonate: sodium citrate dihydrate comprised in said formulation is in the range of 70:1 to 10:1.
19. The pharmaceutical formulation comprising diclofenac according to any of the preceding claims wherein diclofenac used as active agent has average particle size in the range of 1- 100 μιη.
20. The pharmaceutical formulation comprising diclofenac according to claim 19 wherein diclofenac used as active agent has average particle size in the range of 3-60 μπι.
21. The pharmaceutical formulation comprising diclofenac according to claims 19-20 wherein diclofenac used as active agent has average particle size in the range of 5-40 μηι.
22. The pharmaceutical formulation comprising diclofenac according to any of the preceding claims wherein the ratio of d10 value of diclofenac to d90 value of diclofenac is in the range of 1 :1 to 1 :100.
23. The pharmaceutical formulation comprising diclofenac according to claim 22 wherein the ratio of d10 value of diclofenac to d90 value of diclofenac is in the range of 1 : 10 to 1 :75.
24. The pharmaceutical formulation comprising diclofenac according to any of claims 22-23 wherein the ratio of d10 value of diclofenac to d90 value of diclofenac is in the range of
1 :20 to 1 :60.
25. The formulation comprising diclofenac according to any preceding claims, characterized in that the pharmaceutically acceptable excipients that can be used in said formulation are selected from lubricant, sweetener and/or taste regulating agent, solvent, wetting agent, filling agent, binder and combinations thereof.
26. The formulation according to claim 25, characterized in that a composition comprising two different sweeteners is used as the sweetener and/or taste regulating agent in said formulation.
27. The formulation according to claim 26, characterized in that the sweetener composition used as the sweetener and/or taste regulating agent is composed of sodium cyclamate and aspartame.
28. The formulation according to any preceding claims, characterized in that said formulation optionally comprises a second active agent in addition to diclofenac.
29. The formulation according to any preceding claims, characterized in that the second active agent that can be used in addition to diclofenac in said formulation is selected from analgesic, antipyretic, myorelaxant, non-steroidal anti-inflammatory, prostaglandin analogue, gastric proton pump inhibitor (PPI), opiate agonist agents or combinations thereof.
30. The formulation according to claim 29, characterized in that said formulation optionally comprises an opiate agonist as the second active agent in addition to diclofenac.
31. The formulation according to claim 30, characterized in that said formulation optionally comprises codeine as the second active agent in addition to diclofenac.
32. The formulation according to claim 29, characterized in that said formulation optionally comprises a myorelaxant as the second active agent in addition to diclofenac.
33. The formulation according to claim 32, characterized in that said formulation optionally comprises thiocolchicoside as the second active agent in addition to diclofenac.
34. The formulation according to claim 29, characterized in that said formulation optionally comprises a prostaglandin analogue as the second active agent in addition to diclofenac.
35. The formulation according to claim 34, characterized in that said formulation optionally comprises misoprostol as the second active agent in addition to diclofenac.
36. The formulation according to claim 29, characterized in that said formulation optionally comprises a gastric proton pump inhibitor (PPI) as the second active agent in addition to diclofenac.
37. The formulation according to claim 36, characterized in that said formulation optionally comprises rabeprazole as the second active agent in addition to diclofenac.
38. The effervescent formulation comprising diclofenac according to any preceding claims, characterized in that said formulation comprises diclofenac in the range of 0.1-10%, effervescent acid in the range of 10-59%, effervescent base in the range of 15.1-58%, binder in the range of 0.01-3%, lubricant in the range of 1-10%, sweetener and/or taste regulating agent in the range of 0.2-5%, filling agent in the range of 2-15%, acidic buffering agent in the range of 0.05-2%, basic buffering agent in the range of 1-10%, wetting agent in the range of 0.01-2%, solvent in the range of 0.05-4% and flavouring agent in the range of 0.2-3%.
39. The process for preparation of the effervescent formulation comprising diclofenac according to any preceding claims, characterized in that said process is composed of the steps of:
• Granulating diclofenac, the effervescent acid and the effervescent base with a granulation solution comprising at least one excipient and obtaining the 1st mixture,
• Mixing the effervescent acid and the sweetener and granulating them with the granulation solution comprising acidic buffering agent and obtaining the 2nd mixture by adding the effervescent base, the basic buffering agent and at least one excipient into the granules obtained,
• Obtaining the final mixture by mixing the 1st mixture, the 2nd mixture and at least one excipient and compressing them in tablet form.
EP13720143.0A 2012-01-18 2013-01-18 Formulations comprising diclofenac as the active agent Withdrawn EP2804594A1 (en)

Applications Claiming Priority (4)

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TR201200602 2012-01-18
TR201205008 2012-04-30
TR201205319 2012-05-08
PCT/TR2013/000034 WO2013109222A1 (en) 2012-01-18 2013-01-18 Formulations comprising diclofenac as the active agent

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WO2013165327A1 (en) * 2012-04-30 2013-11-07 Mahmut Bilgic Pharmaceutical formulations comprising thiocolchicoside

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US3558690A (en) 1965-04-08 1971-01-26 Gelgy Chemical Corp Substituted derivatives of 2-anilinophenylacetic acids and a process of preparation
US5211957A (en) * 1988-03-25 1993-05-18 Ciba-Geigy Corporation Solid rapidly disintegrating dosage form
DK0642784T3 (en) * 1993-09-07 1999-11-22 Gergely Gerhard Shower mixture with alkali salts or lysinates of insoluble or heavily soluble active substance
EP2307022A4 (en) * 2007-10-31 2011-08-24 Equitech Corp Enhanced nsaid formulations
WO2013052019A1 (en) * 2011-08-19 2013-04-11 Mahmut Bilgic Production method for effervescent formulations comprising diclofenac

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