WO2005115092A2 - Composition pharmaceutique orale - Google Patents

Composition pharmaceutique orale Download PDF

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Publication number
WO2005115092A2
WO2005115092A2 PCT/IN2005/000177 IN2005000177W WO2005115092A2 WO 2005115092 A2 WO2005115092 A2 WO 2005115092A2 IN 2005000177 W IN2005000177 W IN 2005000177W WO 2005115092 A2 WO2005115092 A2 WO 2005115092A2
Authority
WO
WIPO (PCT)
Prior art keywords
isradipine
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
particle size
Prior art date
Application number
PCT/IN2005/000177
Other languages
English (en)
Other versions
WO2005115092A3 (fr
Inventor
Nitin Bhalachandra Dharmadhikari
Vaishali Vijay Dhavse
Original Assignee
Sun Pharmaceutical Industries Limited
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 Sun Pharmaceutical Industries Limited filed Critical Sun Pharmaceutical Industries Limited
Publication of WO2005115092A2 publication Critical patent/WO2005115092A2/fr
Publication of WO2005115092A3 publication Critical patent/WO2005115092A3/fr

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Classifications

    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules

Definitions

  • the present invention relates an oral phannaceutical composition
  • an oral phannaceutical composition comprising isradipine or pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the isradipine or pharmaceutically acceptable salt has a defined particle size.
  • Isradipine [3,5- Pyridinedicarboxylic acid, 4-(4-benzofurazanyl) ,4-dihydro-2.6- dimethyl-, methyl 1- methylethyl ester] is a dihydropyridine calcium channel blocker. It binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and smooth muscle. Isradipine is indicated in the management of hypertension. It may be used alone or concurrently with thiazide-type diuretics. Isradipine is available as DynaCirc ® Capsules, 2.5mg or 5mg capsules,
  • 1,4-dihydropyridines including isradipine, and the like are characterized by very poor water solubility. Consequent low dissolution rate in water may lead to an incomplete absorption and a low bioavailability from its solid medicinal preparations, The reported bioavailability of isradipine is 15 to 24% only. Therefore, it becomes essential that the dissolution rate of the substance be increased to obtain a product with desired bioavailability. Different methods have been tried to increase the solubility and therefore the bioavailability of the 1,4-dihydropyridines.
  • It is an object of the present invention to provide an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt wherein the mean particle size of isradipine or its pharmaceutical acceptable salt is in the range of about 3.5 ⁇ mto about 7.5 ⁇ m.
  • It is another object of the present invention to provide an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt wherein the D 9 0 of the isradipine or its pharmaceutically acceptable salt is in the range of 4 ⁇ m o 15 ⁇ m.
  • It is another object of the invention to provide an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients that meets the above objectives and has bioavailability comparable to isradipine formulation approved by the United States Food and Drug Administration (U.S. FDA) and referenced in the U.S. FDA Approved Drug Products book.
  • U.S. FDA United States Food and Drug Administration
  • the present invention provides an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt wherein the mean particle size of isradipine or its pharmaceutical acceptable salt is in the range of about 3,5 ⁇ m to about 7.5 ⁇ m.
  • the present invention provides an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt wherein the D 90 of the isradipine or its pharmaceutical acceptable salt is in the range of 4 ⁇ m to 15 ⁇ m.
  • the present invention further provides an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the geometric mean area and peak concentration ratio for the said composition is within the range of 0.80-1.25 when comparing equal doses of said composition to isradipine formulation as approved by the United States Food and Drug Administration (U.S. FDA) and referenced in the U.S. FDA Approved Drug Products book,
  • the present invention provides an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt wherein the mean particle size of isradipine or its pharmaceutical acceptable salt is in the range of about 3.5 ⁇ m to about 7.5 ⁇ m.
  • the present invention provides an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt wherein the D 90 of the isradipine or its pharmaceutical acceptable salt is in the range of 4 ⁇ m to 15 ⁇ m.
  • the present invention provides a rapid release oral pharmaceutical composition
  • a rapid release oral pharmaceutical composition comprising particles of isradipine, or its pharmaceutically acceptable salt, having a mean particle size in the range of about 3.5 ⁇ m to about 7.5 ⁇ m.
  • the mean particle size is about 3.5 ⁇ m to about 5 ⁇ m.
  • the mean particle size of the isradipine or its pharmaceutically acceptable salt is about 3.5 ⁇ m to about 4 ⁇ m.
  • the present invention also provides compositions wherein the isradipine or its pharmaceutically acceptable salt has a D 90 in the range of 4 ⁇ m to about 15 ⁇ m. It is preferred that the isradipine particles in the composition have a D 90 of about 5 ⁇ m to about 12 ⁇ m. It is to be noted that the notation D x means that X% of the particles have a diameter less than a specified diameter D, Thus, a D 90 of 5 ⁇ m means that 90% of the particles in an isradipine composition preferably have a diameter less than 5 ⁇ m.
  • the particle sizes stipulated herein refer to particle sizes determined by Malvern light scattering.
  • particles refers to individual particles, whether the particles exist singly or are agglomerated, Thus, a composition comprising particulate isradipine may contain agglomerates that are well beyond the ranges stated above.
  • references to particles of isradipine or its pharmaceutically acceptable salts having a "mean particle size" equal to or more than a given diameter or being within a given particle size range means that the average of all isradipine particles in the sample have an estimated diameter, based on an assumption of spherical shape.
  • Particle size distribution can be measured by Malvern light scattering as known to those skilled in the art.
  • the present invention further provides an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the geometric mean area and peak concentration ratio for the said composition is within the range of 0.80-1.25 when comparing equal doses of said composition to isradipine formulation as approved by the United States Food and Drug Administration (U.S. FDA) and referenced in the U.S. FDA Approved Drug Products book.
  • the pharmaceutical composition of the present invention is bioequivalent to isradipine composition approved by the USFDA and referenced in the USFDA approved drug products book.
  • bioequivalent means that if a dosage form comprising particles of isradipine or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier, said particles having a given mean particle size, is tested in a crossover study (usually comprising of at least 10 or more human subjects), the average Area under the Curve (AUC) and/or the C m3X for each crossover group is at least 80%, and not more than 125%, of the corresponding mean AUC and/or C raax observed when the same group of subjects is dosed with a formulation comprising isradipine and which has been commercially available in the United States of America since December 1990.
  • the commercially available formulation is available under the brand name DynaCirc ® , as an immediate release capsule preparation.
  • the present invention provides a pharmaceutical composition that releases isradipine or its pharmaceutically acceptable salt in a manner to provide desirable blood level profile of isradipine that provides efficacy in the treatment of hypertension, For example, when administered as a single dose to healthy human subjects it provides area under the plasma concentration-time curve (AUC) which is comparable to that provided by the pharmaceutical composition of isradipine commercially available in the United States of America since December 1990, Alternatively, it provides peak plasma levels (C ⁇ ) that are comparable with those provided by the pharmaceutical composition of isradipine commercially available in the United States of America since December 1990.
  • AUC plasma concentration-time curve
  • C ⁇ peak plasma levels
  • the term comparable means that the ratio of the population geometric means between the pharmaceutical composition of the present invention and the isradipine oral drug delivery system commercially available in the United States of America, namely DynaCirc ® , based on log-transformed data, is contained in the limits of 80-125 percent for AUC and C m ax- Bioequivalence may be determined according to United States Food and Drug Administration (USFDA) guidelines and criteria.
  • USFDA United States Food and Drug Administration
  • Isradipine and its pharmaceutically acceptable salt may be used in the present invention in an amount ranging from about lmg to about lOmg.
  • the pharmaceutically acceptable excipients that may be used in the present invention include diluents such as dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, powdered sugar and the like and mixtures thereof; disintegrants such as starch, clays, cellulose derivatives, gums, crosslinked polymers, crospovidone, sodium starch glycolate, croscarmellose and the like and mixtures thereof; binders such as starch, gelatin, sugars, cellulose derivatives, gums and the like; lubricants such as talc, magnesium stearate, stearic acid, colloidal silicon dioxide, polyethylene glycol, hydrogenated vegetable oils and the like and mixtures thereof and other such excipients,
  • the oral pharmaceutical composition of the present invention may be prepared using processes and techniques known to a person skilled in the pharmaceutical art, For example, the composition may be obtained by the
  • the isradipine or its pharmaceutically acceptable salt may be mixed with intragranular excipients and dry granulated by slugging or roller compaction, and mixed with extragranular excipients, prior to encapsulation or compression into tablets.
  • the composition of the present invention can also be obtained by mixing isradipine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, blending them and filling them into capsules, or directly compressing them into tablets.
  • the isradipine or its pharmaceutically salt used has a mean particle size of 3.68 ⁇ m and a D 90 of 7,05 ⁇ m.
  • compositions of the present invention comprising isradipine or its pharmaceutically acceptable salt having a particle size as described above, provide the desired therapeutic efficacy in the fasted and fed state in a subject.
  • the present invention also encompasses compositions wherein the particle size of isradipine or its pharmaceutically acceptable salt may be outside the range described herein, but which have bioavailability comparable to the compositions obtained using the described particle size.
  • compositions comprising isradipine or its pharmaceutically acceptable salt having a mean particle size or D 90 less than 3.5 ⁇ m or 4 ⁇ m, respectively may comprise agents that control release of the isradipine or its pharmaceutically acceptable salt from the composition so as to provide the desired bioavailability.
  • the invention encompasses compositions comprising isradipine or its pharmaceutically acceptable salt having a mean particle size or D 90 more than 7.5 ⁇ ra or 15 ⁇ m, respectively, wherein the composition may comprises solubilising agents, wetting agents, hydrophilic agents and the like to improve dissolution and therefore bioavailability of isradipine.
  • the isradipine and lactose monohydrate (first part) are sifted successively through ASTM 40 # mesh and collect in a polybag.
  • the lactose monohydrate (second part) is sifted through ASTM 40 # mesh and collected in a separate polybag.
  • Pregelatinised starch (Starch 1 00) is sifted through ASTM 40 # mesh and collected in a separate polybag.
  • the Lactose anhydrous is sifted through ASTM 40 # mesh and collected in a separate polybag.
  • the colloidal silicon dioxide and magnesium stearate are sifted through ASTM # 60 mesh.
  • the sifted Isradipine and lactose monohydrate (first part) are loaded in double cone blender and blended for 10 min.
  • the sifted lactose monohydrate (second part) is added to sifted Isradipine and lactose monohydrate (first part) in double cone blender and blended for 10 min.
  • Pregelatinised starch (Starch 1500) is added to the material in double cone blender and blended for 10 min.
  • the Lactose anhydrous is added to the material in double cone blender and blended for 15 min.
  • the colloidal silicon dioxide and magnesium stearate are added to the material in the double cone blender and blended for 5 minutes.
  • the blend is filled into hard gelatin capsule shell on an automatic capsule filling machine to a target weight of 200 / 242 mg per capsule.
  • the particle size analysis was determined by Malvern light scattering using 0.2% Nonidet as dispersion media.
  • the particle size of the isradipine was as given below in Table 2.
  • the pharmacokinetic assessment was based on the plasma levels of isradipine measured by blood sampling. Blood samples were obtained before dosing and at the following times after administration of both the reference and test medications: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours.
  • example 1 has too small a particle size and gives very high blood levels of isradipine compared to the innovator whereas the formulation of example 2 gives low blood levels of isradipine due to much larger particle size.
  • Formulation of example3 provides log-transformed values of AUC and C max that fall within 80-125% of Dynacirc ® and can therefore be considered to be bioequivalent.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne une composition pharmaceutique orale qui renferme de l'isradipine ou son sel pharmaceutiquement acceptable et des excipients pharmaceutiquement acceptables, sachant que l'isradipine ou son sel pharmaceutiquement acceptable présente une taille de particule définie.
PCT/IN2005/000177 2004-05-28 2005-05-30 Composition pharmaceutique orale WO2005115092A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN601/MUM/2004 2004-05-28
IN601MU2004 2004-05-28

Publications (2)

Publication Number Publication Date
WO2005115092A2 true WO2005115092A2 (fr) 2005-12-08
WO2005115092A3 WO2005115092A3 (fr) 2006-03-23

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000177 WO2005115092A2 (fr) 2004-05-28 2005-05-30 Composition pharmaceutique orale

Country Status (1)

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WO (1) WO2005115092A2 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020071870A1 (en) * 1999-06-28 2002-06-13 Vinay K. Sharma Preparation of micron-size pharmaceutical particles by microfluidization
US6645528B1 (en) * 1999-05-27 2003-11-11 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6645528B1 (en) * 1999-05-27 2003-11-11 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US20020071870A1 (en) * 1999-06-28 2002-06-13 Vinay K. Sharma Preparation of micron-size pharmaceutical particles by microfluidization

Also Published As

Publication number Publication date
WO2005115092A3 (fr) 2006-03-23

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