WO2005115092A2 - Micronized oral pharmaceutical composition - Google Patents

Micronized oral pharmaceutical composition 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
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Prior art keywords
isradipine
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
particle size
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PCT/IN2005/000177
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French (fr)
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WO2005115092A3 (en
Inventor
Nitin Bhalachandra Dharmadhikari
Vaishali Vijay Dhavse
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Sun Pharmaceutical Industries Limited
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Publication of WO2005115092A3 publication Critical patent/WO2005115092A3/en

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    • 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

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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

An oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein isradipine or its pharmaceutically acceptable salt has a meou particle size of 3,5 mm to 7,5 mm.

Description

ORAL PHARMACEUTICAL COMPOSITION
The present invention relates 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.
BACKGROUND OF THE INVENTION
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.
The concept of decreasing the particle size of the active agent to increase bioavailability has been known, but there exists no prior art on lowering particle size of isradipine to obtain a formulation that improves the bioavailability of isradipine. Although reduction of particle size is a commonly known means for increasing bioavailability of insoluble drugs, it was surprisingly found that in case of isradipine a minimum size cutoff is essential to provide a formulation that is safe and efficacious, Reduction of particle size of isradipine below the minimum size cutoff provides higher than required plasma levels of isradipine that cause adverse events such as headache, dizziness, edema, palpitations, fatigue and flushing as the preliminary manifestations, followed by more serious effects such as lethargy, sinus tachycardia, transient hypotension, tachycardia with ST depression on ECG, hypotension and the like, Higher plasma levels of isradipine may also cause excessive peripheral vasodilatation with subsequent marked and probably prolonged systemic hypotension, and tachycardia. We have found that reducing isradipine to a particular particle size range provides compositions that provide safe and efficacious therapeutic levels. Use of particle sizes outside the specified range provides compositions that either provide lower plasma isradipine levels such that the therapeutic efficacy is not reached, or provide high plasma isradipine levels that cause serious adverse effects in the patient. OBJECT OF THE INVENTION
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 3.5μmto about 7.5μm.
It is another object of the present invention to provide an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt wherein the D90 of the isradipine or its pharmaceutically acceptable salt is in the range of 4μm o 15μm.
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.
SUMMARY OF THE INVENTION
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 3,5μm to about 7.5μm.
The present invention provides an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt wherein the D90 of the isradipine or its pharmaceutical acceptable salt is in the range of 4μm to 15μm.
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,
DETAILED DESCRIPTION OF THE INVENTION
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 3.5μm to about 7.5μm. The present invention provides an oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt wherein the D90 of the isradipine or its pharmaceutical acceptable salt is in the range of 4μm to 15μm.
The present invention provides 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 3.5μm to about 7.5μm. Preferably, the mean particle size is about 3.5μm to about 5μm. In more preferred embodiments, the mean particle size of the isradipine or its pharmaceutically acceptable salt is about 3.5μm to about 4μm.
The present invention also provides compositions wherein the isradipine or its pharmaceutically acceptable salt has a D90 in the range of 4μm to about 15μm. It is preferred that the isradipine particles in the composition have a D90 of about 5μm to about 12μm. It is to be noted that the notation Dx means that X% of the particles have a diameter less than a specified diameter D, Thus, a D90 of 5μm means that 90% of the particles in an isradipine composition preferably have a diameter less than 5μm. The particle sizes stipulated herein refer to particle sizes determined by Malvern light scattering.
The term "particles" as used herein 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.
Reference 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. In other words, 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. The term "bioequivalent" as used herein 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 Cm3X for each crossover group is at least 80%, and not more than 125%, of the corresponding mean AUC and/or Craax 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.
Approval of a generic version (Abbreviated New Drug Application, AND A) of a proprietary drug (New Drug Application, NDA) by the Food and Drug Administration (FDA) requires demonstration of "chemical equivalence" (similar quantities and availability of the active ingredient in proprietary and generic formulations), and "bioequivalence" (defined by absorption parameters generally falling between 80% and 125% of those obtained with the proprietary agent under the same testing conditions), Hence, a generic drug formulation to be approved by the FDA, has to be bioequivalent to the reference listed drug or the proprietary formulation. 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. Herein, 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 Cmax- Bioequivalence may be determined according to United States Food and Drug Administration (USFDA) guidelines and criteria.
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 process of wet granulation, wherein isradipine or its pharmaceutically acceptable salt is mixed with intragranular excipients, granulated with a solution or a binder and mixed with extragranular excipients, which mixture may be filled in capsules excipients, which mixture may be filled in capsules or compressed to obtain tablets.
Alternatively, 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.
In one embodiment of the present invention, the isradipine or its pharmaceutically salt used has a mean particle size of 3.68μm and a D90 of 7,05 μm.
The 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. For example, compositions comprising isradipine or its pharmaceutically acceptable salt having a mean particle size or D90 less than 3.5μm or 4μm, 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. Similarly, the invention encompasses compositions comprising isradipine or its pharmaceutically acceptable salt having a mean particle size or D90 more than 7.5μra or 15μm, respectively, wherein the composition may comprises solubilising agents, wetting agents, hydrophilic agents and the like to improve dissolution and therefore bioavailability of isradipine.
The examples that follow are merely used as illustrations and do not limit the scope of the present invention. Examples 1-4 Pharmaceutical compositions of the present invention were obtained as per the method given in Table 1 below. Table 1
Figure imgf000008_0001
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.
Table 2
Figure imgf000008_0002
The dissolution studies of the formulations of examples 1-4 were carried out in United States pharmacopoeia Type I apparatus at 100 rpm in 1000 ml 0.05% Tween solution. The results are given in table 3 below. Table 3
Figure imgf000009_0001
The bioavailability of the pharmaceutical compositions of isradipine (Examples 1-3) of the present invention and that of commercially available isradipine capsules, DynaCirc® (5 mg isradipine, Lot no 136G6378, Exp date May 2005) were studied. A single-dose, open label, randomized, comparative and two-way crossover study, with a seven-day washout period, was undertaken for the same.
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.
Fourteen healthy male volunteers were enrolled for the study and all of them completed the two-way crossover study, The subjects were fasted overnight before dosing and for 4 hours thereafter. Drinking water was prohibited 2 hours before dosing and 2 hours thereafter, but was allowed ad lib at all other times. Standard meals were provided at 4 hours and 8 hours after dosing, and at appropriate times thereafter. Meal plans were identical for both the periods,
Subjects received a single capsule of isradipine (5 mg, Examples 1-3) with 240ml of drinking water at ambient temperature as the test medication, and a single oral dose of DynaCirc® (5 mg) also with 240ml of drinking water at ambient temperature as the reference medication,
The plasma concentration of isradipine was determined for samples collected at different time points and averaged over the fourteen volunteers, This data was used to calculate the Cmax and AUC values. These values were compared with those obtained from the reference medication to obtain a %T/R ratio, which is recorded in Table 4 below. Table 4
Figure imgf000010_0001
As can be seen from the bioequivalence results, the formulation of 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 Cmax that fall within 80-125% of Dynacirc® and can therefore be considered to be bioequivalent.
Formulations of example 3 and 4 were also subjected to similar bioequivalence study in Fed condition. The results summarized in Table 5 indicate the bioequivalence with the innovator's product. Table 5
Figure imgf000010_0002
While the invention has been described by reference to specific embodiments, this was done for purposes of illustration only and should not be construed to limit the spirit or the scope of the invention.

Claims

Claims: 1. An oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, wherein the isradipine or its pharmaceutically acceptable salt has a mean particle size of about 3.5μm to about 7.5μm. 2. An oral pharmaceutical composition as claimed in claim 1 wherein the mean particle size is about 3.5μm to about 4μm. 3. An oral pharmaceutical composition comprising isradipine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, wherein the isradipine or its pharmaceutically acceptable salt has a D90 in the range of 4μm to 15μm. 4. An oral pharmaceutical composition as claimed in claim 3, wherein the D90 is 5μm to 12μm. 5. An oral pharmaceutical composition as claimed in claim 1 wherein the pharmaceutically acceptable excipients are selected from one or more diluents, binders, lubricants, antiadherents, disintegrants and wicking agents. 6. An oral pharmaceutical composition as claimed in claim 3 wherein the pharmaceutically acceptable excipients are selected from one or more diluents, binders, lubricants, antiadherents, disintegrants and wicking agents.
PCT/IN2005/000177 2004-05-28 2005-05-30 Micronized oral pharmaceutical composition WO2005115092A2 (en)

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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

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