WO2012026896A1 - Surface modified micronized tacrolimus crystalline particles and pharmaceutical compositions thereof - Google Patents

Surface modified micronized tacrolimus crystalline particles and pharmaceutical compositions thereof Download PDF

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Publication number
WO2012026896A1
WO2012026896A1 PCT/TN2011/000003 TN2011000003W WO2012026896A1 WO 2012026896 A1 WO2012026896 A1 WO 2012026896A1 TN 2011000003 W TN2011000003 W TN 2011000003W WO 2012026896 A1 WO2012026896 A1 WO 2012026896A1
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Prior art keywords
tacrolimus
pharmaceutical composition
surface modified
particles
crystalline
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PCT/TN2011/000003
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French (fr)
Inventor
Lassaâd BOUJBEL
Mohamed Amine Boujbel
Stephen Lukas
Karel Ren
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Les Laboratoires Medis Sa
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Priority to MA35763A priority Critical patent/MA34586B1/en
Publication of WO2012026896A1 publication Critical patent/WO2012026896A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic 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
    • A61K9/4858—Organic 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

Abstract

Pharmaceutical composition comprising surface modified micronized tacrolimus crystalline particles having d90 value of from 2 μm to 10 μm.

Description

Surface modified micronized tacrolimus crystalline particles and pharmaceutical compositions thereof
FIELD OF INVENTION
The present invention is directed to pharmaceutical composition comprising surface modified micronized tacrolimus crystalline particles having d90 value of from2 urn to 10 urn. In particular, the present invention relates to solid dosage units comprising micronized tacrolimus crystalline particles suspended in suitable vehicle together with one or more surface modifier. It further relates to a pharmaceutical composition comprising said particles
BACKGROUND OF THE INVENTION
Tacrolimus, also known as KF 506 is a macrocyclic lactone produced by fermentation of soil microorganisms Streptomyces tsukubaensis, a monotypic species of Streptomyces. Tacrolimus has the empirical formula C44H69NO12.H20 a molecular weight of 822.05, and the following chemical formula:
Figure imgf000003_0001
It appears as white crystals or crystalline powder which are highly lipophilic, poorly water soluble (<10ng/ml) with extremely potent immunosuppressive effect. The pharmacological activities of tacrolimus are described in details in European Patent Application No. 184162.
Tacrolimus is available in various dosage forms such as capsules, injections and an ointment. The conventional capsule dosage form is sold commercially as Prograf® and is approved for prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants. Absorption of orally administered tacrolimus from the gastrointestinal tract is incomplete and variable. The absolute bioavailability of tacrolimus is typically 17±10%. In adult kidney transplant patients (N=26), typically 22±6%. In adult liver transplant patients (N=17), typically 23±9%. In adult heart transplantation patients (N=1 1 ) and typically 18±5%. In healthy volunteers (N=16). It has also been observed that the absorption is affected by the presence of food. The rate and extent of tacrolimus absorption is greatest under fasted conditions. The presence and composition of food decreases both the rate and extent of tacrolimus absorption.
At present tacrolimus, together with cyclosporine A, rapamycin and the morpholinoester or sodium salt of mycophenolic acid, represents the standard approach in management of organ rejection or treatment of autoimmune diseases. A major complication of its clinical use was development of an oral formulation with acceptable stability and bioavailability.
Several methods can be used to improve dissolution rate of water-insoluble drugs, e.g.:
a) Reduction of particle size to increase surface area,
b) Solubilization in surfactant formulations, forming Self Emulsifying Drug Delivery Systems (SEDDS).
c) Modifying the crystallinity of the active ingredient by changing the crystalline form into amorphous one e.g. by solid dispersion.
In general, a solid dispersion is a pharmaceutical formulation comprising a multicomponent System having an amorphous drug dispersed in and around a hydrophilic solid carrier. To prepare solid dispersions, the drug and solid carrier are dissolved in organic solvent, fused and then dried or cooled.
Traditionally, the formulations were prepared by solubilization of tacrolimus in organic solvent together with a water soluble polymer, especially, or exclusively represented by hydroxy propyl methyl cellulose, providing a solid dispersion with tacrolimus present in the amorphous state. The amorphous state is supposed to give a drug, higher thermodynamic activity than in crystalline form. Higher energy level of the active ingredient is believed to result in rapid dissolution, however, in fact with tacrolimus it results in quite unstable product, with high tendency to revert back to the crystalline form which is characterised by variable and decreased solubility/dissolution/bioavailability.
Conventional solid dispersion processes based on solubilization of tacrolimus and a water-soluble carrier in organic solvent has been used to formulate the first oral dosage forms such as those described in United States Patent Application 4,916,138, and European Patent Application 0240773. When orally administered, the formulation provided improved absorption however, both the stability and the bioavailability were variable. The bioavailability is partially influenced by the tacrolimus transport mechanisms and partially by the behavior of the amorphous compound which tends to revert, particularly when stored in a humid atmosphere, to the thermodynamically more stable, less soluble, crystalline form.
United States Patent Application Publication No. 2008/0152720 discloses a nanoparticulate tacrolimus formulation comprising particles of tacrolimus and at least one surfactant stabilizer which can be added to the dispersion media before, during or after particle size reduction. Effective average particle size of tacrolimus is below 2000 nm. Where the formulations are to be injected the particle size should be less than 600 nm.
Nanonization of poorly soluble drug is a complex process and requires additional step during manufacturing. It is true that nanization increases the surface area available for dissolution, however, it also increases change in free energy of the system when exposed to aqueous solution. This results in particle aggregation and decreases the dissolution rate. Also, very fine particles are difficult to handle due to static charge that develops on particle surface during processing. Working with surface modified micronized crystals we identified formulations which have been found to be much more stable and less variable than formulations based on the amorphous tacrolimus. We have found that by using this approach we were able to formulate a product using the crystalline form, which has a similar dissolution profile as a product base on the use of tacrolimus in the amorphous state.
The present invention therefore provides a new approach to prepare more stable products by suspending of surface modified crystalline micronized tacrolimus.
SUMMARY OF INVENTION
The present invention therefore provides a product containing crystalline micronized tacrolimus with d90 value of from 2pm to 10 pm, and one or more surface modifiers which provides the desired in vitro and in vivo profile.
Hence, according to one of the aspects, the invention provides tacrolimus particles having d90 values from 2 pm to 10 μητι.
In another aspect, the invention provides a pharmaceutical composition comprising micronized particles of crystalline tacrolimus having d90 value of from 2pm to 10 pm.
In another aspect, the invention provides a pharmaceutical composition of tacrolimus comprising dispersion of tacrolimus particles and at least one pharmaceutically acceptable excipients wherein said tacrolimus particles have d90 value from 2 pm to 10 pm.
In another aspect, the invention provides a process of preparing a pharmaceutical composition comprising the steps of:
a) dissolution or dispersing one or more pharmaceutically acceptable ingredients in a vehicle, and
b) dispersing tacrolimus particles in the dispersion/solution of step a; wherein said tacrolimus particles have d90 value of from about 2 pm to about 10 pm.
In another aspect, the invention provides a process of preparing a pharmaceutical composition of tacrolimus particles, comprising the steps of: a) dissolving or dispersing one or more pharmaceutically acceptable excipients in a vehicle; b) dispersing sirolimus particles in the dispersion/solution of step a); and
c) processing the dispersion of step b) into suitable pharmaceutical composition;
Wherein said tacrolimus particles have d90 value of from about 2 m to about 10 μιτι.
In another aspect, the invention provides a method of treatment of organ or tissue transplant rejection, or autoimmune disease, the method comprising: orally administering to a subject a pharmaceutical composition comprising tacrolimus particles having d90 value of from about 2 μιη to about 10 μηι.
DETAILED DESCRIPTION OF THE INVENTION
The invention will be now described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
Tacrolimus as used herein means crystalline form of both tacrolimus base, tacrolimus monohydrate, or any other crystalline form of tacrolimus API.
The term "d90 value" means at least 90% of tacrolimus particles have volume diameter in the specified range when measured by a light scattering method Malvern Mastersizer.
Micronization may be carried out using dry milling technique. Various conventional mills available for dry milling can be applied. The milling may be carried out using the tacrolimus alone or with other pharmaceutically acceptable excipients. The desired particle size may be also obtained by modifying the reaction conditions during the manufacturing of tacrolimus API.
"Pharmaceutical composition" as used herein includes both liquid and solid dosage forms such as solution, suspension, tablet, capsule, granules, and pills. The term 'pharmaceutically acceptable excipients" as used herein include surface modifiers, binders, diluents, lubricants/glidant, disintegrating agent, antioxidants, and coloring agents.
The term "surface modifiers" as used herein means agents which are used to disperse the drug in a particular vehicle and also enhance wetting properties of the drug. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Representative examples include gelatin, casein, lecithin (phosphatides), gum Arabica, cholesterol, tagacanth, stearic acid, benzalconium chloride, calcium stearate, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminium silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone. Surfactants include both non-ionic and ionic surfactants suitable for use in pharmaceutical dosage forms.
The vehicle used to prepare the dispersion may be selected from water or its mixture with other organic solvent such as ethanol, methanol, isopropyl alcohol, and ether.
According to one of the embodiment, tacrolimus particles are prepared by micronising tacrolimlus coarser particles by dry milling technique to obtain a desired particle size range.
EXAMPLES
The intention is further illustrated by the following examples but they should not be construed as limiting the scope of this invention in any way.
Example 1
A mixture of micronized crystalline tacrolimus having d90 value of from 2μιτι to 10 μιη, was suspended 1 :1 in water solution of polyvinylpyrrolidone (1 :1 by weight) andmixed thoroughly for 30 min at room temperature. The paste formed was dried under vacuum for 24 hrs and milled. The dried powder of surface modified tacrolimus was passed through a sieve 32 mesh and filled into hard gelatin capsules and used for dissolution. Example 2
A mixture of micronized crystalline tacrolimus having d90 value of from 2 m to 10 pm, was suspended in water solution of polyvinylpyrrolidone (1 :5 by weight) and mixed thoroughly for 30 min at room temperature. The paste formed was dried under vacuum for 24 hrs and milled. The dried powder of surface modified tacrolimus was passed through a sieve 32 mesh and filled into hard gelatin capsules and used for dissolution.
Example 3
A mixture of micronized crystalline tacrolimus having d90 value of from 2 pm to 10 μιη, was suspended in water solution of polyvinylpyrrolidone and sodium lauryl sulphate (1 :1 :1 by weight) and mixed thoroughly for 30 min at room temperature. The paste formed was dried under vacuum for 24 hrs and milled. The dried powder of surface modified tacrolimus was passed through a sieve 32 mesh and filled into hard gelatin capsules and used for dissolution.
Example 4
A mixture of micronized crystalline tacrolimus having d90 value of from 2 m to 10 μηη, was suspended in water solution of polyvinylpyrrolidone and sodium lauryl sulphate (1 :1 : 1 by weight) and mixed thoroughly for 30 min at room temperature. The paste formed was dried under vacuum for 24 hrs and milled. The dried powder of surface modified tacrolimus was passed through a sieve 32 mesh and filled into hard gelatin capsules and used for dissolution.
Example 5
A mixture of micronized crystalline tacrolimus having d90 value of from 2 pm to 10 μιτι, was suspended in water solution of HPMC and sodium lauryl sulphate (1 : 1 :1 by weight) and mixed thoroughly for 30 min at room temperature. The paste formed was dried under vacuum for 24 hrs and milled. The dried powder of surface modified tacrolimus was passed through a sieve 32 mesh and filled into hard gelatin capsules and used for dissolution.
The dissolution profile of the dried mixture, tested in a medium containing 0.005% hydroxylpropyl methyl cellulose, was virtually identical to that of Prograf, tacrolimus immediate release commercially available formulation. The final powder, containing surface modified crystalline tacrolimus was mixed with croscaramelose and lactose and filled into hard gelatin capsule and subject to comparative dissolution test.
Dissolution test
The tests were carried out in Apparatus II according to FDA method, i.e. 900 ml of dissolution medium pH 4.5 with 0.05% MPC, 50 rpm, with sample collection after 30, 60, 90, and 120 min, respectively.
The dissolution rates of surface modified micronized crystalline tacrolimus are shown in the following table.
Dissolution rate (%)
Test Sample 30min. 60min. 90min. 120min
Tacrolimus crystals 0 5 10 12
Example 1 37 45 52 80
Example 2 33 40 45 65
Example 3 85 85 95 100
Example 4 80 80 100 100
Example 5 24 26 28 31
As evident from comparison of dissolution of tacrolimus crystals, surface modification is significantly increasing solubility of tacrolimus API.

Claims

We claim:
1. Pharmaceutical composition comprising surface modified crystalline tacrolimus particles.
2. Pharmaceutical composition comprising crystalline micronized tacrolimus having d90 value of from 2 m to 10 pm.
3. Pharmaceutical composition according to claim 2 prepared by using of milling methods.
4. Pharmaceutical composition of tacrolimus according to claim 1 wherein the final dosage form is a liquid.
5. Pharmaceutical composition of tacrolimus according to claim 1 wherein the final dosage form is a solid.
6. Pharmaceutical composition of tacrolimus according to claim 5 wherein the tacrolimus particles are suspended in vehiculum containing at least one soluble pharmaceutically acceptable excipient.
7. Pharmaceutical composition of tacrolimus according to claim 5 wherein at least one soluble pharmaceutically acceptable excipient is a surface active molecule.
8. Solid dosage form of tacrolimus comprising dried homogenized surface active particles.
9. Final dosage forms according to claim 8 in form of powder, fine granules, granules, tablets, capsules, injections etc, prepared conventionally by mixing with various pharmaceutically acceptable excipients.
10. A composition for use in the treatment of the human or animal body by therapy comprising a tacrolimus containing formulation containing micronized surface modified crystalline tacrolimus.
11. A composition for use in the treatment for the inhibition of organ transplani rejection comprising a tacrolimus containing formulation containing surface modified micronized crystalline tacrolimus.
PCT/TN2011/000003 2010-08-25 2011-08-24 Surface modified micronized tacrolimus crystalline particles and pharmaceutical compositions thereof WO2012026896A1 (en)

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MA35763A MA34586B1 (en) 2010-08-25 2011-08-24 MICRONIZED TACROLIMUS CRYSTALLINE PARTICLES WITH MODIFIED SURFACE AND PHARMACEUTICAL COMPOSITIONS THEREOF

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014201236A1 (en) * 2013-06-12 2014-12-18 Surmodics, Inc. Solvent methods for preparing crystalline macrolide particulates, compositions, and articles containing particulates
US9439892B2 (en) 2013-05-16 2016-09-13 Surmodics, Inc. Macrolide particulates, methods for preparation, and medical devices associated therewith
CN107595772A (en) * 2017-09-26 2018-01-19 山东省药学科学院 A kind of preparation method of tacrolimus nanometer suspension eye drops
US10098846B2 (en) 2016-03-31 2018-10-16 Surmodics, Inc. Drug-containing particulate composition with cationic agent, associated medical devices, and methods for treatment
CN113242732A (en) * 2018-12-04 2021-08-10 莱昂纳米药物有限公司 Nanoparticles comprising tacrolimus
US11123459B2 (en) 2016-12-16 2021-09-21 Surmodics, Inc. Hydrophobic active agent particle coatings and methods for treatment

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EP0184162A2 (en) 1984-12-03 1986-06-11 Fujisawa Pharmaceutical Co., Ltd. Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same
EP0240773A1 (en) 1986-04-02 1987-10-14 Fujisawa Pharmaceutical Co., Ltd. Solid dispersion composition of FR-900506 substance
EP1064942A1 (en) * 1998-03-26 2001-01-03 Fujisawa Pharmaceutical Co., Ltd. Sustained release preparations
US20060159766A1 (en) * 2004-12-15 2006-07-20 Elan Pharma International Limited Nanoparticulate tacrolimus formulations
WO2008013416A1 (en) * 2006-07-27 2008-01-31 Amorepacific Corporation Process for preparing powder comprising nanoparticles of sparingly soluble drug

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0184162A2 (en) 1984-12-03 1986-06-11 Fujisawa Pharmaceutical Co., Ltd. Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same
EP0240773A1 (en) 1986-04-02 1987-10-14 Fujisawa Pharmaceutical Co., Ltd. Solid dispersion composition of FR-900506 substance
US4916138A (en) 1986-04-02 1990-04-10 Fujisawa Pharmaceutical Co., Ltd. Solid dispersion composition of FR-900506 substance
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US20060159766A1 (en) * 2004-12-15 2006-07-20 Elan Pharma International Limited Nanoparticulate tacrolimus formulations
US20080152720A1 (en) 2004-12-15 2008-06-26 Elan Pharma International Limited Nanoparticulate tacrolimus formulations
WO2008013416A1 (en) * 2006-07-27 2008-01-31 Amorepacific Corporation Process for preparing powder comprising nanoparticles of sparingly soluble drug

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9439892B2 (en) 2013-05-16 2016-09-13 Surmodics, Inc. Macrolide particulates, methods for preparation, and medical devices associated therewith
US9949957B2 (en) 2013-05-16 2018-04-24 Surmodics, Inc. Macrolide particulates, methods for preparation, and medical devices associated therewith
US10449180B2 (en) 2013-05-16 2019-10-22 Surmodics, Inc. Macrolide particulates, methods for preparation, and medical devices associated therewith
WO2014201236A1 (en) * 2013-06-12 2014-12-18 Surmodics, Inc. Solvent methods for preparing crystalline macrolide particulates, compositions, and articles containing particulates
US9770537B2 (en) 2013-06-12 2017-09-26 Surmodics, Inc. Solvent methods for preparing crystalline macrolide particulates, compositions, and articles containing particulates
US10098846B2 (en) 2016-03-31 2018-10-16 Surmodics, Inc. Drug-containing particulate composition with cationic agent, associated medical devices, and methods for treatment
US11123459B2 (en) 2016-12-16 2021-09-21 Surmodics, Inc. Hydrophobic active agent particle coatings and methods for treatment
CN107595772A (en) * 2017-09-26 2018-01-19 山东省药学科学院 A kind of preparation method of tacrolimus nanometer suspension eye drops
CN107595772B (en) * 2017-09-26 2020-09-18 山东省药学科学院 Preparation method of tacrolimus nano suspension eye drops
CN113242732A (en) * 2018-12-04 2021-08-10 莱昂纳米药物有限公司 Nanoparticles comprising tacrolimus

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