Tacrolimus For Improved Treatment Of Transplant Patients

a transplant patient and tacrolimus technology, applied in the field of extended release oral dosage form, can solve the problems of reducing the risk of clinical success, extending the release too much, and seriously affecting the bioavailability, so as to improve the treatment effect, improve the bioavailability, and improve the effect of toxicity

US20110275659A1Inactive Publication Date: 2011-11-10VELOXIS PHARMA
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Patent Information

Authority / Receiving Office
US · United States
Patent Type
Applications(United States)
Current Assignee / Owner
Publication Date
2011-11-10
Estimated Expiration
Not applicable · inactive patent

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Abstract

An extended release oral dosage form comprising as active substance tacrolimus or a pharmaceutically active analogue thereof for a once daily immunosuppressive treatment of a patient in need thereof, preferable a kidney or liver transplant patient. The dosage form releases the active substance over an extended period of time. It also provides improved pharmacokinetic parameters due to an extended and constant in vivo release including substantial decreased peak concentrations, despite increased bioavailability, substantial extended times for maximal concentration, and higher minimal concentrations when compared with conventional immediate release dosage forms and a recent modified release tacrolimus dosage form.
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Description

RELATED U.S. APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 61 / 079,015, filed Jul. 8, 2008, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The present invention relates to an extended release oral dosage form comprising as active substance tacrolimus or a pharmaceutically active analogue thereof for use in a once daily immunosuppressive treatment of a patient in need thereof which dosage form releases the active substance over an very extended period of time and which in vivo provides a high bioavailability and an improved pharmacokinetic profile compared to conventional dosage forms.BACKGROUND OF THE INVENTION

[0003] Tacrolimus, also known as FK-506 or FR-900506, is the active ingredient of Prograf®, Protopic®, and Advagraf® approved by the European Agency for the Evaluation of Medicinal Products (EMEA) at 23 Apr. 2007. During development of Advagraf® the product has been known as MR4. Details of Advagra...

Examples

examples

[0251]Materials and methods

Materials

[0252]Tacrolimus (supplied by Eurotrade); batch no RD 03-111[0253]Lactose monohydrate 200 mesh (from DMV)[0254]Granulated silicium oxide, Aeroperl® 300, (Degussa)[0255]Polyethylene glycol 6000, Pluracol® E6000 (from BASF)[0256]Poloxamer 188, Pluronic® F-68 (from BASF)[0257]Glyceryl monostearate, Rylo® MD50, (from Danisco Cultor), Ph.Eur.; batch no. 4010056276[0258]Avicel PH200 (microcrystalline cellulose) (from FMC)[0259]Lactose DCL 11 (from DMV)[0260]Magnesium stearate[0261]Croscarmellose sodium, Ac-Di-Sol® (from FMC)[0262]Eudragit® L30D.55 (from Degussa)[0263]Triethyl citrate (from Merck)[0264]Anti-foam emulsion (from Unikem)[0265]Micro talc[0266]HPMC refers to Metolose 90SH (type 2910, 2208) or Metolose 60SH (type 2910) from ShinEtsu available in various degrees of polymerization (viscosity 3-100,000 cP).

[0267]Tablets, capsules or granules might be enteric coated with different types of polymers such as hydroxypropylmethylcellulose acetate succ...

example 1

Modified Release Poly-Depot Capsule Based on Swelling Hydrocolloid Matrix of Hydroxypropylcellulose

[0281]

Substance%mgTacrolimus0.501.00HPMC20.0040.00Lactose 200 mesh30.0060.00PEG 600034.6569.30Poloxamer 18814.8529.70Total100.00200.00

[0282]Tacrolimus was dissolved in polyethylene glycol 6000 and poloxamer 188 (70:30 w / w ratio) at 70° C. The solution was sprayed on a mixture of 150 g lactose and 100 g HPMC in a fluid bed Strea-1. The granular product was sieved through sieve 0.7 mm and filled into hard gelatine capsules (200 mg).

example 2

Modified Release Poly-Depot Capsule Based on Swelling Hydrocolloid Matrix of Hydroxypropylcellulose

[0283]

Substance%mgTacrolimus0.501.00HPMC 2910 3 cp20.0040.00Lactose 200 mesh30.0060.00Glyceryl monostearate49.5099.00Total100.00200.00

[0284]Tacrolimus was dissolved in glyceryl monostearate at 70° C. The solution was sprayed on a mixture of 150 g lactose and 100 g HPMC in a fluid bed Strea-1. The granular product was sieved through sieve 0.7 mm and filled into hard gelatine capsules (200 mg).