Therapeutical composition containing apomorphine as active ingredient

a technology of active ingredients and therapeutic compositions, applied in the direction of pharmaceutical delivery mechanisms, medical preparations, nervous disorders, etc., can solve the problems of inducing injection site reactions, local subcutaneous site reactions, situ precipitation and chemical degradation under physiological conditions, etc., to increase the local tolerance of treatment, increase the chemical stability of formulations, and increase drug concentration

Inactive Publication Date: 2016-10-27
BRITANNIA PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]To increase the local tolerance of the treatment, the applicant has found a new formulation with a pH close to the physiological pH avoiding in situ precipitation, increasing chemical stability of the formulation and an increased drug concentration allowing the reduction of the injectable volume.
[0016]The term “surfactant” as used herein refers to a compound or excipient with surface active properties, used mainly in the present formulations to improve the aqueous solubility of the active ingredient, help to protect the active substance against degradation and limit in vitro active ingredient precipitation if co-solvent alone is not sufficient.
[0040]A pharmaceutical composition according to the present invention shows a low viscosity and is easily administered by the parenteral route through 27 Gauge (G) needle and more preferably through 29G needle.
[0041]A pharmaceutical composition according to the present invention may be useful in the treatment to reduce “off episodes” in patients with advanced Parkinson's disease.
[0042]In a preferred embodiment, the composition of the present invention is for use as medicament intended to reduce “off episodes” in patients with advanced Parkinson's disease.

Problems solved by technology

However, these formulations induce injection site reactions.
Furthermore, parenteral subcutaneous injection of an active pharmaceutical ingredient (API) formulated in acidic conditions may lead to in situ precipitation and chemical degradation under physiological conditions and pH.
Low pH value of the formulation, as well as potential precipitation and degradation of the drug under physiological conditions, may induce local subcutaneous site reactions such as redness, itching, local indurations and nodules which are sore and troublesome.

Method used

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  • Therapeutical composition containing apomorphine as active ingredient
  • Therapeutical composition containing apomorphine as active ingredient

Examples

Experimental program
Comparison scheme
Effect test

example 4

Local Tolerance

[0122]The local tolerance results of the tested formulations in rats (1 mg / kg—SC) are presented in the Table 3.

TABLE 3ParameterAPO-go ®Test 1Test 2Test 3 Test 4Test 5Concentration (mg / ml)5.029.110.029.429.429.4pH3.35.94.26.05.94.1Toleranceformulation2.72.43.72.33.03.2scoringplacebo0.30.60.50.30.20.8Note:tolerance scoring for the saline solution was 0.1.

[0123]The same tolerance level as the Apo-go® reference is observed for the 5 test formulations, which have a concentration from 2 to 6 times higher than the reference (from 10 to 30 mg / mL for the test formulations vs. 5 mg / mL for the reference).

[0124]Thus, using a formulation according to the present invention, patients will be able to receive a better treatment based on a 6-fold lower injection volume, a formulation at a more physiologically acceptable pH and a formulation that tends to be more tolerated than the APO-go® reference.

example 5

14-Day Subcutaneous Infusion in Vivo Testing

[0125]PK profile of the selected prototypes were evaluated in rats. Subcutaneous micropumps were implanted in 6 rats for each prototype. Micropumps were implanted subcutaneously in the lumbar region for continuous infusion in the scapular region. Animals received a subcutaneous infusion of the formulation at a dose of 6 mg / kg / day (0.3 mg / kg / hour) of the appropriate apomorphine formulations to animals over a 20 h period / day for 14 days. Blood samples were collected at the following time point:[0126]Day 1 at 0 h, 6 h post Start of Infusion and 20 h post Start of Infusion (SOI),[0127]Day 7 20 h post Start of Infusion (SOI),[0128]Day 14 at 0 h, 20 h post Start of Infusion (SOI).

[0129]Plasma concentrations were determined by HPLC-ESI-MS / MS method and PK parameters were calculated.

[0130]In order to evaluate the local tolerance of the tested formulations, tissue from the injection site was collected from each rat and examined by an anatomo-pathol...

example 6

Local Tolerance in the 14-Day Subcutaneous Infusion Experiment

[0144]The local tolerance data of the tested formulations in subcutaneous infusion over 20 h / day in rats at 6 mg / kg / d are presented in the Table 6. The tolerance scoring was established at the 14th day of infusion, i.e., at the EOI.

TABLE 6Test 1Parameter(Reference)Test 2Test 3Test 4Test 5 Test 6Concentration4.5828.929.630.439.537.2(mg / mL)pH3.36.05.85.95.95.9Tolerance scoring3.02.82.32.72.42.6The same tolerance level than the Apo-Go ® reference (Test 1) was obtained with the test formulations that show a 6 to 8 times higher concentration.

[0145]Thus, using a formulation according to the present invention, patients will be able to receive a better treatment based on a 6 to 8 times lower injection volume, a formulation at a more physiologically acceptable pH and a formulation that tends to be more tolerated than the APO-go® reference.

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Abstract

A pharmaceutical composition contains apomorphine as the active pharmaceutical ingredient, a water-miscible co-solvent, an antioxidant, and water. The solution has a pH greater than 4. The pharmaceutical composition is suitable for parenteral administration for the treatment of Parkinson's disease. The process for the manufacture of the pharmaceutical composition includes weighing the apomorphine and introducing it into a container with the co-solvent and the antioxidant under agitation until complete dissolution takes place.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional application of U.S. patent application Ser. No. 14 / 152,000, filed Jan. 10, 2014, which, in turn, is a continuation application of international patent application PCT / EP2012 / 002916, filed Jul. 11, 2012, designating the United States and claiming priority from European application 11290320.8, filed Jul. 11, 2011, and the entire content of the above applications is incorporated herein by reference.FIELD OF THE DISCLOSURE[0002]The present invention relates to a pharmaceutical composition in the form of a solution containing apomorphine as the active pharmaceutical ingredient, and more particularly a pharmaceutical formulation for parenteral administration.BACKGROUND OF THE DISCLOSURE[0003]Apomorphine is a pharmaceutical active ingredient which is used to reduce “off episodes” in patients with advanced Parkinson's disease. Three solutions of apomorphine are currently marketed: a solution for subcutaneous infus...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/473A61K9/00
CPCA61K9/0019A61K31/473A61P25/04A61P25/16
Inventor DEY, MICHAELRICHARD, JOELBARONNET, MARIE-MADELEINEMONDOLY, NATHALIEBERTOCCHI, LAURENTHARNETT, JEREMIAH
Owner BRITANNIA PHARMA LTD
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