RU2483749C2 - Pharmaceutical composition containing insulin and liposomes for topical application in form of biofilm - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, namely to pharmaceutical compositions for topical application containing insulin and liposomes. What is described is a pharmaceutical composition for topical application, containing insulin and liposomes in the form of a biofilm having rapid cutaneous penetration, and an ability to reduce blood glucose.

EFFECT: what is presented is the composition having rapid cutaneous penetration.

4 ex

Description

The present invention relates to medicine, namely to pharmaceutical compositions for topical application containing insulin and liposomes.

Recently, thanks to the achievements of medicine, a number of pharmaceuticals have appeared that can partially solve the problems of ambulatory use of insulin, such as the inconvenience of use and the difficulty of dosing.

Insulin is a hormone produced by the pancreatic β-cells of animals and humans. Insulin has the ability to regulate the metabolism of carbohydrates, proteins and fatty acids (mainly in the liver, muscles and adipose tissue) as a result of its interaction with specific receptors located on the plasma membrane of cells :

promotes the absorption of carbohydrates, proteins and fatty acids by tissues, stimulates the synthesis of proteins and fatty acids, inhibits the release of the latter from fat depots. Insulin is the main specific treatment for diabetes mellitus, as it reduces hyperglycemia and glucosuria and associated with the latter increased diuresis (polyuria) and thirst (polydipsia). Due to the normalization of carbohydrate metabolism, protein and fat metabolism are restored (in the blood and urine ketone bodies — acetone, acetoacetic and β-hydroxybutyric acids — are no longer detected). Emaciation and an overly expressed feeling of hunger (bulimia) associated with the breakdown of fats and the intense conversion of proteins into glucose ceases.

Selection of the dosage of insulin is of no small importance. So, with the introduction of too large doses, as well as insufficient intake of carbohydrates with food, can cause a hypoglycemic state, with the further development of a hypoglycemic coma with loss of consciousness, convulsions and a sharp decline in cardiac activity.

The duration of the action distinguishes the following groups:

a) short-acting insulin preparations

Known drug Actrapid NM Penfill ™. Genetically engineered (biosynthetic) insulin identical to human insulin. Enter subcutaneously, intramuscularly and intravenously. The effect develops 30 minutes after subcutaneous administration, reaches a maximum after 1-3 hours and lasts 8 hours. Available in 1.5 ml and 3 ml Penfill chamber (100 IU / ml) for individual use with an insulin pen.

b) long-acting insulin preparations

Known drug Mikstard NM Penfill ™. A suspension of genetically engineered monocomponent human insulin, consisting of 10-50% soluble insulin and 90-50% insulin isophan-protamine. Enter subcutaneously. The effect develops after 30 minutes, reaches a maximum after 2-8 hours and lasts 24 hours. Available in cartridges of 1.5 and 3 ml (100 PIECES / ml) for NovoPen syringe pens. Combines the properties of short and medium duration insulin preparations (biphasic drug).

The disadvantages of the above funds is the inconvenience of use, as well as their inability to penetrate through the skin on their own.

Topical preparations containing insulin are not described.

искусственно создаваемые замкнутые везикулы, состоящие из одной (моноламеллярные) или многих (мультиламеллярные) липидных бимолекулярных мембран. Липосомы обычно получают из фосфолипидов, молекулы которых в водной среде самопроизвольно образуют замкнутые структуры. Лецитины (синоним: фосфатидилхолины, холин-фосфатиды) сложные эфиры аминоспирта холина и диглицеридфосфорных (фосфатидных) кислот, являются важнейшими представителями фосфолипидов (см. Интернет www.dic.academic.ru).In medicine, liposomes are used as carriers of biologically active substances through the skin. The assortment of liposome drugs contains ointments, creams and gels for the treatment of various diseases. Liposomes (Greek lipos fat + $$s\text{ō}matel\mathrm{about})$$

artificially created closed vesicles consisting of one (monolamellar) or many (multilamellar) lipid bimolecular membranes. Liposomes are usually obtained from phospholipids, the molecules of which in an aqueous medium spontaneously form closed structures. Lecithins (synonym: phosphatidylcholines, choline phosphatides) esters of the amino alcohol choline and diglyceride phosphoric (phosphatidic) acids are the most important representatives of phospholipids (see Internet www.dic.academic.ru).

The well-known Essaven ™ gel, which includes: escin, "essential" phospholipids and heparin sodium salt and is used for phlebitis, thrombophlebitis and hemorrhoids (Mashkovsky MD Medicines. - 15th ed., Revised., Rev. And add. - M.: New Wave, 2006. - S.461-462).

From RU 2188004 C2 (WELFIDE CORPORATION), 08/27/2002, it is known to use hydrogenated lecithin in a pharmaceutical composition for the treatment of hydrogenated lecithin and soya lecithin (p. 4, last paragraph).

From US 7,314,859 A, a composition and method for reducing the risk of hypoglycemia caused by insulin and a diabetic patient undergoing a course of insulin therapy comprising administering glucagon to a patient is known. Glucagon is in liposomal form. On p.17 of the description of US 7314859 A describes the administration of insulin transdermally (topically in the form of a cream or lotion). On p.11 US 7314859 And it is indicated that the pharmaceutical composition may include pharmaceutically acceptable excipients and carriers. The difference between the claimed invention from US 7314859 A is that the composition comprising insulin further comprises liposomes.

From RU 2302857 C2 (Tromsdorf GMBH UND KO.KG ARTSNAIMITT EL) (description, p.8 and 9), purified water is known as a solvent for adhesives, and polyacrylamide is a suitable adhesive for adhesives.

From US 2009/0022784 A1 (KENTARO KOGURE ETAL), 1/22/2009 (formula, example 1, description, paragraphs, [0003], [0006], [0012], [0072], [0073], [0074], [ 0086], [0093]), a pharmaceutical composition for interdermal administration is described comprising insulin and pharmacologically acceptable carriers or excipients, in particular antiseptics (preservatives), as well as liposomes. The difference between US 2009/0022784 A1 and the claimed invention is that the claimed invention uses liposomes containing hydrogenated lecithins in combination with cholesterol.

From US 7,128,909 A, administration of insulin by mixing with phospholipids in the form of liposomes into the lung is known.

From US 20070141136 a composition is known comprising liposomal insulin and phosphatidylcholine with cholesterol.

Pharmaceutical compositions containing topical insulin and liposomes in the form of biofilms are not described.

Thus, it is an object of the present invention to provide a topical pharmaceutical composition containing insulin and associated liposomes containing hydrogenated lecithins in combination with cholesterol, in the form of a biofilm, having rapid penetration through the skin, as well as the ability to lower glucose levels in blood.

According to the present invention, there is provided a topical pharmaceutical composition comprising insulin and pharmaceutically acceptable carriers or excipients, characterized in that it further includes insulin-bound liposomes.

As a preferred embodiment of the claimed invention, a pharmaceutical composition in the form of a biofilm is provided, which has the following composition, wt.%:

insulin 0.004-0.04 liposomes containing hydrogenated lecithins in combination with cholesterol 0.01-20.0 polyacrylamide 0.5-10.0 preservative 0.05-1.0 demineralized water 68.96-99.436

The technical result of the present invention is to obtain a pharmaceutical composition based on insulin and liposomes, with rapid penetration through the skin, as well as the ability to reduce blood glucose. Ease of use and ease of dispensing are additional benefits.

The pharmaceutical composition of the present invention is usually prepared by conventional methods using solid or liquid pharmaceutically acceptable carriers or excipients selected from emulsifiers, dispersants, preservatives, flavorings, pH adjusters, polymer carriers and other excipients that are suitable for the preparation of compositions for topical use. The pharmaceutical composition of the present invention can be prepared in the form of eye drops, patch, gel, cream, ointment and the like.

The rapid penetration through the skin is due to the binding of insulin to liposomes containing hydrogenated lecithins in combination with cholesterol. The structures and mechanism of the formation of liposome-insulin complexes are almost not described. Apparently, at the first stage, the complex arises due to hydrophobic interactions between the hydrophobic "tails" of lecithin and non-polar residues or domains of insulin. The second stage is similar to polymer-induced micelle formation. At this stage of binding, the insulin molecule unfolds, which makes hydrophobic groups of insulin located inside the native globule accessible for interaction with lecithin. Thus, insulin gradually becomes disordered tangles. In this case, to describe the complex of insulin with liposomes, we use the model of the “pearl necklace” structure adopted for synthetic polymers: a garland of small globular micelles that decorates the polypeptide chain.

The present invention is illustrated by the following examples.

According to clause 10.7.4.3 (3) and 10.7.4.5. (3) The administrative regulations for the characterization of the compositions use the qualitative composition (ingredients), the quantitative composition (content of ingredients) in the examples given, the content of each ingredient is indicated in such a unit value that is within the range of values indicated in the claims (when expressing the quantitative content in the formula percent of the invention (by weight or volume), the total content of all the ingredients indicated in the example is 100%.

EXAMPLE 1

The pharmaceutical composition in the form of eye drops based on insulin and liposomes containing hydrogenated lecithins in combination with cholesterol, has the following composition:

insulin 0.004 hydrogenated liposomes lecithins in combination with cholesterol 0.01 polyacrylamide 0.5 preservative 0.05 demineralized water 99,436

The specified composition is prepared according to the following method. In demineralized water are mixed: insulin, liposomes, emulsifier and preservative. The resulting mixture is homogenized and vacuum.

EXAMPLE 2

The pharmaceutical composition in the form of a patch based on insulin and liposomes, containing hydrogenated lecithins in combination with cholesterol, has the following composition:

insulin 0.04 liposomes containing hydrogenated lecithins in combination with cholesterol 20.00 polyacrylamide 10.0 preservative 1.00 demineralized water 68.96

The specified composition is prepared as in EXAMPLE 1.

EXAMPLE 3

Study of a pharmaceutical composition with insulin and liposomes containing hydrogenated lecithins in combination with cholesterol, on the ability to quickly penetrate the skin and reduce blood glucose levels.

To this end, the ability of the rapid penetration into the skin of a composition of the present invention based on insulin and a control composition containing insulin without liposomes was compared. The tests were carried out on rabbits. Previously, rabbits were injected intravenously with 5% glucose solution and its initial level was determined by the method of rapid analysis on an Accuchek glucometer, which was 0.01 mmol / L. These compositions were applied to the inner surface of the rabbit's ear. Absorption was determined by the amount of insulin remaining on the skin of the rabbit 10 minutes after application of the compositions, and expressed as a percentage of the initial amount of insulin in the composition.

Research results: control composition - 50% of the remaining insulin, blood glucose 0.09 mmol / l; the composition of the present invention is 10% of the remaining insulin, the blood glucose content of 0.005 mmol / L.

Thus, the pharmaceutical composition according to this invention has the ability to quickly penetrate the skin, providing a more rapid manifestation of the therapeutic effect exerted by the active substances of the composition.

EXAMPLE 4

The study of the pharmaceutical composition with insulin and liposomes containing hydrogenated lecithins in combination with cholesterol, on the ability in ease of use and ease of dosing.

To this end, the ability in ease of use and ease of dosing of the composition of the present invention based on insulin and the control composition Actrapid NM Penfill ™ were compared. The tests were carried out on rabbits. Previously, rabbits were injected intravenously with 5% glucose solution and its initial level was determined by the method of rapid analysis on an Accuchek glucometer, which was 0.01 mmol / L. The composition of the present invention was introduced into the conjunctival sac of a rabbit eye. The control composition - Actrapid NM Penfill ™ was administered subcutaneously. Blood glucose was measured after 10 minutes, 1 hour, 8 hours and 10 hours.

Research results: control composition - blood glucose: after 10 minutes - 0.0095 mmol / l; after 1 hour - 0.005 mmol / l; after 8 hours - 0.006 mmol / l; after 10 hours - 0.0097 mmol / l, the composition of the present invention is the glucose content in the blood: after 10 minutes - 0.007 mmol / l; after 1 hour - 0.005 mmol / l; after 8 hours - 0.005 mmol / l; after 10 hours, 0.005 mmol. As follows from the data obtained after 10 hours after the application of the control composition, there is a need for reuse of the drug, since the glucose level returns to its original level, while when using the claimed composition it remains stably low.

Ease of dosing was assessed by the presence of side effects that occurred within a month of using the control composition and the composition of the present invention. When using the composition of the present invention for a month, side effects were absent. When using the control composition, dystrophy of the subcutaneous tissue and the formation of infiltrates were observed for a month.

Thus, the pharmaceutical composition according to this invention has the additional advantage of ease of use and ease, manifested in the form of a quick onset of the expected effect, reducing the number of doses of the drug and the absence of side effects.

Claims (1)

A topical pharmaceutical composition in the form of a biofilm containing insulin and pharmaceutically acceptable carriers or excipients, characterized in that it has the following composition, wt.%:
insulin 0.004-0.04 liposomes containing hydrogenated lecithins in combination with cholesterol 0.01-20.0 polyacrylamide 0.5-10.0 preservative 0.05-1.0 demineralized water 68.96-99.436