ITUB20155342A1 - COMPOSITION OF REVERSIBLE THERMOSENSITIVE SOLUTIONS-GEL MUCOADESIVE BASED ON COLLAGEN AND HYALURONIC ACID SALTS - Google Patents

Description

"COMPOSITION OF REVERSIBLE THERMOSENSITIVE GEL SOLUTIONS MUCO ADE SI VE BASED ON COLLAGEN AND HYALURONIC ACID SALTS"

The present invention relates to cosmetic, pharmaceutical compositions or thermosensitive medical devices comprising a poloxamer, collagen and hyaluronic acid or a pharmaceutically acceptable salt thereof and to their use in the treatment of irritated or injured mucosa and / or skin.

Aqueous solutions of polymers capable of transforming "in situ" into gel (insitu gel) as a result of variations in environmental conditions, such as temperature and / or pH, have in recent years been the subject of study in the biomedical, cosmetic and pharmaceutical fields (B Jeong et al. / Advanced Drug Delivery Review 64 (2012) 154-162).

In particular, the class of temperature-sensitive “in-situ gels” has been extensively studied.

On the market there are numerous polymers capable of giving a solution-gel transformation induced by temperature variations; among the best known polymers of this type we can list the N-isopropylacrylamide, the poly (ethylene oxide-b-propylene oxide-b-ethylene oxide), known as poloxamer and its analogues and the poly (ethylene glycol) / poly DL-lactic acid-co glycolic acid).

The polymer poly (ethylene oxide-b-propylene oxide-ethylene b-oxide) marketed under the name Pluronic (BASF) or Poloxamer (ICI) is a polyethylene-polypropylene glycol block copolymer, widely used as a non-ionic surfactant. Its aqueous solutions at particular concentrations show transition phases from solution to gel and vice versa with the variation of the temperature.

An example of transition phase change with consequent viscosity increase can be seen in an aqueous solution of Poloxamer P 407 at a concentration of 20% w / w in water at different temperatures:

Viscosity measured by Brookfield viscometer 10% Poloxamer P 407 concentrations in water show completely different behavior, without any change in transition

However, despite the excellent thermosensitivity characteristics, the poloxamer-based solutions show a limited mucoadhesive capacity.

Hoffman et al. have developed poly (acid acrylic) gpoloxamer compounds with important mucoadhesive abilities (A. S. Hoffman, G.Chen, Int. Pat. Appi. WO95 / 24430,1995).

Y.Yuan (Y.Yuan et al./International Journal of Pharmaceutics 430 (2012) 114-119) highlighted the same mucoadhesive limits of poloxamer solutions and developed thermosensitive formulations for rectal use containing nimesulide as the active ingredient, combining the poloxamer with mucoadhesive excipients such as sodium alginate or hydroxypropylmethyl cellulose (HPMC).

Historically polymers of natural origin have been used in both the pharmaceutical and food fields, such as gelatin (protein obtained from partial hydrolysis of collagen), agarose (extracted from algae). Important studies have also been carried out on chitosan (A.Chenite et al./Biomaterials 21 (2000) 2155-2161).

K.Y Cho et al. (K.Y. Cho et al. / International Journal of Pharmaceutics 260 (2003) 83-91) studied the poloxamer-hyaluronic acid adduct for use in ophthalmology (K.Y. Cho (K.Y. Cho et al. / International Journal of Pharmaceutics 260 (2003)) 83-91) A poloxamer chemically linked to hyaluronic acid by 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and N-hydroxylsuccinamide was used in this study.

It has now been found that thermosensitive “in situ-gel” based on compositions containing a poloxamer, collagen and hyaluronic acid have excellent mucoadhesive qualities as well as having moisturizing and soothing properties of skin and mucous membrane irritations. Furthermore, these “in-situ gels” are able to promote the healing of lesions of the skin and mucous membranes.

The present invention relates to a cosmetic, pharmaceutical or thermosensitive medical device composition comprising a poloxamer, collagen and hyaluronic acid or a pharmaceutically acceptable salt thereof.

The poloxamer used in the present compositions is preferably selected from the types of Poloxamer 407, 188 and 124; more preferably it is Poloxamer P 407 commercially obtainable from BASF under the trade name Kolliphor P 407.

The collagen may be native Type I collagen, more preferably it is marine collagen. Marine collagen (INCI name: Soluble Collagen) is obtained through an extraction process from fish skin. The extraction process was standardized in order to obtain reproducibility of the product between batch and batch. Below are the specifications of the marine collagen produced by the company Gattefosse (France) with data relating to the chemical and physical characteristics of six industrial batches produced by the French company:

Collagen of marine origin, when compared with bovine collagen, has a hydroxyproline content of 80 residual amino acids per 1000, the same peptide subunit structure (Type I collagen) and the same elliptical structure.

Chemical-physical compatibility studies were conducted on aqueous solutions of Poloxamer P 407 with marine collagen; these studies have shown excellent compatibility both at room temperature and at 40 ° C.

The hyaluronic acid present in the composition can be in salified form, the sodium salt is particularly preferred. Hyaluronic acid or its salt has a molecular weight between 500,000 and 3 million Dalton, preferably between 600 and 2 million Dalton, particularly preferred is hyaluronic acid with a molecular weight of 1 million Dalton.

The poloxamer preferably has a concentration comprised between 15 and 35% w / w of the composition.

The collagen preferably has a concentration comprised between 0.5 and 5% w / w of the composition.

Hyaluronic acid or its pharmaceutically acceptable salt preferably has a concentration between 0.1 and 5% w / w of the composition.

The compositions can contain polyethylene glycol, preferably PEG 300, PEG 400, PEG 600, PEG1000, PEG1500, PEG 3350 and PEG4000 preferably at a concentration comprised between 0.5 and 10% w / w of the composition. Particularly preferred is polyethylene glycol 400 (PEG400).

Polyethylene glycol (PEG) 400, in percentages higher than 1%, allows to obtain formulations that are in the form of a solution at room temperature and gel at a body temperature of 37 ° C.

To ensure good patient compliance, the compositions of the invention must be medium-low viscosity solutions (between 2000 and 10000cps) at 25 ° C and be transformed into high viscosity gels (between 15,000 and 50,000cps) at body temperature ( 37 ° C).

The compositions may contain additives such as antioxidant agents, chelating agents and preservative / disinfectant agents.

A further object of the present invention are cosmetic, pharmaceutical compositions or medical devices further containing one or more dermofunctional ingredients or active ingredients in the pharmacological or cosmetic field, such as for example in the cosmetic field: pyrrolidon carboxylic acid, alpha and beta hydroxy acids, d-chiro-inosinol , papain, trehalose, azelaic acid etc.

A further object of the present invention is the pharmaceutical or cosmetic use of the compositions of the present invention in the treatment of irritated or injured mucosa and / or skin.

The compositions of the invention show excellent chemical-physical characteristics in comparison with the corresponding compositions containing other known mucoadhesive agents.

The table shows some tests relating to combinations of poloxamer / marine collagen / mucoadhesive agent. Lot P16 / 1 was made using sodium alginate as muco-adhesive, lot P16 / 2 hydroxypropyl methyl cellulose (Methocel - Dow), lot P16 / 3 polycarbophyl Noveon AA-1 - Lubrizol, lot PI 6/4 Acid hyaluronic and batch PI 6/5 Medium molecular weight chitosan Sigma Aldrich. The quantities expressed in the table refer to weight / weight percentage.

Table:

Lot n.

P16 / 1 P I 6/2 PI 6/3 PI 6/4 PI 6/5 Poloxamer P

20.0% 20.0% 20.0% 20.0% 20.0% 407

Collagen

5.0% 5.0% 5.0% 5.0% 5.0% Marine

Sodium alginate 1.0% - - - -

Hydroxypropyl

methyl cellulose

- 1.0% - - - Methocel

Dow

Polycarbophyl

- - 1.0% - -Noveon AA1

Acid

Hyaluronic Na

- - - 1.0% - (p.m .. = l Mio

Dalton)

Chitosan a

medium weight

- - - - 1.0% molecular - Sigma Aldrich

Purified water q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. at 100%

Of the tests described above (lots P16 / 1, P16 / 2, P16 / 3, P16 / 4 and P16 / 5) the Poloxamer / Collagen / hyaluronic acid combination (test P16 / 4) turns out to be the formulation with excellent chemical-physical / mucoadhesive characteristics .

Some examples of formulations are described below:

Example no

Cold manufacturing method

lot PI 6/11

x 100 gr x 1 kg Poloxamer P 407 20.00 200

Marine Collagen 5 50

Hyaluronic Acid Na (1 million

Dalton) 1.00 10

Polyethylene glycol 400 (PEG

400) 2 20

silver sulphadiazine 0.5 5

Purified water q.s. to 100 g 715

Preparation method:

Phase 1#. In a glass container the useful capacity of 1 liter was

added a weighed quantity of purified water.

Step 2 #. Poloxamer was added and dispersed to the water of phase 1 #

P 407. The dispersion was stirred slowly and the container placed in a

ice bath bringing the temperature around 5 ° C to complete

dissolution of the poloxamer.

Step 3 #. To the poloxamer solution obtained in step 2 # was

added and dissolved the polyethylene glycol, Once dissolved, the temperature

of the solution was reported at 25 ° C.

Step 4 #. In phase 3 # the following were added in order: marine collagen,

hyaluronic acid Na, silver sulfadiazine.

Step 5 #. The solution was brought to homogeneity, then filtered

through an 8 mm Sartorius cellulose nitrate filter membrane

Microns.

Step 6 #. The solution thus obtained was divided into polyethylene pipes

10 ml which have been heat sealed.

Example n. 2

Hot manufacturing method

lot P16 / 12

x 100 gr x 1 kg

Poloxamer P 407 20.00 200

Marine Collagen 5 50

Hyaluronic Acid Na (1 million

Dalton) 1.00 I.

Polyethylene glycol 400 (PEG

400) 2 20

methyl p-hydroxybenzoate 0.15 1.5

propyl p-hydroxybenzoate 0.05 0.5

Purified water q.s. to 100 g 718 g

Preparation method:

Phase 1#. In a glass container the useful capacity of 1 liter was

added a weighed quantity of purified water and the temperature was raised

at about 85 ° C.

Step 2 #. Α1Γ water from step 1 # was added and dissolved below

vigorous stirring of methyl p-hydroxybenzoate and propyl p-hydroxybenzoate;

then, once the two preservatives had been dissolved, it was added and dissolved

the Poloxamer P 407.

Step 3 #. To the solution thus obtained in step 2 # was added and

of dissolved polyethylene glycol. The solution thus obtained was cooled to

room temperature.

Step 4 #. In phase 3 # were added in order: marine collagen and

hyaluronic acid Na.

Step 5 #. The solution was stirred to homogeneity and then filtered up

an 8 Microns Sartorius cellulose nitrate filter membrane.

Step 6 #. The solution thus obtained was divided into polyethylene pipes

10 ml which have been heat sealed.

Claims (15)

CLAIMS 1. A cosmetic, pharmaceutical or thermosensitive medical device composition comprising a poloxamer, collagen and hyaluronic acid or a pharmaceutically acceptable salt thereof. The cosmetic, pharmaceutical composition or medical device according to claim 1 wherein the poloxamer is Poloxamer P 407. The cosmetic, pharmaceutical composition or medical device according to claim 1 or 2 wherein the collagen is type I of marine origin. 4. The cosmetic, pharmaceutical composition or the medical device according to each of the preceding claims in which the hyaluronic acid has a molecular weight between 600 Dalton and 2 Mio Dalton. The cosmetic, pharmaceutical composition or medical device according to claim 1 wherein the poloxamer is Poloxamer P 407, the collagen is marine type I collagen and the hyaluronic acid is in the form of sodium salt and has a molecular weight of 1 My dalton. The cosmetic, pharmaceutical composition or medical device according to each of the preceding claims in which the poloxamer has a concentration comprised between 15 and 30% w / w of the composition. 7. The cosmetic, pharmaceutical composition or medical device according to each of the preceding claims in which the collagen has a concentration of between 0.5 and 5% w / w of the composition. 8. The cosmetic, pharmaceutical composition or the medical device according to each of the preceding claims in which the hyaluronic acid or its pharmaceutically acceptable salt has a concentration between 0.1 and 5% w / w of the composition. The cosmetic, pharmaceutical composition or medical device according to each of the preceding claims further containing polyethylene glycol. The cosmetic, pharmaceutical composition or medical device according to claim 9 wherein the polyethylene glycol has a molecular weight of between 300 and 4000. The cosmetic, pharmaceutical composition or medical device according to claim 9 or 10 wherein the polyethylene glycol has a concentration of between 0.5 and 10% w / w of the composition. The cosmetic, pharmaceutical composition or medical device according to each of the preceding claims further containing additives such as antioxidant agents, chelating agents and preservative / disinfectant agents. 13. The cosmetic, pharmaceutical composition or medical device according to each of the preceding claims further containing one or more dermofunctional or pharmacologically active principles. The pharmaceutical composition or medical device according to each of the preceding claims for use in the treatment of irritated or injured mucosa and / or skin. 15. Use of the cosmetic composition according to each of claims 1 to 13 for the treatment of irritated mucosa and / or skin.