ITMI20111239A1 - ORAL AND TOPIC COMPOSITIONS INCLUDING CRITHMUM MARITIMUM EXTRACTS AND EXTRACTIVE DERIVATIVES CONTAINING CARNOSIC ACID AND CARNOSOL FOR THE PREVENTION AND TREATMENT OF PANNICULAR-LOBULAR HYPERTROPHY AND LOCALIZED ADIPOSITY - Google Patents

Description

â € œORAL AND TOPICAL COMPOSITIONS INCLUDING CRITHMUM MARITIMUM EXTRACTS AND EXTRACTIVE DERIVATIVES CONTAINING CARNOSIC AND CARNOSOL ACID FOR THE PREVENTION AND TREATMENT OF PANNICULAR-LOBULAR HYPERTROPHY AND LOCALIZED ADIPOSITIESâ €

The present invention relates to oral and topical compositions comprising Crithmum maritimum extract and extractive derivatives containing carnosic acid and carnosol, for the prevention and treatment of panniculo-lobular hypertrophy (cellulite) and localized adiposity.

State of the art

The subcutaneous tissue, also known as panniculus adipose, is a â € œfibro-fatâ € tissue placed between the dermis and the muscle fascia whose main task is to insulate the deep tissues against thermal dispersion and to protect the epithelia and connective tissues from traumatic insults. This tissue is composed of three main elements: adipocytes, fibrous trabeculae and blood vessels. Adipocytes are organized in units of several cells called lobules, each lobule is separated by a fibrous septum and has its own blood vessels, lymphatics and nerves. Each adipocyte is then surrounded by a dense network of capillaries.

As is well known, the subcutaneous tissue can be involved in what are generally referred to as lipodystrophies. These, while not presenting the typical problems of serious pathologies (lipoblastoma, hibernoma, lipoma, angiolipoma, liposarcoma, acute and chronic panniculitis), are often a source of significant aesthetic problems that can negatively influence the psychology of the subject.

The most frequent lipodystrophy is undoubtedly panniculo-lobular hypertrophy. This, unlike generalized adiposity, is present only in some sites (axillary pillars, mammary area, abdomen, buttocks, pubis, trochanteric area, inner face of the knee and perimalleolar area) and can occur in patients who do not have other notes of obesity. This adipose dystrophy is known to the patient with the term â € œcelluliteâ €.

The genesis of panniculo-lobular hypertrophy is currently the subject of numerous studies and, to date, has not yet been fully clarified.

According to some researchers, this lipodystrophy would be generated by a circulatory defect of the septal vessels which, inducing an edematous state, would lead to a sclerosis of the septa and finally to an altered metabolism of the adipocytes.

However, there is a second theory according to which this lipodystrophy originates from a trophic response of the adipocyte to endocrine and / or neuroendocrine stimuli and vascular damage, edema and fibrosis are caused by compression due to the hypertrophy of the lobule itself.

Therefore, since this disorder is the expression of a real histoangiopathy linked to disorders of the vascular-connective trophism, only a therapy that addresses circulatory problems, sclerosis of the septa and, above all, the alteration of local metabolic phenomena (adipocytic ) has the greatest chance of success. To better combat the adipocyte problem, medicinal plants or mixtures of these plants were investigated, capable of reducing the progression from preadipocyte to adipocyte, a stage in which it is difficult to intervene to try to obtain localized lipolysis.

Description of the invention

It has now been surprisingly found that an association of Crithmum maritimum extract and extracts containing carnosic acid and carnosol is able to effectively counteract the progression from preadipocyte to adipocyte and to favor the de-differentiation of adipocyte to preadipocyte phases, and it therefore constitutes a valid means for the treatment and / or prevention of cellulite and localized adiposity.

The invention therefore relates to compositions comprising: a) Crithmum maritimum extract e

b) extracts containing carnosic acid and carnosol,

for the treatment and / or prevention of cellulite and localized fat deposits.

According to a preferred aspect, the extracts contained in the compositions of the invention will be food grade extracts, ie extracts obtained using solvents compatible with food use (water, ethanol, etc.). According to a preferred aspect of the invention, the extracts containing carnosic acid and carnosol will be extracted from rosemary, sage, oregano.

The compositions of the invention can be administered systemically (orally) or topically, obviously by suitably adapting the dosages according to the chosen route of administration.

More specifically, the oral compositions will contain the active components within the following dose ranges per unit dose:

a) Crithmum maritimum extract: between 5 and 500 mg / dose, preferably 100 mg / dose;

b) extracts containing carnosic acid and carnosol: in quantities such as to provide an intake of carnosic acid between 10 and 500 mg / dose, preferably 200 mg / dose.

The topical compositions will contain the active components within the following weight percentage ranges:

a) Crithmum maritimum extract: between 0.001 and 10%, preferably 2%;

b) extracts containing carnosic acid and carnosol: in quantities such as to provide a contribution of carnosic acid between 0.001 and 10%, preferably 0.2%.

According to a preferred aspect, the compositions of the invention may also contain extractive derivatives, with a merely complementary action, from Centella asiatica and medicinal plants characterized by their content in coumarins (Melilotus officinalis, Aesculus hyppocastanum).

Description of the main assets

Crithnum maritimum, also called sea fennel, belongs to the Apiaceae family and grows as a shrub especially near the sea coasts. For some time the extractive derivatives from this plant (both aqueous and alcoholic) have been biologically investigated, by virtue of their evident antioxidant action, linked to the strong presence of phenols and phenolic derivatives (Meot-Duros L et al. Plant Physiol Biochem. 2009 Jan ; 47 (1): 37-41), and of a moderate antibacterial and cytotoxic action (Meot Duros L et al. Food Chem Toxicol. 2010 Feb; 48 (2): 553-7).

We surprisingly found that Crithnum maritimum extracts obtained with food solvents are characterized by the ability to favor the de-differentiation of adipocyte cultures into preadipocyte cell forms. Our data show how the addition of the preparation to normal culture media favors the transition to pre-adipocyte phases with percentages ranging from 30 to 60% of the culture (with a differentiation in the control cultures between 1 and 10%). This result appears even more evident when plant extracts (rosemary, sage, oregano) obtained with food solvents and characterized by the presence of carnosic acid and carnosol are added to the crop. In this case, in fact, the culture differs towards pre-adipocyte forms for values corresponding to 80% of the culture (in adipocyte cultures, the extractive derivatives containing carnosic acid and carnosol do not cause changes towards adipocyte phases to a different extent than do the check). This remarkable and surprising increase in de-differentiation towards pre-adipocyte forms can be ascribed to a synergy mechanism that is established between the two different components of the compositions of the invention.

Carnosic acid is a diterpene that can be easily isolated from various food grade extracts of plants such as common sage, rosemary, oregano. This diterpene, as well as its carnosol derivative, is endowed with an important antioxidant profile which makes it the ideal choice as a food antioxidant in some situations.

It is also an excellent competitive inhibitor of human lipase. In this regard it demonstrates an IC50 of 12 microM and an inhibition K of about 5 microg / mL. Its primary intrafoliate metabolite, carnosol, is even more potent with an IC503 times higher (4 microM). This action, in vivo, is expressed and manifests itself not only as a reduction of circulating triglycerides, generated by the action of the digestive lipase and dietary triglycerides, but also through a partial anti-obesity effect.

The extraction of carnosic acid from sage and its inhibitory effect on pancreatic lipase activity are described, for example, in Bioorg Med Chem Lett. 2004 Apr 19; 14 (8): 1943-6. Its action of inhibition of progression from pre-adipocyte to adipocyte in mouse cell cultures has also been described (Takahashi et al. Biochem Biophys Res Commun. 2009 May 8; 382 (3): 549-54). The same phenomenon is not observed, however, using cultures of human preadipocytes, unless the culture medium (RPMI and FCS at 5%) does not contain, in addition to the derivative, also the extract of C. maritimum (see data above described).

Description of ingredients with complementary action

Gotu kola

Centella asiatica, also known as Hydrocatyle asiatica, belongs to the Apiacea family. Centellaâ € ™ s therapeutic action was already known centuries ago: used for skin care, its healing properties were soon highlighted. As often happens, scientific research later justified its use, having recently highlighted its lymphatic drainage action and, above all, its stimulating properties for the production of collagen.

The active substances of the plant are known with the term â € œtriterpene fractionâ €. By means of an extremely complex purification process it is possible to obtain, starting from the aerial part of Centella asiatica, a mixture of this fraction composed as follows: madecassic acid (30%), Asian acid (30%), asiaticoside (40%).

These substances, known from a toxicological point of view, recognize the fibroblast as the main target and, interacting with it, perform their functions. In fact, it has been shown that these triterpenes accelerate the uptake and metabolism of Lysine and Proline (two essential amino acids for the final structure of collagen), increase the synthesis and release of tropocollagen and stimulate the turnover of mucopolysaccharides. acids in the connective tissue.

One of the problems of panniculo-lobular hypertrophy is undoubtedly the sclerosis of the septa caused by a deficit in the turnover of collagen fibers. It therefore appears evident that the use of a mixture of substances capable of increasing this turnover is fundamental for obtaining satisfactory results. In fact, the usefulness of the triterpene fraction of Centella asiatica in the prevention and treatment of cellulite has been repeatedly demonstrated in clinical studies starting from 1983. In these studies, the clinical, histological and instrumental evaluation made it possible to ascertain that in In 70-80% of cases, the treated subjects presented an improved vascular-connective tissue tropism, a decrease in the diameter of the thigh and a reduction in subjective signs such as the sensation of heaviness and pain on pinching.

According to a preferred aspect of the invention, the entire triterpene fraction of Centella asiatica will be used in a complexed form with a phospholipid, in particular a soy phospholipid, such as diasteroylphosphatidylcholine. These forms complexed with phospholipids, called phytosomes, are described for example in the European patent EP 441 279 and improve the pharmacokinetics and bioavailability of the Asian and madecassic acids and of the Asiaticoside.

Toxicological studies performed on animals and pharmacokinetics on humans have in fact demonstrated the absence of toxicity and greater absorption of the ingredient administered as a phytosome compared to the ingredient administered in free form (both for local and systemic use ).

Melilotus officinalis

One of the aspects that most characterizes panniculo-lobular hypertrophy is the presence of localized edema in the subcutis. The origin of this edema is still quite controversial (see introductory note) and currently it is still debated whether to consider it a cause rather than the consequence of damage. On the other hand, there is agreement in attributing most of the edematous symptoms to an altered permeability of the vessel wall. The exchanges of liquids that normally occur between the lumen of a capillary and the extravasal connective matrix are in fact made possible by the fenestration present on the endothelial walls. This fenestration also has the task of maintaining a certain balance between the volumes of liquid that extravasate and those that are reabsorbed thanks to the drainage of the lymphatic vessels. When this balance is lacking, as in the case of panniculo-lobular hypertrophy, tissue edema occurs.

Precisely to deal with this problem, it is possible to include the standardized extract of Melilotus officinalis in the formulation of the product in question. Thanks to the presence of some active ingredients such as melilotin (3,4 dihydrocumarin), melilotic acid (hydroxycoumarinic acid), Melilotus officinalisside (melilotin glucoside) and some flavonoids with vitamin P-like activity, it is possible to proven effective in increasing capillary resistance, decreasing vascular permeability, promoting venous return and increasing lymphatic circulation. These activities have been demonstrated in various animal models (rabbit, rat) in which changes in capillary permeability were induced by various inflammatory stimuli (adrenaline, histamine, formaldehyde, propylene glycol, albumin).

It is also possible to find coumarin structures also in derivatives obtained from horse chestnut bark (nominally esculoside). These coumarins have the same properties as those found in Melilotus officinalis and their use in the proposed formulations must be seen as interchangeable.

In addition to the aforementioned ingredients, the oral formulations may also contain products known to have a diuretic (ortosiphon, lespedeza, birch, thyme) or thermogenic (camellia, capsicum, cinnamon) effect. In the case of topical preparations, the formulations may also contain ingredients such as extracts and derivatives from alga, derivatives of horse chestnut (aescin, esculoside), derivatives of gelidum, derivatives of G. biloba and herbal or non-herbal derivatives, however characterized by the presence of methylxanthines .

The compositions of the present invention will be formulated in a manner suitable for oral or topical administration, prepared according to conventional methods well known in the pharmaceutical technique, such as those described in â € œRemingtonâ € ™ s Pharmaceutical Handbookâ €, Mack Publishing Co., N.Y., USA, using conventional excipients.

The preparations for local application can be formulated in gel, cream, ointment, emulsions, micro-emulsion, concealer. Preparations for oral administration may also be developed to promote

time and / or pH-dependent scheduled transfer of assets. These last

formulas can be developed in tablets, even multi-layer, capsules

and granulates (including gold-soluble), syrups, liquids and their emulsions, as well as

form of sub-lingual spray.

Some examples of formulations of the invention are reported below.

EXAMPLE 1 - ORAL FORMULATION IN TABLETS

Ingredient Quantity (in mg) Rosemary

e.s. tit. 10% in Carnosic acid 200 mg equal to carnosic acid 20 mg Crithmum maritimum 100 mg Betula alba leaves tit. 2.5 in hyperoside 200 mg Orthosiphon e.s tit. 0.2% in sinesetin 75 mg Gotu kola d.e. 50 mg tit to 20% in total triterpenes

Melilotus officinalis d.e. tit to 20% in coumarin 50 mg

EXAMPLE 2 - ORAL FORMULATION IN CAPSULES

Ingredient Quantity (in mg) Rosemary

e.s. tit. 10% in Carnosic acid 100 mg equal to carnosic acid 10 mg Crithmum maritimum 100 mg Betula alba leaves tit. 2.5 in hyperoside 100 mg Orthosiphon e.s tit. 0.2% in sinesetin 75 mg Gotu kola d.e. 50 mg tit to 20% in total triterpenes

Melilotus officinalis d.e. tit to 20% in coumarin 50 mg

EXAMPLE 3 - ORAL FORMULATE IN GRANULES

Ingredient Quantity (in mg) Rosemary

e.s. tit. 10% in Carnosic acid 200 mg equal to carnosic acid 20 mg Crithmum maritimum 100 mg Betula alba leaves tit. 2.5 in hyperoside 200 mg Lespedeza extract 100 mg Centella asiatica d.e. 50 mg tit to 20% in total triterpenes

Melilotus officinalis d.e. tit to 20% in coumarin 50 mg

EXAMPLE 4 - LIQUID FORMULATE

Ingredient Quantity (% by weight) Rosemary

e.s. tit. 10% in Carnosic acid 100 mg equal to carnosic acid 10 mg Crithmum maritimum 100 mg Birch sap 300 mg Orthosiphon e.s tit. 0.2% in sinesetin 75 mg Gotu kola d.e. 50 mg tit to 20% in total triterpenes

Melilotus officinalis d.e. tit at 20% in coumarin 50 mg EXAMPLE 5 - TOPICAL FORMULATE IN GEL

Ingredient Quantity (% by weight) Rosemary

e.s. tit. with 10% carnosic acid

equal to 0.5% carnosic acid Crithmum maritimum 2.0% Sphacelaria alga 0.5% Caffeine 3.0% Gelidium cartilagineum 2.0% Escin 0.3%

EXAMPLE 6 - TOPICAL FORMULATE IN GEL

Ingredient Quantity (% by weight) Rosemary

e.s. tit. with 10% carnosic acid

equal to carnosic acid 0.2% Crithmum maritimum 2.0% Sphacelaria alga 0.5% Caffeine 2.0% Gelidium cartilagineum 2.0% Escin 0.5%

EXAMPLE 7 - TOPICAL FORMULA IN CREAM

Ingredient Quantity (% by weight) Rosemary

e.s. tit. with 10% carnosic acid

equal to 0.5% carnosic acid Crithmum maritimum 2.0% Fucus vesciculosus 0.5% Camellia sinensis 2.0% Gelidium cartilagineum 2.0% Esculoside 0.3%

Claims (7)

CLAIMS 1. Oral or topical compositions comprising: a) Crithmum maritimum extract e b) extracts containing carnosic acid and carnosol. for the treatment and / or prevention of cellulite and localized fat deposits. 2. Oral compositions according to claim 1, containing the active components within the following dosage ranges per unit dose: a) Crithmum maritimum extract: between 5 and 500 mg / dose; b) extracts containing carnosic acid and carnosol: in quantities such as to provide an intake of carnosic acid between 10 and 500 mg / dose. 3. Oral compositions according to claim 2, containing the active components in the following dosages per unit dose: a) Crithmum maritimum extract: 100 mg / dose; b) extracts containing carnosic acid and carnosol: in quantities such as to provide an intake of carnosic acid of 200 mg / dose. 4. Topical compositions according to claim 1, containing the active components within the following weight percentage ranges: a) Crithmum maritimum extract: between 0.001 and 10%; b) extracts containing carnosic acid and carnosol: in quantities such as to provide a contribution of carnosic acid between 0.001 and 10%. 5. Topical compositions according to claim 4, containing the active components in the following percentages by weight: a) Crithmum maritimum extract: 2%; b) extracts containing carnosic acid and carnosol: in quantities such as to provide a 0.2% contribution of carnosic acid. 6. Compositions according to the preceding claims, further comprising plant extracts selected from the group of extracts of Centella asiatica, Melilotus officinalis, and Aesculus hyppocastanum. 7. Compositions according to the preceding claims, for use in the prevention and treatment of panniculo-lobular hypertrophy and localized adiposity. Milan, 4 July 2011