JP2003519093A - Colloidal ingredients for cosmetic correction - Google Patents

Abstract

  (57) [Summary] The present invention relates to methods and chemical components that are used for the purpose of correcting dermatological disorders, and in particular, for correcting dermatological defects, for example, for wrinkling, nasolabial folds, lip reduction and contouring, keratinization. Ingredients administered to humans to correct skin aging spots and alterations associated with ailments, enlarged cheeks, reduced earlobes, depression in the buttocks, natural aging or by the action of external agents such as sunlight. .

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to a method and a chemical composition used for the purpose of correcting skin diseases, and in particular, for correcting wrinkles, nasolabial folds and lips to correct dermatological defects. Humans to correct shrinking and contouring, keratoses, increased cheeks, decreased ear lobes, depressed buttocks, aging spots and deterioration of the skin due to age-related or external action factors such as sunlight. To the ingredients administered to.

BACKGROUND OF THE INVENTION Human skin, when intact, is a barrier to many natural and synthetic substances. While cosmetics and pharmaceuticals may be pharmaceutically effective by oral or other systemic administration, many currently known drugs are of little or no effect when applied topically to the skin.

The topical efficacy of a drug depends on two main factors: (a) the biological efficacy of the active ingredient in the topical formulation and (b) the absorption, penetration and diffusion of the active ingredient in the treated skin area. .

Wrinkles can form due to skin damage from aging and / or sunlight. Most of the fine wrinkles on the face are due to natural or congenital aging, while deep wrinkles on the face are due to acne on the skin or the action of sunlight. Despite the fact that the true mechanism of wrinkle formation has not been elucidated, not only atrophy of the dermis and reduction of adipose tissue but also a decrease in the number and diameter of elastic fibers in the papillary dermis are responsible for the visible formation of fine wrinkles. It is recognized that there is.

Histopathological and electron microscopy studies have shown that excessive attachment of abnormal elastic substances in the epithelium and thickening of the skin cause deep wrinkles.

Although the skin is not physiologically important if not perfect, it can nevertheless cause serious physiological problems to people with defective skin. In many societies, people with defective skin do not like to show signs of aging, and wrinkles have been a major concern of people since ancient times.

The explants and implants currently available to correct depressions and physical defects have long been used and have proven difficult to handle, complex and defective.

In the state of the art, it is known to use various media for the purpose of correcting aesthetically imperfections. Bovine collagen is one such medium. Bovine collagen is a long-chain protein with a high risk of allergies,
It is passive in the transport of viruses such as bovine encephalitis, or also leads to future complications such as inflammatory processes, severe allergic events and predominantly autoimmune diseases (eg rheumatoid arthritis).

Liquid silicon is also known in the state of the art as another medium, but liquid silicon produces silicon granulomas and is not fully licensed by the authorities for medical use. .

Among the typical treatments for removing wrinkles, a brief description of dressing surgery is given. Cosmetic surgery presents several deficiencies such as wrinkling while leaving orthopedic scars on the skin, and it is often very difficult to hide such scars.

Another method of removing wrinkles is to use implants made from various materials.
For example, the Brazilian patent application PI 9503052-2, filed June 22, 1995 in the name of Miguel Marques Oliveira Jr, is hereby incorporated by reference. PI 9503052-2
Describes inanimate material surgical implants for augmentation and / or dressing modeling for forehead dressing determination. The prosthesis formed according to PI 9503052-2 is made of semi-hard solid silicon and is implanted in the forehead to correct defects, but this implant has many drawbacks including rejection and allergic reactions. Yes, the effect is limited to a limited range.

Brazilian Patent PI 8907235-9 assigned to Dr. Martin Lemperle on September 24, 1996
Refers to ingredients used in cosmetic medicine, which patent is hereby incorporated by reference. PI 8907235-9 describes the ingredients that fill in imperfections at the skin level. The components are polymethylmethacrylic acid (poly
methylmetecrilate) It uses micro balloons. The suspension medium comprises water, alcohol or a mixture thereof, or a surfactant such as Tween 80. However, this component is not stable and must always be kept frozen under strict storage conditions.

It is disclosed here that dermatological defects can be corrected without presenting the drawbacks associated with the state of the art.

SUMMARY OF THE INVENTION The present invention relates to methods and chemical components, particularly those used for the treatment of skin diseases, but which may also be used in other reconstructive surgery.

The main object of the present invention is that the preservation is practical, it does not need to be frozen, it is easy for the doctor to handle, it does not induce allergies or infectious diseases, and it is not carcinogenic.
eous), biocompatible, and low cost to provide components and methods having a complete combination of materials.

The main object of the present invention is to correct skin diseases such as wrinkle removal, nasolabial fold, lip shrinkage and contouring, keratosis, cheek enlargement, ear lobe reduction, buttocks depression, addition. It is an object of the present invention to provide a novel method and component for the correction of age-related spots and deterioration of the skin, which are related to age or by the action of external factors such as sunlight.

The components of the present invention can be utilized by injecting the components just below the area of skin where dermatological defects have occurred.

The ingredients of the present invention are virtually not absorbed by the human body and therefore are not rejected by humans or cause an allergic reaction.

Furthermore, the method of injecting a component according to the invention is easily and reliably available and does not require the patient to be anesthetized.

BEST MODE FOR CARRYING OUT THE INVENTION The component according to the present invention comprises a colloidal formulation called magnesium-containing carboxyglyconic acid hydrolactic acid.

[0021]   This formulation (A) about 5-70 g of a cellulose ether, (B) About 800 to 1300 ml of Ringer's lactic acid, (C) about 2 to 20 g of EDTA, (D) 20-120 ml of calcium glycolate, (E) optionally containing 0-10% xylocaine.

[0022]   The amounts of ingredients can be varied in any range until the proper viscosity is obtained.

Among the cellulose ether polymers, those having a low molecular weight or a low viscosity are preferable. Examples include hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, methyl cellulose and / or ethyl cellulose.

Ringer's lactic acid is an inert solution containing sodium chloride, potassium chloride, dihydrated calcium chloride, sodium lactate and water.

Trihydrated ethylenediamin trihydrate
EDTA, called e trisodium tetraacetate), is chemically active and therefore
Apart from the fact that it does not decompose in other substances, it does not react with other chemical substances in the components of the present invention or in the human body, and is therefore suitable for pharmaceutical use. Chemical _{formula, C 10 -H 16 -N 2 -O} 8.
It is 3Na.

The process of preparing the components of the present invention involves mixing all the components in a stainless steel tube,
The process of stirring is included. The mixing temperature can be varied between 30 ° C and 70 ° C, but is preferably around 50 ° C and mixed for about 3 hours.

[0027]   This process is repeated two more times until the final product is obtained.

[0028]   A colloidal solution is obtained in this process.

Next, the resulting colloidal product is filtered and the pH value is verified to determine about 6.0.
As shown.

[0030]   The product density will show a value equal to 1.

The resulting product, the magnesium component-containing carboxyglyconic acid hydrolactic acid, already has the required pH and density and is ready for diffusion when injected into a 20 ml vial and labeled.

Animal experiments were conducted to illustrate the invention. The experiment was carried out on the basis of the investigation of the reaction occurring in the tissues of the animals after administration of the foreign substances according to the invention.

(Experiment 1) Comparative histology study of cell changes and extracellular matrix resulting from injection and implantation of carboxyglyconic acid hydrolactic acid containing magnesium colloid into the inferior skin of white rat <Preliminary result> In Experiment 1, 108 rat In the group, possible different tissue reactions due to the infusion of carboxyglyconic acid hydrolactic acid containing colloidal magnesium were investigated. Samples were taken at 1, 2, 4, 8 and 16 weeks with another 20 rats injected with saline (maintained in identical conditions for use as a control).

Materials and Methods Seventy two adult white rats (Wistar females) were inhaled with ether for superficial anesthesia, divided into three parts at the back (interscapular region) using an electric razor, and on the mid back line. ,
The area where two surgical sutures were applied was selected sagitally with a black line (1.5 cm spacing). 0.5 ml of carboxyglyconic acid hydrolactic acid containing a magnesium colloid component was infused from the back to 36 rats in one group in the interscapular region, and the mice were placed in 3 suitable plastic cages (13 cm each). The bottom of the cage is sterile wood and is provided with food and filtered water to the voles at will. Thirty-six rats in the two groups were treated in the same manner, but saline was infused and kept under the same conditions for use as a control.

After 1, 2, 4 and 8 weeks, 14 animals (7 magnesium-containing carboxyglyconic acid hydrolactic acid, 7 saline infused) were deeply anesthetized with ester, When growth was noted, skin, kidney, liver, pancreas, heart and lung fragments were collected at the same time the primitive lymph nodes were examined for final histopathological studies.

The fragments were fixed in 10% formaldehyde / PBS at 4 ° C. for 3-5 days and then washed with running water for 15 minutes. In addition, a second piece of skin from the injection area was collected from each animal and fixed in 5% paraformaldehyde / PBS for 4 hours for subsequent immunohistochemical studies and washed with PBS before histological examination. The fragments were processed in the same manner as the others for processing.

Next, all the fragments were dehydrated with a solution of increasing ethanol concentration and cleared with xylene, whereby the fragments were permeated into paraffin and finally embedded in paraffin. A 5 μm section was prepared using a Spencer 820 rotary microtome manufactured by American Optical Co., and the section was previously prepared with formaldehyde / PBS.
It was fixed in the medium, placed on a slide glass and stained with hematoxylin / eosin stain. Op coupled to automatic AFX II photometer with 35mm camera
The preparations were examined on a tiphoto model Nikon microscope and thus micrographs of Kodak 100 ASA Kodacolor film were obtained.

In the first stage of observation, visualization of skin taken from animals injected with magnesium-containing carboxyglyconic acid hydrolactate allowed colloidal particles (recognizable as amorphous and basophilic at 1 week). ) Is surrounded by mononuclear cells. It penetrates vigorously into the infused area near the epidermis and near the appendage. At the second week, the penetration continues, and not only giant multinucleated cells but also microphages can be observed around the colloidal particles. At the 4th and 8th weeks, macrophages appear and either form the initial capsule or penetrate between colloidal particles. Finally, at 16 weeks, macrophages, fibroblasts and associated matrix surround the clot of colloids, still identifiable by basophilic spots at this point.

Furthermore, observing the image of the regression of plasma anchored inside blood vessels close to the surface of the endothelium can be confused with the possible presence of fine microballoons in the blood, but in the blood vessels of animals injected with NaCl. Since such an image exists, it is actually impossible to make a mistake. No signs of neoplasia were detected in the skin fragments studied.

From the second week of the experiment, the colloid is already retained within the granuloma, which normally exists under the muscle during the formation stage, but it can pass through the muscle layer and reach the dermis. .
The granuloma evolves until it forms a sac that contains a colloid surrounded by macrophages. At 16 weeks, it is possible to observe the binding matrix between macrophages and fibroblasts as part of the bound capsule surrounded by granuloma.

Conclusion of Experiment 1 From the observation of Experiment 1, it can be concluded as follows. Injection of magnesium-containing carboxyglycolic acid hydrolactate into the inferior skin of the white rat promotes the formation of granuloma that responds to foreign substances preferentially localized at the injection site, the lower part of the skeletal muscle layer of the inferior skin (present in the mouse). To be done. However, in some cases granulomas reach the superior muscles of the inferior skin and deep into the dermis. This granuloma becomes stable about 2 weeks after the injection, and it is possible to visualize magnesium colloid-containing carboxyglyconic acid hydrolactic acid in an apparently stable form surrounded by huge foreign substances. From the 8th week onward, the initial capsule that extends inwardly into the septum surrounds the granuloma and causes the granulomas to diverge. No neoplasia was observed.

[0042] (Experiment 2) In the magnesium colloid-containing carboxymethyl glycone acid hydro lactic results The results of the injected implanted under skin of the RAT cell change and extracellular matrix compared histological study of <Evaluation of Matrix> Experiment 2, Wistar breed Female adult white rats were used.

In this Experiment 2, tissue mutations resulting from graft injection of magnesium-containing carboxyglyconic acid hydrolactic acid into 108 white rats were evaluated. 108 rats were infused with magnesium-containing carboxyglyconic acid hydrolactic acid from the interdorsal region previously divided into three parts. Inject saline into the other 20 rats,
The same conditions were kept for use as a control.

Materials and Methodologies The methodology used to obtain animal tissue is described below.

Skin, kidney, liver, pancreas, heart and lung fragments were harvested after deep anesthesia in white rats. Fragments were fixed in 10% formaldehyde / PBS at 4 ° C for 3-5 days and then washed with running water for 15 minutes. All fragments were dehydrated in a solution of increasing ethanol concentration, clarified with xylene, permeated with paraffin and finally embedded in paraffin. A 5 μm section was prepared using a Spencer 820 rotary microtome manufactured by American Optical Co., and the section was fixed in formaldehyde / PBS in advance, and this was placed on a slide glass and stained with hematoxylin-eosin or Gomori's trichrome staining method. Staining with either of The preparations were examined with an Optiphoto model Nikon microscope coupled to an automatic AFX II photometer with a 35 mm camera, thus obtaining micrographs of Kodak's 100 ASA Ektachrome film.

Tissue samples were taken from white rats at 1, 2, 4, 8, and 16 weeks to assess possible differences in tissue response due to injection of magnesium-containing hydrocarboxylate carboxyglyconate.

Infusion of magnesium-containing carboxyglyconic acid hydrolactic acid into the inferior skin of the white rat produces granulomas that react to foreign matter preferentially localized at the injection site, that is, below the skeletal muscle layer of the inferior skin (present in the mouse). It was verified that the formation was promoted. However, in some cases granulomas reach the superior muscles of the inferior skin and deep into the dermis. This granuloma becomes stable about 2 weeks after the injection, and it is possible to visualize magnesium colloid-containing carboxyglyconic acid hydrolactic acid in an apparently stable form surrounded by huge foreign substances. From the 8th week onward, the initial capsule that extends inwardly into the septum surrounds the granuloma and causes the granulomas to diverge. No neoplasia was observed.

When the component of the present invention is used, the collection of magnesium colloid-containing carboxyglyconic acid hydrolactic acid, which shows basophilicity in an irregular shape, can be observed by a micrograph, and is it a group among macrophages? Observed either in a state of being surrounded by a huge foreign body.

Injection of carboxyglyconic acid hydrolactic acid containing magnesium colloids causes an inflammatory response at the end of the first week, filling the area with macrophages that penetrate between the particles of amorphous and basophilic colloids, well below the muscle layer. Promotes visible matrix attachment. The muscular layer has a large number of reticulated fibers, is exposed to the refringency of green light, and is comparable to those of the surrounding and endomysium.

At the second week, macrophages have already formed a thick layer around the collected colloidal particles and penetrated between the colloidal agglomerates, with the reticulated fibers being thinner and the collagen fibers being thicker. Form septa, which are rich in extracellular matrix and exhibit more extensive attachment of extracellular matrix.

At the 4th and 8th weeks, when the magnesium-containing carboxyglyconic acid hydrolactic acid was infused, the generation of an amorphous space containing a basophilic substance (colloid) forming separate aggregates was clearly observed. be able to. In the 4th and 8th weeks,
Fiber dominance with green light birefringency is observed in the interstices of agglomerates of colloidal particles. This is consistent with the dominance of type III collagen, especially reticulum fibers.

At week 16, colloid granulomas show a predominant birefringence of green light in the gaps of the thinner septum and a birefringence of yellow or red light in the thicker septum and capsule. Is observed. This is because a large amount of type III collagen is present due to the gap between the smaller septa.

Conclusion of Experiment 2 From the observation of Experiment 2, it can be concluded as follows. Injection of magnesium-containing carboxyglycolic acid hydrolactate into the inferior skin of the white rat promotes the formation of granulomas in response to foreign substances that have the same properties as the extracellular matrix. The granuloma thus formed becomes stable about 2 weeks after the injection, and it is possible to visualize the colloid in an apparently stable form surrounded by giant foreign cells. Already in the first week, when actual macrophages penetrate the colloid, they have begun to promote the differentiation of future granuloma containing the early products of extracellular matrix. Granuloma shows more advanced septum formation at 2 weeks, and has an inwardly extending thick type I collagen-enriched initial capsule in the septum at 8 weeks. Clearly separate the leaves. However, it is worth noting that the type III collagen is abundant in the leaflets. The abundance of type III collagen in stable granulomas is what characterizes the condition of fibrosis when the type I collagen-rich, thick connective fibers (collagen fibers) dominate, with the thin connective fibers present there. It tends to be shown to be absent.

(Method for Treating Skin Disease) A method for treating skin disease by filling or correcting unaesthetic changes using the component of magnesium-containing carboxyglyconic acid hydrolactic acid according to the present invention will be described below.

The components are obtained by the process previously described herein, ie, a process that includes mixing and agitating all components in a stainless steel tube. Mixing temperature is 30 ℃ to 70 ℃
The temperature can be changed up to 0 ° C, but preferably, the mixture is mixed at about 50 ° C for about 3 hours.

[0056]   This process is repeated two more times until the final product is obtained.

[0057]   A colloidal solution is obtained in this process.

The resulting colloidal product is then filtered and the pH value verified. The pH should be about 6.0 and the density equal to 1.

The resulting product, magnesium-containing carboxyglycolic acid hydrolactic acid, already has the required pH and density and is poured into 20 ml vials.

In order to inject the product, it is first necessary to identify the treatment area, if necessary the patient is placed in an upright position and the treatment area is pre-labeled. Next, if the treated portion is the ventral side of the head, the patient is placed in a supine position at an angle of 45 to 60 ° while sitting, and if the treated portion is the dorsal side, the patient is placed in the prone position.

[0061]   Next, aseptic treatment and antiseptic treatment are performed using a usual antiseptic.

As a routine procedure, inhibition or even local infiltration with preservatives is carried out so that the patient is less stressed and more comfortable during the procedure.

No preliminary testing is required as the product is inert and biocompatible. That is, there are no allergic or toxic reactions. The formulation of the components prevents contamination by fungi or bacteria according to the invention.

The contents of the vial are aspirated with a needle or cannula. The latter has diamond points. The size of the needle or cannula will depend on the amount required to fill the treatment area.

The components of magnesium-containing carboxyglycolic acid hydrolactic acid are administered by needle or cannula, depending on the therapeutic area.

The injection of ingredients should not result in the formation of bubbles like a pearl necklace. This is because the results can be irregular with this method.

Since it was a permanent transplant, it was hypocorrected. If desired, one or more complementary sessions can occur at session intervals of 25-30 days. This time interval was established for further infusions in order to obtain totally safe and better results. This spacing is the basis for the attachment of collagen and fibrin fibers and provides the necessary support for microimplants.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/18 A61K 47/18 47/38 47/38 A61P 17/00 A61P 17/00 23/02 23 / 02 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, C , CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT , UA, UG, US, UZ, VN, YU, ZW F terms (reference) 4C076 AA16 BB16 CC18 DD23 DD41 DD49 EE32A 4C206 AA01 AA02 DA07 GA31 MA03 MA05 MA41 MA87 NA06 NA07 NA08 NA14 ZA01 ZA89

Claims (6)

[Claims] 1. An (a) ether of about 5 to 70 g of cellulose, (b) about 800 to 1300 ml of Ringer's lactic acid, (c) about 2 to 20 g of EDTA, and (d) 20 to 120 ml. Magnesium carboxy glyconate hydrolactic of mag, such as (e) optionally containing 0-10% xylocaine.
nesium) is a colloidal component for cosmetic correction characterized by containing a colloidal formulation called nesium. 2. The cellulose ether is a cellulose selected from hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, methyl cellulose and / or ethyl cellulose. The colloid component according to claim 1, which is a polymer of ether. 3. The colloidal component according to claim 1, wherein the Ringer's lactic acid is an inert solution containing sodium chloride, potassium chloride, calcium dihydrate calcium chloride, sodium lactate and water. 4. In order to correct dermatological defects, for example, wrinkle removal, nasogenian furrow, lip shrinkage and contouring, keratosis, increased cheeks, decreased ear lobe, buttocks. The colloidal component according to claim 1, wherein the colloidal component is administered to a human in order to correct aging spots and deterioration of skin caused by depression, aging, or the action of external factors such as sunlight. 5. A process for preparing a colloidal component for cosmetic correction, comprising: (a) a step of mixing an ether of cellulose, Ringer's lactic acid solution, EDTA and calcium glycolate; and (b) a step of (a). The product obtained in the steps of (a), (c) and (b) being repeated twice, and (d) and (c) being stirred at a temperature varying from 30 ° C to 70 ° C for about 3 hours. And (e) adjusting the pH of the filtered product to 6.0. 6. The process of claim 5, further comprising adding xylocaine as an optional ingredient.