INJECTION COMPOSITION COMPRISING HYALURONIDASE FOR REMOVAL OF TOPICAL FAT

Abstract

The present invention relates to an injection composition comprising hyaluronidase for topical fat reduction. More particularly, the present invention relates to an injection composition comprising 300 IU to 600 IU of hyaluronidase and a local anesthetic, an antihistamine, a lipolysis stimulator and a collagen production stimulator. The present invention promotes the reduction of topical fat tissue, thereby improving obesity and helping weight loss and maintenance of body shape while preventing side effects or skin imbalance by the even removal of fat. Further, at the same time, the present invention can achieve a skin lifting effect where skin resilience is maintained by the stimulation of collagen production.

Claims

1. An injection composition for topical fat removal comprising 300 IU to 600 IU of hyaluronidase and, based on the weight of the total composition, 0.08 to 0.4% by weight of lidocaine as local anesthetic, 0.01 to 0.02% by weight of pheniramin as antihistamine, 0.01 to 4.0% by weight of L-carnitine as lipolysis stimulator, and 0.1 to 2.0% by weight of vitamin C as collagen production stimulator, with the remainder being saline solution, wherein the composition is characterized as being injected at a unit volume of 0.5 to 2 cc with an interval between injection points of 0.5 to 1.5 cm.

Description

DETAILED DESCRIPTION

[0053] The present invention will now be described in detail with reference to specific working examples.

[0054] Hyaluronidase is a water-soluble enzyme secreted from mammalian vas deferens or testes, characterized by its actions to remove barriers between tissues by hydrolyzing the glucosaminic bonds between hyaluronic acid, a major intercellular substance, and connective tissues to dissolve the bonds and reduce fibroplasia in tissues. Hyaluronidase is also known to relieve swelling and edema in tissues.

[0055] Using the characteristics of hyaluronidase that hydrolyzes and dissolves substances within skin tissues, LLD (Lipolytic Lymph Drainage) treatment is widely used in which hyaluronidase is directly injected subcutaneously to degrade substances including fibers in subcutaneous tissues, thereby facilitating lymphatic circulation to help drainage of adipose tissue to reduce adipose tissue and relieve obesity.

[0056] However, the above treatment, though helpful in reducing adipose tissue, has been associated with various side effects.

[0057] That is, using high doses of hyaluronidase to remove adipose tissue causes allergic symptoms such as redness or itching, and excessive lysis of adipose tissue leads to bruising due to subcutaneous bleeding or dimpling, resulting in frequent discontinuation of the LLD treatment to take care of these side effects and difficulty of continued treatment due to patients' repulsion arising from pain.

[0058] Furthermore, using high doses of hyaluronidase makes it difficult to narrow the interval between injection points (about 5-cm interval). As a result, fat removal is concentrated only around injection points to cause indentations or sagging and wrinkling in the skin, and these side effects lead to imbalance. Significant reduction in skin resilience also resulted in the dissatisfaction of patients.

[0059] Having strived to address the above problem, the present inventor discovered that the minimum amount of hyaluronidase exhibiting efficacy is 300 IU and that above 600 IU, adipose cells are excessively hydrolyzed, giving rise to concerns about dimpling or subcutaneous bleeding. Thus, by administering an injection composition of the present invention having the above compositional ranges, the side effects from using the drugs are minimized and fat removal over a wide area can be carried out using a minimal volume.

[0060] It was shown in clinical trials that at a hyaluronidase of 300 IU, the diameter of the diffusion range for the injection composition is about 1 cm. Thus, by injecting the composition at narrow intervals between injection points of 0.5 to 2 cm, even fat removal as well as collagen production by skin stimulation can be facilitated.

[0061] By comprising a local anesthetic to alleviate the pain from injection, an antihistamine to prevent allergic side effects, a lipolysis stimulator to rapidly transport fatty acids from degraded fat into mitochondria and degrade them, and a collagen stimulator, the injection composition of the present invention also prevents allergic symptoms like redness or itching as well as pain and bruising, accelerates fat removal, and excels in maintaining skin resilience by collagen production.

[0062] As the above local anesthetic, drugs commonly used in injectable solutions can be used. The present invention uses lidocaine in an amount of 0.08 to 0.4% by weight based on the total weight of the composition.

[0063] When the amount of the local anesthetic is below 0.08%, analgesic effect is unsatisfactory, and when the amount is above 0.4%, the duration of anesthesia is prolonged and is uneconomical.

[0064] As for the other ingredients, the antihistamine pheniramin is contained in an amount of 0.01 to 0.02% by weight, the lipolysis stimulator L-carnitine in an amount of 0.01 to 4.0% by weight, and the collagen stimulator vitamin C in an amount of 0.1 to 2.0% by weight.

[0065] The composition of the present invention may also comprise one or more substances selected from a tonicity agent, a nonionic surfactant, a stabilizer, a preservative, etc. that are commonly used in injectable solutions, within dose ranges allowable for injection compositions. The composition of the present invention may further comprise a lipolytic agent such as phosphatidylcholine, aminophylline, caffeine, or the like as well as placenta components or pentoxifylline which improves blood circulation, in amounts of 0.01 to 4.0% by weight.

[0066] The amounts of the above ingredients were determined within their respective maximum daily doses in preparation for a case where 300 IU of hyaluronidase is administered at a daily dose of 15,000 IU.

[0067] Most preferably, the injection composition of the present invention is injected to give 300 IU to 600 IU of hyaluronidase per injection, at a unit volume of 0.5 to 2 cc with an interval between injection points of 0.5 to 1.5 cm. The daily dose of hyaluronidase is preferably 15,000 IU or less, and the unit dose and injection points can be suitably adjusted according to the unit of hyaluronidase given in one injection.

[0068] The injection composition of the present invention can be injected 50 times based on a volume of 1 cc containing 300 IU of hyaluronidase, and the site of injection can be any body area where fat is accumulated including abdomen, buttocks, thighs, calves, chin, forehead, arms, and the like.

EXAMPLES

[0069] Preparation of Injection Compositions

TABLE-US-00001 Comp. Comp. Comp. Example Example Example Example Example Example Example Ingredients 1 2 3 4 1 2 3 Hyaluronidase 30,000 IU 30,000 IU 60,000 IU 30,000 IU 25,000 IU 65,000 IU Lidocaine 210 mg 210 mg 210 mg 210 mg 210 mg Peniramin 12 mg 12 mg 12 mg 12 mg 12 mg L-Carnitine 660 mg 660 mg 660 mg 660 mg Vitamin C 600 mg 600 mg 600 mg Saline solution q.s. q.s. q.s. q.s. q.s. q.s. 100 Total Amount 100 100 100 100 100 100 100 (cc)

[0070] For hyaluronidase, Liporase Inj. of Daehan New Pharm Co., Ltd (1500 IU/vial, including 13.3 mg lactose hydrate) was used, to which lidocaine (Hanmi Pharm. Co., Ltd.), Peniramin (Yuhan Co.), L-carnitine (Dream Pharma) and vitamin-C (Daewoo Pharm Co., Ltd.) were added in the amounts listed in the above table, and the mixture was dissolved in saline solution to prepare 100 cc of a solution composition for injection.

Experimental Example 1

[0071] Lipolytic effect of the injection composition of the present invention

[0072] Changes in waist circumference after the administration of the injection composition of Example 4 and those of Comparative Examples 1 to 3, as well as after endomology treatment for edema were measured and presented in Table 1.

[0073] The subjects of treatment were a total of 40 patients (20 male, 20 female) having abdominal obesity with a BMI of 25 or greater, selected from adult outpatients of age 20 or above.

[0074] In the abdominal area between the ribs and pubic bones, 1 cc each of an injection composition was injected at 50 points, arranged in a manner that they are apart 1 cm each starting from the navel. The above injection was repeated weekly for four weeks, with the points of injection moved each time. Decreases in waist circumference were measured 1 week after completion of the treatment, and then again 1 month after completion of the treatment. The average values of the measurements are presented in Table 1.

[0075] Endomology treatment, designed for edema, was carried out for four weeks, one 30-minute session per week, with the decrease in waist circumference measured after one week and one month, and the results are shown in Table 1.

[0076] For statistical analysis, the statistics package SPSS was used to obtain the distribution of measurements and the paired t-test was used to assess the effects of test injections on the decrease in waist circumference. The analysis used a 95% confidence interval, adjusted for weight changes.

TABLE-US-00002 TABLE 1 1 week after Difference 1 month after 4 Difference Baseline 4 sessions after 1 week sessions after 1 month Comp. 90.7 1.2 91.0 1.8 +0.3 1.2 90.5 1.3 0.2 1.2 Example 3 Comp. 91.0 1.0 89.4 0.4 1.6 0.6 89.8 1.3 1.2 0.3 Example 1 Comp. 90.7 1.3 Example 2 Example 4 90.8 1.7 81.4 0.5 9.4 0.2 81.3 0.3 9.5 0.4 Endomology 92.0 2.0 89.8 1.4 2.2 0.8 92.2 1.2 +0.2 1.5 Example 4, body fat analysis using the body fat analyzer Inbody showed an average fat loss of 1.5 to 2 kg.

[0077] According to Table 1, a change of 0.21.2 cm in waist circumference was observed in Comparative Example 3, where only saline solution was given. In Example 4 according to the present invention, however, a difference of 9.40.2 cm in waist circumference was seen at one week after the four sessions, and the difference was maintained as 9.50.4 cm at one month after the four sessions, indicating that there was no yo-yo effect.

[0078] On the other hand, in Comparative Example 1 where 250 IU of hyaluronidase was administered, the difference was 1.60.6 cm at one week after the treatment and 1.20.3 cm at one month after the treatment, showing a significantly lower effect than the present invention. In Comparative Example 2 where 650 IU of hyaluronidase was administered, the treatment was discontinued after the first session due to dimpling and bruising.

[0079] In the case of endomology, a decrease in waist circumference from the removal of edema was not significant and disappeared after one month, clearly indicating that a decrease in waist circumference obtained by using hyaluronidase is not only a result of edema removal but also from lipolysis.

[0080] As can be seen from the above results, the injection composition of the present invention has been demonstrated to have an excellent effect in topical fat removal, with remarkably reduced side effects and no yo-yo effect.

[0081] In addition, the injection composition of the present invention has also been shown to have minimized side effects and improved topical fat removal effect despite the use of a lower dose of hyaluronidase compared to the high dose hyaluronidase injection composition of the prior art KR 10-2009-0111916A.

Experimental Example 2

[0082] Assessment of side effects of the injection composition of the present invention.

[0083] The injection compositions of Examples 1 to 4 and those of Comparative Examples 1 to 3 were administered as in Experimental Example 1, and the side effects observed in each patient in clinical trials are indicated in Table 2.

TABLE-US-00003 TABLE 2 Pain above Skin Redness Swelling Itching VAS 3 Bruising Dimpling Sagging resilience Comp. 1 1 0 0 0 0 0 3 Example 1 Comp. 4 3 4 2 10 15 0 2 Example 2 Comp. 0 0 0 0 0 0 0 3 Example 3 Example 1 11 10 11 13 1 0 1 3 Example 2 1 0 1 0 0 0 1 3 Example 3 1 1 0 0 0 1 1 3 Example 4 1 0 0 0 0 0 0 5 *Skin resilience was determined by tactile assessment using a 5-point scale: 1: Very poor, 2: Poor, 3: Fair, 4: Good, 5: Very Good.

[0084] As shown in Table 2, with the injection composition of Example 1 according to the present invention, which does not contain local anesthetics or antihistamines, side effects such as bruising or dimpling were remarkably reduced compared to the high dose composition of Comparative Example 2, though pain and allergic reaction were observed. The compositions of Examples 2, 3, 4 containing a local anesthetic and an antihistamine were shown to have remarkably reduced allergic redness, swelling, itching and pain compared with Example 1 or Comparative Example 2.

[0085] These effects are thought to result from the use of a local anesthetic and an antihistamine as well as the low dose hyaluronidase.

[0086] Further, in Example 3, some patients developed slight dimpling and sagging as a result of fat removal by the lipolysis stimulator, which were limited to highly obese patients and were recovered within a short period.

[0087] In Example 4, the inclusion of a collagen production stimulator allowed the rapid recovery of skin resilience, with no occurrence of dimpling or sagging.

[0088] Taken all together, the above effects are thought to result from the minimized unit dose of hyaluronidase, which allows administration of the injection composition over a wide area leading to even removal of fat, and the enhanced skin resilience due to the collagen production stimulator.

[0089] Hyaluronidase is an effective substance for topical fat reduction that has no particular side effects. It is known to have an efficacy nearly comparable to other conventional drugs and show few adverse interactions with other drugs. Thus, it is expected that hyaluronidase may maximize the therapeutic effect on obesity through combined administration with other drugs.

[0090] However, there have been many cases where treatment was discontinued or allergy drugs had to be administered due to side effects of the injection such as pain in injection sites or itching and swelling from allergic side effects. The present invention has been devised to provide an injection composition that can prevent the problem that the treatment must be discontinued due to such side effects despite being an effective and safe treatment for obesity, and remove fat over a wide area with a minimal dose.

[0091] It is to be understood that the above detailed description and working examples are provided by way of illustration only and are not to be taken by way of limitation.

[0092] Accordingly, a person of ordinary skill in the art would readily understand that various modifications and equivalents may be made without departing from the scope of the present invention.

[0093] Thus, the scope of protection for the present invention will be determined by the appended claims and equivalents thereof.