KR100482356B1 - Topical pharmaceutical compositions for healing wounds - Google Patents

Abstract

The present invention provides a topical pharmaceutical composition for the treatment of wounds comprising an effective amount of (a) Borneol and (b) Bismuth subgallate. The topical pharmaceutical compositions of the present invention can promote wound healing while being mild to irritation to damaged skin, and prevent the formation of scars or granulated tissue, allowing the skin to regenerate with its original touch and appearance.

Description

Topical pharmaceutical compositions for healing wounds

The present invention relates to topical pharmaceutical compositions for the treatment of wounds and, more particularly, to topical pharmaceutical compositions for promoting the treatment of burns or scalding.

The skin is the outer covering of the body. It is a barrier to environmental stress. The skin suffers from wounds caused by mechanical stress (eg trauma with a knife), physical stress (eg sunburn or frostbite) or chemical stress (eg strong acid or strong alkali). easy. People in modern society cannot avoid skin damage (such as wounds, scalding or sunburn).

Skin damage caused by thermal, chemical or electrical contact results in swelling of the wound site and loss of intravascular fluid capacity primarily caused by increased vascular permeability. Occasionally, secondary systemic syndromes, such as shock and infection due to reduced blood volume, occur, which are more life threatening than the primary effects.

In natural healing, dead tissue takes off when new epithelium begins to cover the damaged area. Generally in shallow burns (eg sunburn) regeneration occurs rapidly from intact epidermal elements, vesicles and glands. If an infection does not occur, scars rarely occur.

In the case of damage to the epidermis or dermis, re-epithelialization begins with the edges of the wound, scattered skin residues or remaining dermis. This process is relatively slow. Excess granular tissue is formed before the damaged area is covered by the epithelium. Without proper and immediate treatment, the wound eventually contracts, resulting in unsightly and unrenewable scars.

Topical medications for the treatment of wounds on the human body are well known in the art. Such drugs include antibacterial agents such as povidone iodide or silver sulfadiazine; Antibiotics such as neomycin; And compound preparations containing corticosteroids (eg hydrocortisone). However, conventional antimicrobials are toxic, irritating and merely prevent infection at the wound site. The expected effect of the application of antibiotics cannot be achieved due to the resistance factors widely known in modern bacteriology. In some cases, topical application of antibiotics (eg neomycin) can cause contact dermatitis in a patient. Corticosteroids are known to be most effective as anti-inflammatory agents. However, these are known to exacerbate complications (eg fungal infections). In the case of topical application of corticosteroids with a patchy dressing covering the treatment site, sweat ducts, glandular atrophy or bacterial infection due to obstructive therapy are involved. In children with mucosal or cortisol suppression, continued treatment for large areas of obstruction.

Most importantly, traditional topical formulations comprising the agent (s) as described above cannot exhibit both functions of promoting wound healing and suppressing scar or granulation tissue formation. In general, unsightly wounds or granular tissue in a patient who has recovered trauma have a secondary, even permanent, negative impact, especially where they are clear and swollen, such as the head or face.

Therefore, in the technical field to which the present invention pertains, there is a need for the development of a novel pharmaceutical composition that can promote the healing of wounds and regenerate in their original form while having a normal tactile feel and can suppress the formation of scars or granulated tissue Still exists.

Therefore, the technical problem to be achieved by the present invention is to promote the treatment of wounds with little irritation to the damaged skin, and to help the damaged area to be reproduced in its original shape with a normal touch to form scars and granule tissue It is to provide a topical pharmaceutical composition for the treatment of wounds.

In order to achieve the above technical problem, the present invention (a) 0.1 to 5% by weight of borneool; (b) 3 to 15 weight percent bismuth subgallate; And it provides a topical pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier.

Topical pharmaceutical compositions according to the present invention not only contain an effective amount of Borneol and bismuth subgallate, but also pharmaceutically acceptable excipients or carriers.

Borneol was initially known to be extracted from Dryobalnanops aromatica or similar plants, and has a molecular formula of C ₁₀ H ₁₇ OH. Recently industrially synthesized borneol. Borneol has an unusual odor and has been used as a fragrance (see US Pat. No. 4,983,394) and as an inert additive in pharmaceuticals (see US Pat. Nos. 5,164,184, 5,190,757 and 5,593,691). Borneol-derived esters have generally been used in the manufacture of perfumes. US Pat. No. 4,931,475 proposes the use of borneol as an active agent in the treatment of gallstones.

Bismuth subgallate is the reaction product between gallic acid, glacial acetic acid and nitrate bismuth, and the molecular formula is C ₆ H ₂ (OH) ₃ COOBi (OH) ₂ . Bismuth subgallate is an oral antidiarrheal agent that is effective in treating acute or chronic diarrhea because it can alleviate pain and diarrhea caused by gas stimulation to the gastrointestinal tract by reacting with H ₂ S present in large quantities in the gastrointestinal tract by abnormal fermentation. Known as Bismuth subgallate can also be used as a disinfectant because of its properties as a benzene derivative.

Preferably, topical pharmaceutical compositions according to the invention comprise (a) 0.05 to 10% by weight of borneool; (b) 1 to 30 weight percent bismuth subgallate and a pharmaceutically acceptable excipient or carrier.

More preferably, the Borneol content of the topical pharmaceutical composition according to the invention is 0.1 to 5% by weight.

Most preferably, the Borneol content of the topical pharmaceutical composition according to the invention is 0.5 to 1% by weight.

More preferably, the bismuth subgallate content of the topical pharmaceutical composition according to the invention is 3 to 15% by weight.

Most preferably, the bismuth subgallate content of the topical pharmaceutical composition according to the invention is 4 to 8% by weight.

The pharmaceutical composition according to the invention may further comprise an acceptable fungicide as a drug such as boric acid. In the pharmaceutical composition according to the present invention, the content of the fungicide is preferably 0.5 to 25% by weight,

The pharmaceutical composition according to the invention may further comprise an acceptable antimicrobial agent as a drug, such as benzenesulfonamide. In the pharmaceutical composition according to the present invention, the content of the antimicrobial agent is preferably 0.5 to 25% by weight.

In a preferred embodiment of the present invention, the pharmaceutical composition may further comprise boric acid as a bactericide and benzenesulfonamide as an antimicrobial agent.

Preferably, the topical pharmaceutical composition according to the present invention further comprises 1 to 6% by weight of boric acid and 1 to 6% by weight of benzenesulfonamide.

Apart from the active ingredients as described above, the pharmaceutical compositions according to the invention may further comprise other traditional medicines, such as anti-inflammatory agents, astringents, emollients or analgesics, in a range that does not inhibit the expected effect. have. Inclusion of such traditional agents in the pharmaceutical compositions according to the invention can be readily used by those of ordinary skill in the art.

Suitable excipients or carriers for the pharmaceutical compositions according to the invention are those conventionally used in gels, pastes, ointments, frosts, powders, emulsions or aerosols.

The pharmaceutical compositions according to the invention can be applied without particular limitation by external drugs or by other suitable methods. For example, those skilled in the art to which the present invention pertains cosmetics, sunscreens or wash lotions to prevent and control skin damage caused by exposure of the pharmaceutical compositions of the present invention to sunlight (ultraviolet rays) Can be added to

Pharmaceutical compositions according to the present invention can be formulated using conventional formulation methods available to those of ordinary skill in the art.

Hereinafter, the present invention will be described in detail through examples. The following examples do not limit the scope of the invention. Those skilled in the art can modify and replace the present invention without departing from the scope and spirit of the present invention.

<Example 1>

The pharmaceutical compositions according to the invention were prepared as a paste formulation according to formulation methods known in the art to which the ingredients as shown in Table 1 below were mixed.

ingredient Content (mg) weight% Borneol 7 0.7% Bismuth Subgallate 45 4.5% Boric acid 45 4.5% Benzenesulfonamide 55 5.5% vaseline 848 84.8% Total amount 1000 100%

<Example 2>

Comparative control samples for animal testing with the ingredients as shown in Table 2 below and 5 pastes (A, B, C, E and G) formulations according to formulation methods known in the art to which the present invention pertains. Was prepared.

 Produce A B C E G Boric acid 45mg Benzenesulfonamide 55 mg Borneol 7mg Bismuth Subgallate 45mg vaseline 1000 mg 955 mg 945 mg 993 mg 955 mg Total amount 1000 mg 1000 mg 1000 mg 1000 mg 1000 mg

<Example 3>

Animal testing

1. Methods and Procedures

1.1 test animals

Ten mature New Zealand female rabbits (average weight 2.25 kg) were bred on a regular diet (Purina Rabbit Chow, Purina Mills, Inc., MO) at room temperature with repeated light / dark cycles at 12-hour cycles.

1.2 Operation

On the day of operation (day 0), the back hairs of all test animals were shaved to make four rectangular shapes (1.5 cm x 2 cm) (two for each side), followed by ketamine (35 mg / kg) and cytosol ( 50 mg / kg), followed by a three-second brazing heater at 500 ° C. under general anesthesia by lidocaine injection.

1.3 Post-Operation Processing

The composition prepared in Example 1 (denoted as Treatment F), an ointment commercially available for burn treatment containing silver sulfadiazine as the main active ingredient (Flamazine, Smith & Nephew, England; represented as Treatment D) and Example 2 5 control samples (designated as treatments A, B, C, E and G according to their preparation name) randomly selected for test animals and wound sites, resulting in 5 wound sites of 10 test animals. Applied to any one of Five wounds out of five out of ten animals were not treated. Randomly chosen arrangements for the treatment of wound sites in each test animal are shown in Table 3. All wound sites were covered with sterile (ethylene oxide) dressing (YIYONG BUZHANSHABU, Taiwan). 2 mg of drug was applied to each wound and freshly applied daily. The shape of each wound site was read approximately once every two days by integration calculation and the results were recorded. Observation was completed 20 days after application.

Test animal number Treatment for wounds One A, D, E, and O 2 B, C, F and G 3 A, C, D and F 4 B, C, D and E 5 B, E, F and G 6 C, F, G and O 7 A, D, G and O 8 A, B, E and O 9 A, B, D and F 10 C, E, O and G

2. Results

2.1 Effect of Treatment on the Wound

The composition according to the invention (treatment F), commercial ointment containing silver sulfadiazine (treatment D) and the examples according to the method of measuring the area of the wound site of the test animal from the date of application to the 20th day after application and the examples The effect of the 5 control compositions of 2 (Treatments A, B, C, E and G) on wound healing was analyzed and shown in Table 4. Each area measured represents the mean area of five wound sites (cm ² ) treated by the same method.

After application process A B C D E F G O Area of wound (cm ² ) 0 days 3 3 3 3 3 3 3 3 2 days 5.1 5 5.1 5 5.3 5.3 5.3 3.6 4 days 6.1 5.3 5.7 5.4 6 5.7 5.5 4.7 6 days 4.9 5.3 4.8 5.9 5.8 5.1 5.3 4.1 8th 4.8 5.4 4.6 5 5.2 5.1 5.2 4.5 10 days 5.2 5.1 4.3 4.8 5.4 5.2 5.5 4.4 12 days 4.6 4.3 4.1 4.1 4.5 1.3 4.8 4.2 14 days 4.5 4 3.3 3.9 4.6 0.9 5.3 4 16th 3.7 2.6 2.8 2.4 3.8 0.3 4.5 3.9 18 days 2.2 2.3 2.3 1.7 2.6 0.2 4 3.6 20 days 1.9 1.5 2.1 0.9 2 0 3.1 2.9

The data in Table 4 is shown in Table 5, with the area changed in percent based on the artificially damaged area.

After application process A B C D E F G O % Change in wound area 0 days 100 100 100 100 100 100 100 100 2 days 170 167 170 167 177 177 177 120 4 days 203 177 190 180 200 190 183 157 6 days 163 177 160 197 193 170 177 137 8th 160 180 153 167 173 170 173 150 10 days 173 170 143 160 180 137 183 147 12 days 153 143 137 137 150 43 160 140 14 days 150 133 110 130 153 30 177 133 16th 123 87 93 80 127 10 150 130 18 days 73 77 77 57 87 7 153 120 20 days 63 50 70 30 30 0 103 97

In order to clarify the distinct differences between the compositions according to the invention and the effects of each control sample, comparative graphs of FIGS. 1 to 6 are shown according to the data shown in Tables 4 and 5. Wounds treated with only petroleum jelly (Treatment A) improved over untreated wounds, with an average area reduction of 63% due to the petroleum jelly covering the wound. However, it is evident that the wound site treated with the composition according to the invention (treatment F) was fully recovered 20 days after the operation. This is superior to the result of process A (FIG. 1). Wound sites treated with a composition containing boric acid (Treatment B) as a single active ingredient had only a 50% reduction in their average area (FIG. 2). Wound sites treated with a composition containing benzenesulfonamide (Treatment C) as the single active ingredient are less effective since their average area is only 30% reduced (FIG. 3). Although the average area of the wound site treated with commercially available ointment (treatment D) was reduced by 70%, tissue regeneration of the wound site treated with the composition according to the invention was promoted 8 days after the operation while the same symptoms were treated. The wound site by D was observed 14 days after the operation (FIG. 4). The therapeutic progression of the wound site treated with the composition comprising Borneol as a single active ingredient is similar to that seen in Treatments A and B (FIG. 5). As shown in Figure 6, the wound site treated with the composition containing bismuth subgallate (Treatment G) as a single active ingredient appeared identical to the wound site (Treatment O) without any treatment.

2.2 Observation of Tissue Regeneration

At 4 days after the operation, the area of the wound site was observed to increase in all treatments. The reduction of the wound area began on day 6 after the operation, but ulcers were found in the wound area where some scabs were sitting. At 8 days after the operation, skin peeling was observed in some wounds and area reduction and ulcer formation were observed in most wounds. The area of the wound area gradually decreased, and skin peeling generally occurred on day 12 after the operation. However, except for the surface of the wound area dried under treatments D and F, ulceration occurred on the skin peeled wound site. In particular, the area of the wound site under treatment F decreased rapidly without ulceration.

At the 18th day after the operation, part of the wound area under treatment F was completely recovered, and normal appearance was observed. Although the incidence of skin peeling and the area of the wound area continued to decrease in the wound area under the rest of the treatment, the ulceration still proceeded except for the surface of the wound area dried under the treatment D.

The wound site treated with the composition according to the invention (treatment F) was observed to recover completely 20 days after the operation. Except for the surface of the wound site dried under Treatment D, the other wound sites continued to reduce the area of ulcers and wound areas that occurred in the exfoliated wound site.

In addition, a portion of the wound site under Treatment D recovered 20 days after the operation. However, the regenerated tissue at the wound site under Treatment D did not have a smooth surface and had fine lines, while on the surface of the wound site treated with the composition according to the present invention (Treatment F) it normally exhibited a soft touch and appearance. It could be observed.

In the animal test as described above, the formation of granular tissue was not found in the treatment of wounds advanced under Treatment F. However, some granular tissue formation was found in some of the wound healing procedures under treatment D. The formation of granular tissue could not be measured for the remaining wound sites under treatment D and all wound sites under treatments A, B, C, E and G because the wound did not recover until the end of the test.

As described above, the composition according to the present invention can promote the treatment of the wound with little irritation to the damaged skin, inhibit the formation of scars and granule tissue, and regenerate the original form while the damaged area has a normal touch. To help.

1 is a graph showing the effect on the wound treatment by the application of the pharmaceutical composition according to the present invention in artificially burned rabbits compared with the control sample applied with excipient (petrolatum only) and the control sample without any treatment. ,-◇-(A) is a control applied only petrolatum,-●-(O) is a control without any treatment, -O- (F) represents a case where the pharmaceutical composition according to the present invention is applied.

FIG. 2 shows the effect on wound healing by application of the pharmaceutical composition according to the present invention to artificially burned rabbits compared to a control with only a single active ingredient (boric acid) and a control without any treatment. As a graph,-■-(B) represents a control standard applied only with boric acid,-●-(O) represents a control without any treatment, and -O- (F) represents a case where the pharmaceutical composition according to the present invention is applied. .

FIG. 3 compares the effect on wound healing by application of the pharmaceutical composition according to the present invention to artificially burned rabbits with a control with only a single active ingredient (benzenesulfonamide) and a control without any treatment. In the graph shown,-▲-(C) is the control group to which only benzenesulfonamide is applied,-●-(O) is the control group without any treatment, and -O- (F) is the pharmaceutical composition according to the present invention. The case of application is shown.

Figure 4 shows a control sample applied only a single active ingredient (silver sulfadiazine) and no treatment control for the wound treatment by the application of the pharmaceutical composition according to the present invention for artificially burned rabbits; As a graph shown in comparison,-□-(D) is a control with silver sulfadiazine only,-●-(O) is a control without any treatment, and -O- (F) is a pharmaceutical according to the present invention. The case where a composition is applied is shown.

FIG. 5 compares the effect on wound healing by application of the pharmaceutical composition according to the present invention to artificially burned rabbits compared to a control with only a single active ingredient (borneeol) and a control without any treatment. In the graph shown,-□-(E) is the control with Borneol only,-●-(O) is the control without any treatment, and -O- (F) is the case with the pharmaceutical composition according to the present invention. Indicates.

FIG. 6 is a control sample with only a single active ingredient (bismuth subgallate) applied to the wound treatment by the application of the pharmaceutical composition according to the present invention for an artificially burned rabbit and a control sample without any treatment. -*-(G) is the control with bismuth subgallate only,-●-(O) with no treatment, -O- (F) with The case where a pharmaceutical composition is applied is shown.

Claims (10)

(a) 0.1 to 5 weight percent bornone; (b) 3 to 15 weight percent bismuth subgallate; And A topical pharmaceutical composition for treating wounds, comprising a pharmaceutically acceptable excipient or carrier. delete The topical pharmaceutical composition according to claim 1, comprising 0.5 to 1% by weight of the bornoneol. delete The topical pharmaceutical composition according to claim 1, comprising 4 to 8% by weight of the bismuth subgallate. The topical pharmaceutical composition according to claim 1, further comprising 1 to 6% by weight of a pharmaceutically acceptable fungicide. 7. The topical pharmaceutical composition according to claim 6, wherein the fungicide is boric acid. The topical pharmaceutical composition according to claim 1, further comprising 1 to 6% by weight of a pharmaceutically acceptable antimicrobial agent. 9. The topical pharmaceutical composition according to claim 8, wherein the antimicrobial agent is benzenesulfonamide. The topical pharmaceutical composition according to claim 1, further comprising 1 to 6% by weight of boric acid and 1 to 6% by weight of benzenesulfonamide.