HK1027036B - Topical pharmaceutical compositions for wound healing - Google Patents

Description

Topical pharmaceutical composition for healing wounds

The present invention relates to topical pharmaceutical compositions for healing wounds, and in particular to topical pharmaceutical compositions that promote healing of burns or sunburns.

The skin and mucous membrane are distributed on the human body surface and serve as barriers between the human body and the external environment. However, skin and mucous membranes, especially skin, are particularly susceptible to environmental mechanical (e.g., cuts), physical (e.g., burns or frostbites), and chemical (e.g., chemical exposure) damage. In the current social development situation, even the general public may often suffer skin injuries such as minor trauma, burning (scalding) or sunburn.

Whether slight trauma, burning (scalding) or sunburn, the skin (or mucous membrane) is injured, which first causes various external symptoms such as redness, swelling, heat and pain, and later causes infection or even the whole body due to improper treatment. In the healing stage, scar formation or capillary hyperplasia (pyogenic granuloma) may also occur due to tissue regeneration, both of which deposit and keratinize or bulge new skin pigments, but in severe cases, the appearance is affected, although there is no sequelae.

Topical medicaments for healing wounds in the human body are well known in the medical field. Commonly used external drugs include antiseptics such as povidone iodine and silver sulfadiazine (silversfadizine); antibiotics, such as neomycin; and agents containing corticosteroid hormones (e.g., cortisones). However, conventional antiseptics are mostly strongly irritating or toxic, and the antiseptics themselves have only the effect of killing bacteria in skin and mucosal wounds. The bactericidal efficacy of antibiotics is often affected by the presence of resistance to pathogens, and topical antibiotics (such as neomycin) sometimes cause contact dermatitis. As for corticosteroid hormones, they are effective as external anti-inflammatory drugs, but they aggravate lipid disorders of hair follicle (such as acne), and they occasionally cause sequelae such as skin atrophy and pigment regression in long-term or large-scale use, and even inhibit the activity of pituitary gland in children.

Most importantly, the traditional medicines have no adverse side effects such as scabbing or granuloma resistance. Therefore, a patient suffering from skin injury or burn may have rough skin or scars or protrusions on the skin even after recovery, and particularly when the skin is on the head, face, hands, or the like, the appearance of the patient may be changed, which may continuously affect the life of the patient.

In view of the above, there is a need for a pharmaceutical for wound healing, which not only can promote wound healing, but also can maintain the appropriate softness and elasticity of the new skin or mucosa without causing undesirable effects such as scabbing or granuloma during the healing process.

The present invention has an object to provide a topical pharmaceutical composition for wound healing which can not only reduce irritation to injured skin or mucosa and promote wound healing, but also maintain appropriate softness and elasticity of newly-formed skin or mucosa without causing undesirable effects such as scabbing or granuloma during the healing process. Furthermore, the topical pharmaceutical compositions of the present invention are particularly useful for treating skin or mucosal damage caused by sunburn and burns.

The present invention provides a topical pharmaceutical composition for healing a wound, comprising:

(a)0.05 to 10% by weight of borneol, and

(b)3 to 15% by weight of bismuth subgallate (bismuth subgallate),

and a pharmaceutically acceptable excipient or carrier.

The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of the invention.

Description of the drawings:

fig. 1 shows the effect on wound healing using the pharmaceutical composition of the invention after surgical burns in rabbits, relative to the vehicle (vaseline) control group, - (a): vaseline, - ● - (O): untreated, - (F): the invention relates to a pharmaceutical composition.

FIG. 2 shows the effect of using the pharmaceutical composition of the present invention on wound healing after rabbit surgical burns, relative to a control group of single active ingredient (boric acid), - ■ - (B): boronic acid, - ● - (O): untreated, - (F): the invention relates to a pharmaceutical composition.

FIG. 3 shows the effect of using the pharmaceutical composition of the present invention on wound healing after rabbit surgical burns, relative to a control group of a single active ingredient (sulfanilamide), -. diamond-, - (C): sulfanilamide, - ● - (O); untreated, - (F): the invention relates to a pharmaceutical composition.

Fig. 4 shows the effect of using the pharmaceutical composition of the present invention on wound healing after rabbit surgical burns, relative to a single active ingredient (silver sulfadiazine) control group, -oro- (D): silver sulfadiazine, - ● - (O): untreated, - (F): the invention relates to a pharmaceutical composition.

Fig. 5 shows the effect of using the pharmaceutical composition of the present invention on wound healing after rabbit surgical burns, relative to a single active ingredient (borneol) control group, — mouth- (E): borneol, - ● - (O): untreated, - (F): the invention relates to a pharmaceutical composition.

Fig. 6 shows the effect of the pharmaceutical composition of the present invention on wound healing after rabbit surgery burns, relative to the single active ingredient (bismuth subgallate) control group, - (G): bismuth subgallate, - ● - (O): untreated, - (F): the invention relates to a pharmaceutical composition.

Fig. 7 shows the appearance of the restored skin resulting from a rabbit being treated in a different manner after being surgically burned, wound a: treatment with vehicle (petrolatum), wound C: treatment with sulfanilamide, wound D: treatment with silver sulfadiazine, wound F: treated with the pharmaceutical composition of the present invention.

Disclosed is a topical pharmaceutical composition for healing wounds, comprising:

(a)0.05 to 10% by weight, preferably 0.1 to 5% by weight, more preferably 0.5 to 1% by weight of borneol, and

(b)3 to 15 wt.%, preferably 4 to 8 wt.% of bismuth subgallate,

and a pharmaceutically acceptable excipient or carrier.

Borneol (borneol) is named after it can be extracted from plants such as Dryobalanops aromatica (Dryobalanops aromatica), but it can be synthesized artificially at present, and its molecular formula is C₁₀H₁₇And (5) OH. Borneol has a characteristic odor and can be used as a flavoring agent (e.g., US 4983394) or as an inactive additive in pharmaceuticals (e.g., US 5164184, US 5190757, US 5593691, etc.), and esters derived therefrom have been commonly used in the manufacture of perfumes. In addition, US 4931475 proposes a cholelithiasis drug containing borneol as a main component.

The basic bismuth gallate is obtained by reacting gallic acid, glacial acetic acid and bismuth nitrate in water solution, and has molecular formula of C₆H₂(OH)₃COOBi(OH)₂. The bismuth subgallate can be used as an oral antidiarrheal agent for treating acute or chronic diarrhea, and can form bismuth sulfide with a large amount of hydrogen sulfide generated by abnormal fermentation in intestinal tracts, so that diarrhea and pain caused by gas stimulation to large intestines are reduced. The bismuth subgallate belongs to benzene derivatives, so the bismuth subgallate also has the function of antisepsis.

The pharmaceutical composition of the present invention may further comprise a conventional disinfectant, such as boric acid. Typically, in the pharmaceutical compositions of the present invention, the amount of disinfectant is from about 0.5 to about 25% by weight.

The pharmaceutical composition of the present invention may further comprise a conventional antibacterial agent, such as sulfanilamide. Typically, the amount of the antibacterial agent in the pharmaceutical composition of the present invention is from about 0.5 to about 25% by weight.

In one embodiment, the pharmaceutical composition of the present invention further comprises 1 to 6% by weight of boric acid and 1 to 6% by weight of sulfanilamide together.

In addition to the above-mentioned essential ingredients, other ingredients known to aid wound healing, such as anti-inflammatory agents, astringents, analgesics, detumescence agents, emollients, etc., may be included in the topical pharmaceutical composition of the present invention without impairing the effects of the present invention. The combination of the topical pharmaceutical compositions of the present invention with conventional agents will be apparent to those of ordinary skill in the art.

The topical pharmaceutical compositions of the present invention may employ excipients or carriers that are routinely used in the formulation of liquid, gel, paste, cream, powder, emulsion, spray and solid forms, and the like.

The application of the topical pharmaceutical composition of the present invention is not particularly limited, and it can be applied as a topical medicine or in other ways. For example, the topical pharmaceutical compositions of the present invention may be added to cosmetics, sunscreens, lotions to treat or condition sunburn of the skin caused by exposure to sunlight (ultraviolet light).

The topical pharmaceutical compositions of the present invention may be formulated in any suitable conventional manner, and such methods and procedures of formulation are known to those skilled in the art.

Preferred embodiments of the present invention will be further exemplified in the following examples.

Examples

The following examples illustrate the practice of various aspects of the present invention, but are not intended to limit the scope of the invention. Example 1: preparation of the pharmaceutical composition of the present invention

The ingredients listed in Table 1 below were mixed in a conventional manner to prepare a paste-like preparation.

TABLE 1

Component (A)	Weight of milligram	Weight percent of
			Borneol (borneol)	7	0.7％
Bismuth subgallate	45	4.5％
			Boric acid	45	4.5％
Sulfanilamide derivatives	55	5.5％
			Vaseline	848	84.8％
Total of	1000	100％

Example 2: preparation of a composition as a control

The compositions listed in the following Table 2 were mixed in a conventional manner to prepare paste formulations, respectively.

TABLE 2

	Composition numbering
						A	B	C	E	G
	Boric acid		45 mg of
Sulfanilamide derivatives								55 mg of
	Borneol (borneol)				7 mg of
Bismuth subgallate										45 mg of
	Vaseline	1000 mg of	955 mg (Perkin Elmer)	945 mg of	993 mg of						955 mg (Perkin Elmer)
Total of						1000 mg of	1000 mg of	1000 mg of	1000 mg of	1000 mg of

Example 3: animal experiment 1, method and procedure:

1.1 Experimental animals

Female New Zealand white rabbits (average body weight 2.25 kg) three months after removal were placed in well ventilated cages 10 and fed a regular diet, maintained for a 12 hour light/dark cycle at room temperature.

1.2, surgical operation

Animals were general anesthetized with ketamine (35 mg/kg) and Citosol (50 mg/kg) on the day of surgery and then infiltrated with lidocaine. In operation, 2 rectangular areas (1.5 cm. times.2 cm) were dehaired on each rabbit's back side, followed by exposure of the dehaired area to 500 ℃ ferrochrome for 3 seconds, resulting in burns and scalds.

1.3 post-operative treatment

The above-mentioned five compositions (treatment method code: A, B, C, E, G) of the pharmaceutical composition of the present invention in example 1 (treatment method code: F), the commercially available ointment for treating burn injury containing silver sulfadiazine as the main ingredient (Fumeijing ointment (Flumazinecam), Smith & Nephew, England, treatment method code: D) and the preparation method in example 2 were applied to wounds of rabbits, respectively, and each composition was randomly applied to one of 5 back wounds of 10 rabbits, and 5 wounds were left without any treatment (treatment method code: O). The animal numbers and their wound management patterns are arranged in table 3 below. The treated and untreated wounds were covered with a sterile (ethylene oxide gas sterilized) non-stick gauze (yiyongbuzhanshu, kaoho gmbh, taiwan) dressing change daily and the amount of composition used per wound was about 2 grams. The wound shape was traced and area calculated every 2 days, the observation period being by day 20 post-surgery.

TABLE 3

Animal numbering	The code of the way of treating four wounds respectively
		1	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 different treatment modalities on wound area

Table 4 shows the effect on wound healing of the rabbit wounds by applying the pharmaceutical composition of the present invention of example 1 (treatment F), the five compositions of example 2 (treatment A, B, C, E and G), and the commercially available ointment for treating fire injury (treatment D), and the untreated wound (treatment O). The area calculation for each set of treatments in the table is taken as the median of five wounds, expressed in square centimeters.

TABLE 4

Area of wound		Processing mode code
										A	B	C	D	E	F	G	O
		Number of days after hand	Day 0	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
			8 days	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
			16 days	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

Table 5 below further shows the percentage change in wound area in table 4.

TABLE 5

Percent change in wound area		Processing mode code
										A	B	C	D	E	F	G	O
		Number of days after hand	Day 0	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
			8 days	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
			16 days	123	87	93	80	127	10								150	130
18 days	73									77	77	57	87	7	133	120
			20 days	63	50	70	30	67	0								103	97

As can be seen from tables 4 and 5, the treatment of the wound with only the excipient (vaseline, treatment method a) can isolate the wound from the external environment, and recover the wound better than the untreated wound (the wound area is reduced to 63%), but the wound treated with the pharmaceutical composition of the present invention heals completely on day 20 after the operation, which is far better than the result obtained by treating the wound with vaseline (fig. 1). In the same way, by treating the wound with a composition comprising boric acid as the single active ingredient (treatment B), the wound area was reduced to only 50% at day 20 after surgery (fig. 2). When the wound was treated with the composition comprising sulfanilamide as a single active ingredient (treatment mode C), it was found that the wound was not satisfactorily healed within 20 days after the operation and the wound area was reduced to 70% (fig. 3). The wound was treated with a commercially available burn treatment ointment (treatment D), which did not heal completely, although the wound area was reduced to 30% by a large amount on day 20 after surgery; and wounds treated with the pharmaceutical composition of the present invention increased the rate of healing from day 8 post-surgery, a similar situation was not observed in treatment regimen D at day 14 post-surgery (figure 4). The wound was treated with the composition containing borneol as the single active ingredient (treatment E), and the wound healed (FIG. 5) similar to treatment A and C (67% reduction in wound area). The wound healing (fig. 6) was similar to that of the untreated wound (treatment O) using the composition with bismuth subgallate as the single active ingredient (treatment G).

2.2 Observation of wound surface tissue restoration

Within 4 days after surgery, there was an increase in the area of some of the wounds for each treatment. The area of each group of wounds is reduced gradually on the 6 th day after the operation, and partial burn wounds scab and wounds have ulceration. Most of the wounds of each group were reduced in area at day 8 after the operation, and some of the scab wounds began to fall off, but the ulceration of each wound tended to increase. The area of each group of wounds is reduced again on the 12 th day after the operation, the situation that the wounds of each group are scabbed and shed is increased, most of the wounds after scabbed and shed show ulceration, the wounds only treated in the treatment modes D and F are dry, and particularly the area of the wounds in the treatment mode F is rapidly reduced, and the wounds do not have ulceration.

On day 18 after surgery, some wounds in the treatment mode F are completely recovered and present the original cortex of the rabbit, most of the remaining wounds scab and continuously fall off, but most of the wounds are ulcerated, and the wound area is continuously reduced.

On day 20 after surgery, the wounds treated with the pharmaceutical composition of the present invention (treatment mode F) were fully healed, the area of the wounds of the other groups was continuously reduced, the wounds were scabbed and exfoliated, and the wounds were still partially ulcerated, and the wounds were dry only in treatment mode D. Figure 7 is a photograph taken on day 20 post-surgery of animal No. 3 showing wound a (treated with vehicle petrolatum only) healed but with significant scarring; wound C (treated with sulfanilamide) has a rough and protruding healed skin portion, in addition to scabbing and incomplete healing; wound D (treated with sulfadiazine) was also mostly scabbed and not fully healed; the wound F (treated by the pharmaceutical composition of the invention) is not only completely healed, but also the restored skin presents the original cortex of the rabbit, and the touch is soft and elastic.

Although part of the wounds treated by treatment method D were completely restored on day 20 after the operation, the skin treated by treatment method D had a rough touch and fine wrinkles due to tight wounds compared to the cortex of the wound restoration, whereas the skin treated by treatment method F was soft and elastic without tight fine wrinkles.

In the animal test, the wounds in the treatment mode F did not produce granulomatous reaction during the recovery process, the wounds in the treatment mode D had slight granulomatous reaction (with respect to a part of the recovered wounds), and the wounds in the other treatment modes were not healed after the operation on day 20, so that it was impossible to judge whether or not the recovered wounds produced granulomatous reaction.

The examples provided above are merely illustrative of the present disclosure and are not intended to limit the scope of the present disclosure. It is understood that modifications and variations may be apparent to those skilled in the art without departing from the teachings of the present invention, and are intended to be within the scope of the claims of this application.

Claims (10)

1. A topical pharmaceutical composition for healing a wound, comprising:

(a)0.05 to 10% by weight of borneol;

(b)1 to 30 weight percent of bismuth subgallate,

and a pharmaceutically acceptable excipient or carrier.

2. A topical pharmaceutical composition according to claim 1, wherein the amount of borneol is 0.1 to 5% by weight.

3. A topical pharmaceutical composition according to claim 2, wherein the amount of borneol is 0.5 to 1 wt%.

4. A topical pharmaceutical composition according to claim 1, wherein the amount of bismuth subgallate is from 3 to 15% by weight.

5. A topical pharmaceutical composition according to claim 4, wherein the amount of bismuth subgallate is from 4 to 8% by weight.

6. A topical pharmaceutical composition according to claim 1, further comprising 0.5 to 25% by weight of a pharmaceutically acceptable disinfecting agent.

7. A topical pharmaceutical composition according to claim 6, wherein the pharmaceutically acceptable antiseptic agent is boric acid.

8. A topical pharmaceutical composition according to claim 1, further comprising 0.5 to 25% by weight of a pharmaceutically acceptable antiseptic.

9. The topical pharmaceutical composition according to claim 8, wherein the pharmaceutically acceptable antiseptic is sulfanilamide.

10. The topical pharmaceutical composition according to claim 1, further comprising 1 to 6% by weight of sulfanilamide and 1 to 6% by weight of boric acid.