TWI737952B - USE OF β-1 ADRENERGIC RECEPTOR ANTAGONIST FOR PREPARING COMPOSITION FOR TREATING WOUND AND APPARATUS THEREOF - Google Patents

Abstract

Use of β-1 adrenergic receptor antagonist for preparing composition for treating a wound or promote wound healing are provided. Also provided is apparatus for wound healing, comprising a dressing and a composition including an effective amount of β-1 adrenergic receptor antagonist.

Description

Use of β-1 adrenergic receptor antagonist for preparing composition for treating wound and its equipment

The present invention relates to the use and equipment of a beta-1 adrenergic receptor antagonist, in particular to the use and equipment of a beta-1 adrenergic receptor antagonist for preparing a composition for treating wounds and accelerating wound healing.

Wound healing caused by any etiology is a dynamic process that covers many overlapping stages, including inflammation, epithelialization, angiogenesis, and matrix deposition. In the stage of epithelialization, keratinocytes migrate to the wound bed to cause the re-epithelialization required for wound closure and restoration of skin integrity. Keratinocytes only express β2 adrenergic receptor, and activation of β2 adrenergic receptor delays wound healing (Pullar, CE, Grahn, JC, Liu, W., & Isseroff, RR (2006). β2-adrenergic receptor activation delays wound healing. The FASEB Journal, 20(1), 76-86). Other related studies have also confirmed that β2 adrenaline antagonists accelerate the re-epithelialization of wounds on the skin due to β2 adrenaline blockade to prevent the binding of endogenous synthetic adrenaline (Pullar, CE, Rizzo, A., & Isseroff, RR (2006). β-adrenergic receptor antagonists accelerate skin wound healing: evidence for a catecholamine synthesis network in the epidermis. Journal of Biological Chemistry, 281(30), 21225-21235.).

The wound healing process generally leads to wound maturation and a certain degree of scar formation. Although there are many factors that affect wound healing, including age, nutrition, obesity, repetitive wounds, skin moisture, concurrent diseases (such as diabetes), and medications, most wounds heal without difficulty following a predetermined course of treatment.

Since the discovery of the first growth factor (epidermal growth factor) and the concept of treating moist wounds in 1962, the science of wound repair and care has improved significantly. Despite these advanced wound care treatments, a small number of wounds do not respond to current wound management methods.

Therefore, there is still a need for wound treatment and promotion of wound healing. The present invention addresses these and other needs.

In one embodiment, the present invention discloses a method for treating wounds or promoting wound healing, which comprises the step of administering a composition containing an effective amount of β-1 adrenergic receptor antagonist to a patient in need.

The present invention also discloses a device for treating wounds or promoting wound healing, which comprises (a) a dressing; and (b) a composition containing an effective amount of β-1 adrenergic receptor antagonist.

The terms "invention", "the invention", "this invention" and "the present invention" used in this case are intended to broadly refer to the subject matter of the invention in this case and the following Apply for the entire scope of the patent. Statements containing these terms should be understood as not limiting the meaning or scope of the subject matter of the invention described herein or the scope of the following patent applications. The invention embodiments covered by this case are defined by the scope of the following patent applications, not by the content of the present invention. The content of the present invention is a high-level overview of various aspects of the present invention, and introduces some concepts that are further described in the following embodiments. The content of the present invention is not intended to identify the key or essential features of the claimed subject matter, nor is it intended to be used solely to determine the claimed subject matter of the invention. The subject matter of the invention should be understood by referring to the entire specification, any or all drawings, and the appropriate part of the scope of each patent application.

Reading in conjunction with the accompanying drawings and the following detailed description will make the present invention more obvious and understandable.

As described herein, the articles "一(a)" and "一(an)" refer to one or more (meaning at least one) grammatical objects of the article.

The terms "subject" and "patient" can be used interchangeably and refer to mammals that have been diagnosed with wounds or suspected of having wounds. Individuals include primates, preferably humans.

An "effective amount" of an antagonist refers to an inhibitor that can produce a certain amount of the desired effect, such as improving the wound healing rate by at least 1% compared to an untreated individual.

As used herein, the proprietary term "treatment" refers to treatment and preventive or protective measures. Patients in need of treatment are meant to include patients who have had wounds or have related disorders, as well as those who are prone to wounds or who have related disorders, or those who intend to prevent wounds from occurring.

All numbers in this text can be understood as modified with "about". As used herein, the term "about" means to include a variation of plus or minus 10%.

Methods of wound healing

The present invention is directed to a method for treating wounds or promoting wound healing, including the step of administering a composition containing an effective amount of β-1 adrenergic receptor antagonist to patients in need.

As used herein, "wound" refers to any damage to an individual's internal or external body structure (e.g. epithelial tissue) for any reason, including but not limited to, for example, mechanical (ie contusion, penetrating injury), heat, Traumatic injuries such as chemical, electrical, radiation, shock and incision injuries; such as selective injuries of surgery and incisional hernias and fistulas caused by them; acute wounds, chronic wounds, infected wounds and sterile wounds, and related to disease states Wounds (paronychia caused by chemotherapy or targeted therapy, ulcers or venous stasis caused by diabetic neuropathy). Non-limiting examples of wounds include paronychia, acute ulcers, ulcers, surgical wound dehiscence, burns, lacerations, incisions or abrasions. Targeted therapy as used herein includes the inhibition of cancer cell growth by interfering with specific target molecules required for cancer formation and cancer growth, rather than simply interfering with drug treatments of rapidly dividing cells (such as conventional chemotherapy), such as kinase inhibition Agent, angiogenesis inhibitor, epidermal growth factor receptor (EGFR) inhibitor, HER2/neu receptor, or a combination thereof.

In some embodiments, the wound is a chronic wound. In an exemplary embodiment, a chronic wound may refer to a wound that at least partially has one or more of the following characteristics: (1) Inflamed state of chronic self-sustaining wound, (2) Deficient and defective wound extracellular matrix (ECM), (3) Wound cells with poor response (senescence), especially fibroblasts, which limit the production of ECM, and (4) the failure of re-epithelialization, partly due to the lack of necessary ECM arrangements (ECM orchestration) and lack of scaffold for migration. Non-limiting examples of chronic wounds include venous ulcers, arterial ulcers, compression ulcers, vasculitis ulcers, and diabetic ulcers.

In some embodiments, the wound is characterized by delayed or incomplete wound healing in whole or in part. In an exemplary embodiment, delayed or incomplete wound healing may include at least part of a wound having one or more of the following characteristics: (1) prolonged inflammation phase, (2) slow formation of extracellular matrix (ECM), and (3) The speed of epithelialization stagnates or decreases.

In other embodiments, "wound healing" means one or more of the following: improving tissue repair, accelerating or accelerating wound healing, reducing scar formation in the healing area, the injured area has a tissue strength close to that of the uninjured tissue, and the function of the injured tissue To a certain degree of recovery. In an exemplary embodiment, administering the composition described herein increases the speed of wound healing compared to individuals who are not administered the composition described herein, and involves increasing the metastasis or proliferation of epithelial cells by at least 1%, 5%, 10%, 20%, 30%, 40%, 50%.

In some embodiments, the composition includes a β-1 adrenergic receptor antagonist. In some embodiments, the composition is substantially free of β-2 adrenergic receptor antagonists or non-selective β-adrenergic receptor antagonists. The composition can be administered in a pharmaceutically acceptable carrier.

This composition can be formulated for systemic (e.g. oral or intravenous), intradermal, subcutaneous, intramuscular or topical administration. In some embodiments, the composition is formulated in one of the following forms for topical delivery: ointment, cream, solution, gel, suspension, spray or lotion. In some embodiments, the composition is formulated for slow or sustained release.

Non-limiting examples of beta-1 adrenergic receptor antagonists include atenolol, betaolol, bisoprolol, esmolol, acebutolol , Metoprolol, nebivolol, or a combination thereof.

In one embodiment, the method further includes the step of administering at least one therapeutic agent that helps wound healing. Such therapeutic agents include but are not limited to growth factors, cytokines, chemokines, antibodies, inhibitors, antibiotics (with or without silver), immunosuppressants, steroids, zinc, hyperbaric oxygen, antifungal, antiviral, and others Cell type (such as stem cells, bioengineered skin, skin substitutes, and skin equivalents) or debridement (such as SANTYL Collagenase SANTYL and Cadexomer iodine). In certain embodiments, it can be used in combination with a therapeutic agent that helps wound healing.

When the β-1 adrenergic receptor antagonist composition is combined with or alternately administered with at least one therapeutic agent that helps wound healing, less β-1 adrenergic receptor antagonist composition requires less administration. The time point of the medicine and/or the increase of the time interval of the medicine have a therapeutic effect.

In addition, those skilled in the art can quickly determine the β-1 adrenaline for a specific type of wound based on, for example, the severity and type of the wound, the patient’s age, weight, sex, complications, and other drugs administered to the patient. The appropriate dose and number of doses of the body antagonist. Those skilled in the art will understand that the preferred dosage is the dosage that produces a therapeutic effect on patients in need, such as accelerating wound healing. In certain embodiments, a single dose is administered once a day for a given number of days (ie, 7 days, 1 month, etc.). In other embodiments, multiple doses may be administered in one day (every 2 hours, 4 hours, 6 hours, or 12 hours, etc.). The present invention even considers the administration of multiple doses per day for multiple days.

Equipment for wound healing or wound treatment

The present invention also provides a device for wound healing and wound treatment, which comprises (a) a dressing; and (b) a composition containing an effective amount of β-1 adrenergic receptor antagonist.

The term "dressing" refers to a dressing that is applied topically to a wound. Non-limiting examples of dressings include at least one layer of woven or non-woven textile/fabric material (e.g. gauze, sponge, cellulose, cotton or rayon), foam (e.g. polyurethane foam), hydrogel (e.g. polyurethane hydrogel, transparent Hydrogel or polyacrylate hydrogel, gelatin, carboxymethyl cellulose, pectin, alginate, silicon, collagen, transparent film, filler, biodegradable polymer matrix, any Appropriate biocompatible materials or combinations thereof).

The dressing may be soaked with the composition described herein, or at least one surface of the dressing may be coated with the composition described herein. In one embodiment, the device further includes instructions for using the composition contained therein for wound healing.

The embodiments of the present invention are illustrated by the following examples, which should not be construed as limiting its scope in any way. In contrast, those skilled in the art should clearly understand that after reading the description herein, and the teachings thereof do not deviate from the spirit of the present invention, various other embodiments, modifications and equivalents thereof can be adopted. During the study described in the examples below, unless otherwise noted, conventional procedures were followed. Part of the program is described below for illustrative purposes.

Example 1:

A female patient with severe recurrent paronychia and purulent granulomatous lesions (caused by Tofac) on the left thumb, previously used betamethasone valerate ointment, puromycin sulfate cream (gentamicin sulfate cream), and 10% silver nitrate aqueous solution for topical treatment, did not see any improvement (Figure 1A).

Subsequently, in the case of occlusion, 0.25% betaolol drops were used once a day (Alcon Laboratories, USA) for local treatment for 4 weeks. Figure 1B shows that paronychia and pyogenic granulomatous lesions completely resolved after 4 weeks of treatment with 0.25% betaolol drops daily.

Example 2:

Ten patients with deep lacerations on the palms or soles of the feet caused by EGFR inhibitors were treated locally with 0.25% betaolol drops (Alcon Laboratories, USA) once a day. Please refer to Figure 2A and Figure 2B. All deep laceration wounds of 10 patients healed within one week after treatment.

The results showed that 0.25% betaolol drops is an effective method for the treatment of deep lacerations.

Example 3:

Rats were used for in vivo studies to examine the effectiveness of non-selective beta blockers and beta 1 blockers. The rats were divided into 3 groups: (a) control group (n = 2); (b) non-selective beta blocker (n = 1); and (c) beta 1 blocker (n = 1). On day 0 of the experiment, 3 dorsal incisions were made on each rat. As shown in Figure 4A, the cut sizes of the upper, middle, and lower cuts are 1.5 cm × 1.5 cm, 1 cm × 1 cm, and 0.5 cm × 0.5 cm.

The rats in the control group received no treatment, and the rats in the non-selective β-blocker group received 0.5% Timoptol drops twice a day (Mersk Pharmaceuticals, USA) (top 30 μl incision, 13 μl middle incision, 3.3 μl lower incision), and rats in the β1 blocker group received 0.25% Betoptic drops twice a day (American Alcon experiment Chamber) (upper incision 30 μl, middle incision 13 μl, lower incision 3.3 μl).

Figures 3C to 3E show that the back incision that received 0.25% Beiteshu drops had less erythema and less erythema after 7 days of treatment compared with 0.5% dimerol drops and untreated back incisions. Small size. This result indicates that Beiteshu (Betaolol) has a better effect on promoting wound healing.

Figures 4A to 4C show the changes under the microscope of the 1 cm×1 cm back wounds of the 3 groups of rats on the 10th day. The back incision treated with 0.25% betaolol drops for 10 days was almost completely healed, the fibrous tissue cells were regenerated, the epidermis was completely re-epithelialized, and there was no sign of debris (Figure 4C). The back incision healed with 0.5% Dimorro drops for 10 days was incomplete, the epidermal re-epithelialization was incomplete, the fibrous tissue cell activity was low, and there were signs of debris.

without

Exemplary embodiments of the present invention will be described in detail below with reference to the following drawings.

Figures 1A and 1B show the left thumb of a patient with recurring severe paronychia and purulent granulomatous lesions before 4 weeks of betaxolol topical treatment (Figure 1A) and after (Figure 1B) Figure) photos.

Figures 2A and 2B are photos of the right thumb of a patient with a deep laceration before (Figure 2A) and after (Figure 2B) 4 weeks of topical therapy with Betaolol.

Figures 3A to 3E illustrate the use of no treatment (control group), the use of Timoptol (non-selective β-adrenergic inhibitor), and the use of beta-adrenergic (β1 adrenergic inhibitor). ) Under the influence of day 0 (Figure 3A), day 1 (Figure 3B), day 4 (Figure 3C), day 7 (Figure 3D) and day 10 (Figure 3E) A series of photos.

Figures 4A to 4C show the back wounds of rats treated without any treatment (Figure 4A), or with Timoptol (Figure 4B) or Betaolol (Figure 4C) for 10 days A series of microscopic images.

Claims (9)

A beta-1 adrenergic receptor antagonist is used to prepare a composition for treating patient wounds or accelerating the healing of patient wounds, wherein the wound is a purulent granulomatous lesion, paronychia (paronychia), surgical wound dehiscence, vein Ulcers, arterial ulcers, compression ulcers, vasculitis ulcers or deep lacerations. The use described in item 1 of the scope of patent application, wherein paronychia is caused by chemotherapy or targeted therapy. The use described in item 1 of the scope of patent application, wherein the β-1 adrenergic receptor antagonist is selected from atenolol, betaolol, bisoprolol, esmolol, acebutolol, and The group and combination of Torol and Nebirol. The use described in item 1 of the scope of the patent application, wherein the composition is used together with a therapeutic agent for wound healing. The use described in item 4 of the scope of the patent application, wherein the therapeutic agent for wound healing is selected from the group consisting of growth factors, cytokines, chemokines, antibodies, inhibitors, antibiotics, immunosuppressants, steroids, zinc, hypertension Oxygen, anti-fungal, anti-viral, stem cells, bioengineered skin, debridement and combinations thereof. A device for treating wounds, comprising (a) a dressing; and (b) a composition containing a β-1 adrenergic receptor antagonist, wherein the wound is a purulent granulomatous lesion, paronychia (paronychia), surgical wound dehiscence, venous ulcer, arterial ulcer, compression ulcer, vasculitis ulcer or deep laceration. The device described in item 6 of the scope of patent application, wherein the dressing is selected from the group consisting of fabrics, hydrogels, foams, collagen, silicon, and combinations thereof. The device described in item 6 of the scope of patent application, wherein the β-1 adrenergic receptor antagonizes The antagonist is selected from the group consisting of betaolol, atenolol, metoprolol, nebivolol and bisoprolol. The device described in item 6 of the scope of the patent application further includes a therapeutic agent administered for wound healing.

Images