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University of Sergipe, Lagarto, Brazil; 3Department of Physiology, University of Sergipe, São ..... A composition including honeycomb, sesame seed oil, myrrh ...
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Recent Patents on Medicinal Plants/Natural Products as a Therapeutic Approach to Wounds and Burns Healing Mairim Russo Serafini1,*, Adriana Gibara Guimarães2, Lucindo José Quintans-Júnior3, Paula Santos Nunes4, Isabella Gonçalves Matos4, Shanmugan Saravanan4 and Adriano Antunes de Souza Araújo4 1

Department of Pharmacy, University of Sergipe, Lagarto, Brazil; 2Department of Health Education, University of Sergipe, Lagarto, Brazil; 3Department of Physiology, University of Sergipe, São Cristóvão, Brazil; 4Department of Pharmacy, University of Sergipe, São Cristóvão, Brazil Received: January 07, 2015

Revised: February 26, 2015

Accepted: February 28, 2015

Abstract: For healing wounds, burns and ulcers has a great impact on economy. New medications, technologies and other interventions are being used for skin injuries and to eliminate infections. Despite several technological and strategic advances in this field, wound care has returned to the roots of medicine and some of the remedies used millennia ago have been studied at present. This review gives an awareness of commercially available drugs to healing of wounds from natural origin. The research was conducted based on the requests for patents deposited in the Espacenet (European Patent Office) and in the WIPO (World Intellectual Property Organization). The research focused on exploring the uses of medicinal plants/natural products as a therapeutic approach to wounds and burns healing. Further, this study discusses the recent trends in the usage of natural products in topical formulations and the patents on it were reviewed, in addition to, future investigations and application of natural products in healing of wounds. Natural products have great therapeutic potential and should be used in the development of new products for the treatment of skin injuries.

Keywords: Burns, healing skin, health, natural products, wounds. INTRODUCTION Scientific research on the advances in treatment of skin injuries is an ongoing process observed in the literature constantly. Many laboratories throughout the world are studying skin lesions and tested new treatments that enable an improvement in patient’s survival and quality of life. Many studies in this area are focused on the acceleration of the physiological processes of wound healing and the development of topical and systemic medications to cure these lesions. Special attention has been given to patients with chronic lesions (e.g. diabetes or vascular disorders) and burns, since these injuries require a long period of treatment, resulting in high cost health care [1, 2]. The skin lesion usually increases fluid loss, causes hypothermia and leads to compromised immunity. These changes increase the possibility of developing infectious processes that may endanger the patient's life. In addition, it often generates scars that can change body’s image [3, 4]. The high rates of sepsemia observed in burn patients for example, the resistance to antibiotics, and the high cost in treatment for such patients, have increased the interest of many researchers to test and develop new products, such as ointments and *Address correspondence to this author at the Department of Pharmacy, University of Sergipe, Lagarto, Brazil; Tel:/Fax: ???????????????????????; E-mail: [email protected] 1872-2083/14 $100.00+.00

dressings for regeneration and repairing of injured tissue [5-7]. A perfect dressing should be able to absorb wound excess exudate, creating a moist environment for it. Furthermore, the dressing should be occlude so that it protects the wound against microorganisms, but should be removed easily without trauma and should allow gaseous exchange. It also should be nontoxic and biocompatible [5, 8]. The use of medicinal herbs for treatment of skin lesions, is a common practice for decades. They are popularly used in various formulations (extracts, oils, ointments, and several others) for the purpose of healing wounds and/or burns on the skin [9]. These, natural product-based polymers are widely used in regenerative medicine as dressings for wounds and burns, owing to their biocompatibility, biodegradability and similarity to the extracellular matrix [10, 11]. Several products such as gauzes, hydrogels, foams, hydrocolloids (carboxymethyl-cellulose), alginate, quitosans, collagen, cellulose, cotton/rayon, transparent films (polyurethane) are recommended as passive dressings for wounds and burns, because of their influence on local cellular response [9, 12-15]. A perusal of literature showed that the healing process of natural products exhibit different actions such as angiogenesis [16], inflammation [17], fibroplasia [6], epithelization [18], collagenation [7] and wound contraction © 2014 Bentham Science Publishers

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[19]. However, a detailed inspection on innovations, registration of patents, later stages of clinical trials and product marketing remains lacking. Therefore, the present review attempts to investigate researches that were developed and patented, and evaluating the therapeutic approach of healing of wounds and burns from natural products. METHODOLOGY This review was conducted based on the requests for patents deposited in the Espacenet (European Patent Office) and in the WIPO (World Intellectual Property Organization). The research focuses on the uses of medicinal plants/ natural products as a therapeutic approach to healing of wounds and burns. The keywords used were: burn and/or healing. “Title” and “summary” were used as search fields and the IPC (International Patents Classification) A61K 36/00: (Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines) was used. The documents found were processed individually in an attempt to characterize the technological advances of these patents considering the deposit year (between 2013 and 2014), IPC and depositing country. The limitations referring to the non-disclosure agreement period were respected. The search was performed in October 2014.

  Fig. (1). Flowchart of studies included.

Serafini et al.

RESULTS AND DISCUSSION The uses of natural compounds in a mixture to heal the human skin from the adverse biological effects of the burn and wounds have been receiving great interest in recent years. From Table 1, several inventions containing natural compounds patented for wound healing in the WIPO and Espacenet databases, key-words burn and or healing and CIP A61k36 are observed. All the patents in the last 2 years (2013-2014) were analyzed. After the removal of duplicated patents Fig. (1), we have selected the patents published in English or Spanish, and screenings for relevant titles and abstracts in recent years, a total of 16 patents were submitted for a full-text review, concerning natural products application on healing/burn (Table 2). In the patent US 20130209592 the authors describes a formulation with sugarcane plant extract and a gelling agent. This research was conducted in a human pilot study, with twenty four adult patients. The patient population consisted of both males and females who were diagnosed with a moderate to severe wound. Patients were instructed to apply the healing compound, with sugarcane block, to open wounds on a daily basis and to cover wounds with a moist saline dressing. This pilot study shows that the wound healing compound has an excellent activity as an adjunctive wound healing agent [20].

 

Recent Patents on Medicinal Plants/Natural Products

Table 1.

Recent Patents on Biotechnology, 2014, Vol. 8, No. 3

Natural products to healing skin.

Database

Publication date

Patents

WIPO (front page)

Unlimited

3,321

Burn and/or healing and A61k361

2010 to 2014

1,475

2013-2014

157

Espacenet (title or abstract)

---

348

Burn and/or healing and A61k36

2010 to 2014

67

2013-2014

20

1

A61K36: Medicinal preparations of undetermined constitution containing material from

algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines.

Another study, in the same patent describe above, was conducted on the healing of deep partial thickness wounds using a well-established porcine model. Wounds from the pig were evaluated by histological analysis to determine the percent re-epithelialization. The analysis showed increased re-epithelialization with the wound healing compound versus untreated controls at both day 3 and day 5 of analysis. Furthermore an anti-microbial study was conducted to determine the effect of the wound treatment compound on Pseudomonas aeruginosa (ATCC27312). According to the authors, the formulation showed in vitro antimicrobial activity against Pseudomonas aeruginosa and Methicillin Resistant Staphylococcus aureus (MRSA). In 2014, the CelaCare Technologies published a patent (EP 2704729) application comprising the use of Aloe vera and silver salt that has potent antimicrobial activity against bacteria, protozoa, fungi and viruses. The antimicrobial activity of silver citrate in USP purified water and silver antimicrobial hydrogel, was tested using the microtube dilution method for determining minimal inhibitory concentrations (MIC) and was compared against two currently marketed drugs (miconazole/MIC and silver sulfadiazine/SSD) in a small group of diverse microorganisms: Candida albicans (yeast); Pseudomonas aeruginosa (gram negative bacterium), Staphylococcus aureus (gram positive bacterium), and Trichomonas vaginalis (protozoan). This test demonstrated that the constituents of the silver citrate appear to have equal to or greater potency than silver sulfadiazine in inhibiting the growth of tested strains of Pseudomonas aeruginosa and Staphylococcus aureus, and demonstrates that it has greater inhibitory properties against Candida albicans than Miconazole as well as having inhibitory properties against Trichomonas vaginalis [21]. The UNICAMP- Brazil is responsible for four patents in this area: the first invention (WO/2014/066968) described a composition containing rice oil having a high wound healing capacity. The authors affirmed that the composition is capable of maintaining adequate moisture content in the wound healing region and by keeping the surrounding regions dry and protected, and can also have a systemic effect, these all being factors that accelerate the healing process. The second invention (WO/2014/075157) describes a formulation based on coffee oil with high skin wound healing capacity. Finally, the WO/2013/091056 invention relates a pharmaceutical

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compositions comprising Arrabidae chica extract in controlled release systems, in the form of liposomes, microparticles or nanoparticles, and the use of the pharmaceutical composition to prepare a medicinal drug for the healing of tissue wounds [22, 24, 30]. Independent inventor related in EP 2586450 a cream for burns, the purpose of this invent is immediately relieve the pain and itching of the patient who suffers a burn, effectively and rapidly recover the surface of burned area without leaving any sign of a scar on the skin. More specifically, the cream of the invention is obtained from a mixture of virgin olive oil, elderberry bark scrapings, peeled and chopped chestnuts and beeswax in proportions such that the amounts by weight of olive oil is between 18% and 23%, elderberry bark is between 13% and 18%, pealed chestnuts are between 42% and 50% and beeswax is between 15% and 21%. The tests to confirm the activity is not showed [23]. Researchers from Taiwan, has deposited a patent (US 20130052289) where we can gather the use of extracts of Ficus microcarpa for healing wounds including ulcerous wounds of a diabetic patient. In the study, mice are grouped into a control group, a shaping agent added application group, an oral administration group, a sole application group, and a combination of application and oral administration group. Medicine is applied to each mouse of both the shaping agent added application group and the sole application group once per 24 hours. Mice of each of the five groups have a significantly decreased wound area in skin due to the promotion effect of the medicine with respect of wound healing [25]. Another invention, developed by Hong Kong University of Science and Technology relates to pharmaceutical compositions comprising Rhizoma arisaematis extract and compounds isolated from Rhizoma arisaematis (such as 3-O- (9, 12 -octadecadienoyl)–glyceryl-β-D-galactopyranoside, N-(βD-ribofuranos-1-yl)-henylalanine, and adenosine) for promoting wound healing. Experiments were carried using "Imprinting Control Region" (ICR) mice. Two full-thickness wounds were generated on the shaved backs of each mouse using a 6-mm diameter sterile puncher. After wounding, each mouse received Rhizoma arisaematis extracts on one wound, and the other wound was left untreated. The result shows that the topical administration of the water fraction of Rhizoma arisaematis promoted wound closure on day 2 [26]. The invention EP 2570124 relates oleuropein compositions for healing wounds and ulcers. The experiments were carried in humans, showing reasonable results. The researchers claim the use of the pharmaceutical composition containing oleuropein for the treatment of diabetic foot, for the treatment of venous ulcers and pressure ulcers [27]. The patent WO/2013/050902 describes the evaluation of the extract of a plant of the genus Helichrysum in Jojoba oil. The effect of the extracts on cell proliferation of dermal keratinocytes was carried using Human keratinocytes. Different methods of extraction were tested. In general, extract provided a good cell proliferation stimulation on keratinocytes. The effectiveness of the extract in treating skin injuries associated with stomata was used in 10 patients. From the analysis of preliminary data, a reduction is observed in

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Table 2.

Serafini et al.

Natural products patented for burn/ wound healing. PATENTS

Patent Nº

01

Title

Plant extract based compositions and methods for US 20130209592 treating chronic wounds [20]

Applicant

Denstman Steven C.

Antimicrobial silver hydrogel composition for - CelaCare Technolothe treatment of burns and gies wounds [21]

Year

2013

02

EP 2704729

03

Composition and formula- Universidade Estadual WO/2014/066968 tion containing rice oil and De Campinas 2014 uses thereof [22] Unicamp

Cream for Burns [23]

Lombardero Calzon Ricardo

2014

Compound (s)

Indication/mechanism

US

Sugarcane plant extract and a gelling agent that includes at least one of xanthan gum and hydroxyethyl cellulose

Treating wounds, burns and cosmetic enhancement

EP

Antimicrobial therapeutic A pharmaceutical and/or composition that can serve medical grade silver salt, and as a treatment for burns an Aloe vera gel or extract and as a wound/lesion dressing

WO

Rice oil

Accelerate the healing process

EP

A mixture based on four components that are virgin olive oil, elderberry bark, peeled chestnuts and beeswax

Burn, with effective recovery of the surface or burned area without leaving any sign of scaring on the skin.

Skin wound healing

04

EP 2586450

05

Composition and formula- Universidade Estadual WO/2014/075157 tion based on coffee oil, De Campinas 2013 and uses thereof [24] Unicamp

WO

Coffee oil

06

Medicine containing extracts of ficus microUS 20130052289 carpa for healing wounds of a diabetic patient [25]

Chiang Shou-Hsun

US

Healing wounds including Extracts of Ficus microcarpa ulcerous wounds of a diabetic patient

07

Rhizoma arisaematis extracts and uses thereof WO/2013/056514 for wound-healing effects [26]

The Hong Kong University Of Science 2013 And Technology

WO

Rhizoma arisaematis extracts

Wound-healing effects

08

EP 2570124

Oleuropein compositions for healing wounds and ulcers in elderly people and/or diabetics [27]

Sanidad Y Residencias 21 S A

2013

EP

Oleuropein compositions

Healing wounds and ulcers in elderly people and/or diabetics

09

Jojoba oil helichrysum extract and compositions WO/2013/050902 thereof, in particular, for treating a skin condition [28]

Del Corso, Simone

2013

WO

Jojoba oil helichrysum extract

Wounds/ burns/ skin ulcers

10

WO/2014/117056

Wintermute Biomedical, Llc

2014

WO

L-Arginine, undecylenic acid, and Rheum officinale extract

Skin infections or wounds

11

Pharmaceutical compositions comprising ArUniversidade Estadual rabidaea chica extract in WO/2013/091056 De Campinas 2013 controlled release systems, Unicamp production process and use thereof [30]

WO

Arrabidae chica extract

Healing of tissue wounds.

Therapeutic compounds [29]

2013

Country

2013

Recent Patents on Medicinal Plants/Natural Products

Recent Patents on Biotechnology, 2014, Vol. 8, No. 3

5

(Table 2) Contd…. PATENTS Patent Nº

Title

Applicant

Year

Country

Compound (s)

Indication/mechanism

12

WO/2014/055338

Decubitus treatment system [31]

North Texas Medical Center

2014

WO

Aloe vera

Wound care, decubitus ulcers

13

Topical transdermal method for delivering nutrients through the skin US 20140199367 Orofino Donald P. for expedited wound healing and skin rejuvenation [32]

2014

US

Proteins, amino acids, and nucleic acid molecules

Riboswitch-like activation and curation of wounds

14

WO2014147638

A multifunctional natural Datt Mediproducts wound healing matrix [33] Ltd

2014

WO

Silver nanoparticles with tulsi plant extract and also zwitterionic chitosan

Wound healing

15

US 8741353

Ointment for healing burns and wounds [34]

2014

US

Honeycomb, sesame seed oil, myrrh, curcumin, mukul, Burns and wounds and potassium alum

US 2013323337

Novel herbal composition for the treatment of wound healing, a regenerative medicine [35]

US

Extracts obtained from Curcuma longa, Glycyrrhiza Treatment of wound glabara, Hamiltonia healing suaveolens, Typha angustifolia and Azadirachta indica

16

Al-Mutawaa May Ghaith M

Patankar Suresh Balkrishna

the injuries after treatment with Helichrysum oil in all the patients (100 %) after three weeks of treatment, and a complete recovery is observed in five patients (50 %). No cases of allergic reaction were observed, or of intolerance to the product based on the Jojoba oil Helichrysum extract. Therefore, Helichrysum oil is a safe and effective aid in the treatment of skin injuries in stoma-bearing patients [28]. Another patent (WO/2014/117056) showed compounds like L-Arginine, undecylenic acid, and Rheum officinale extract for the treatment of skin diseases (e.g., psoriasis and eczema), infections (microbial, viral, and fungal), and wounds (e.g., cuts and burns). The experiments were carried in vitro and in vivo. In vitro testing was conducted to measure the efficacy of compounds at inhibiting the growth of clinically relevant bacteria. Methicillin resistant staphylococcus aureus (MRSA), S. pyogenes and S. pneumoniae were all completely inhibited by the compounds. Furthermore, the in vivo combination treatment attenuates MRSA infection in rats [29]. The North Texas Medical Center (WO/2014/055338) claims compositions and methods for cleaning, treating, protection and resolution of decubitus ulcers comprising: a first composition comprising a wound cleaning solution comprising Aloe vera gel comprising at least 5,000 MPS (mucopolysaccharide), a balanced salt solution; and a second composition comprising a wound healing gel comprising Aloe vera gel comprising at least 10,000 MPS, a thickening agent, and one or more preservatives and, optionally, a third composition comprising a moisture barrier cream comprising a vegetable-based emulsifier, a cosmetic ester for dry skin that has low occlusivity, an ester-based emollient that is oxidation stable and has low occlusivity; a beeswax; a hydrogenated

2013

oil, glycerin, a buffering agent, Aloe vera gel comprising at least 2,000 MPS and water [31]. The US 20140199367 invention relates to liquid application for skin rejuvenation created from specific amino acids, lipids, nucleic acids and vitamins. Second, from the invention, this collection of molecules delivers precisely the factors necessary to a specific site requiring healing; a direct intervention system to most expeditiously remodel skin with building blocks. Key is a lipophilic carrier with nuclear and mitochondrial ligands that rapidly penetrate and permeate all membranes and truncates the inflammatory site quickly manifesting curation [32]. The invention WO2014147638 provides a zwitterions chitosan, prepared from natural chitosan by conjugating succinic anhydride molecule. Silver nano particles prepared from tulsi extract were mixed with zwitterion chitosan to make multifunctional effects like antibacterial, biocompatible, antioxidant and anti-inflammatory activities. Various experiments were conducted to check the above said efficacy of matrix. Antimicrobial activities were studied using Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureu,s Candida albicans and Aspergillus niger. The biocompatibility, antioxidant and antiinflammatory property of the said matrix were evaluated using human dermal fibroblasts viability, DPPH • (2,2diphenyl-l-picrylhydrazyl) inhibition and Cox, Lox inhibition assay, respectively. The clear results were obtained showing termination of these bacteria within few hours of application thus indicating the efficacy of matrix components. The bandage was successful in destroyed all the forms of bacteria and fungi within 24 hours of treatment [33].

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Serafini et al.

A composition including honeycomb, sesame seed oil, myrrh, curcumin, mukul, and potassium alum was related for healing burns and wounds (US 8741353). The inventors describe that a male patient with severe burns and inflammation on his hand was treated with this ointment. The affected area of the hand was cleaned. A gauze pad, containing a thin layer of the ointment, was placed over the affected area and wrapped with layers of dry gauze. The ointment was applied to the burn in this manner twice a day. After four days of application of ointment, inflammation of the hand was seen subsided and skin appeared smooth with only minor discoloration. After one week of application of this ointment, the skin was completely restored with significant reduction of discoloration [34].

proof and comparison with the products currently already used [36].

The inventors of US 2013323337 relates that herbal composition (Extracts obtained from Curcuma longa, Glycyrrhiza glabara, Hamiltonia suaveolens, Typha angustifolia and Azadirachta indica) was subjected to standard models to evaluate wound healing activity like incision, excision and dead space wound models in laboratory animals. There was less inflammation in the animals treated with present herbal composition as compared to control animals. Generally to determine turnover of collagen, the estimation of hydroxproline is carried out, which is a breakdown product of collagen. There was a significantly higher level of Collagen as well as Hydroxproline which indicates more synthesis and turn-over of Collagen during the process of wound healing due to the presence of herbal composition. Further, the final stage of the wound healing remodeling, resulted due to regaining its strength and elasticity through reorganization of collagen and elastic fibers for reconstruction of dermis. In this stage also there was significantly more activity in the animals treated with herbal composition. Thus, herbal composition is exhibiting wound healing activity through promoting various stages in general and promoting formation as well as turnover of collagen, which is playing important role in the process of healing of tissue in particular [35].

CONFLICT OF INTEREST

Currently, within the medical centers and between research groups observed the use of several products already on the market, and the development of various products with acting in the tissues of the burn injury. The dressings have a wide variety of formulations and components. They may have antiseptic/biological activity or not. Some have silver in their composition (e.g ActicoatTM) others have exclusive action occlusion the lesion (e.g BiobraneTM, polyurethane film, Tegaderm, Jelonet and others) [14]. Hermans 2006 reported silver sulfadiazine cream and impregnated gauze are the most used products in the nonsurgical treatment of burns and donor sites. [36] Other products marketed are being studied in scientific research such as silver dressing (ActicoaTM) [37-39], (Aquacel Ag®) [40, 41], (Mepilex Ag®) [42], (Actisorb Ag®) [38]; synthetic membrane (Tegaderm®) [43, 44]; hydrocolloid dressing (Duoderm®) [45, 46] and biosynthetic temporary cover (Biomembran®) [42]. Hermans 2006 noted that many of these products have action similar to the gold standard product, silver sufadiazina. They also reported that limited global availability, the cost of some new products and techniques lead to poor compliance of new materials for treatment of burns. Furthermore, many new products have not yet true clinical

CURRENT AND FUTURE DEVELOPMENT In conclusion, these data helps us to understand the present days, that it is possible to employ the herbal ingredients with real scientific claims. Natural products have great therapeutic potential and should be used in the development of new products for the treatment of wound and burns healing. They should go through all the necessary methodological steps (preclinical and clinical) to prove its effectiveness. And should be tested in various compositions and compared to products gold standards.

The author(s) confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS Declared none. REFERENCES [1] [2]

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