DermaMed Pharmaceutical Inc. focuses on product innovation, development and manufacturing in large markets where the benefits of controlled delivery of therapeutic herbal active ingredients can create value in treating skin diseases, arthritis, hemorrhoids, cold, flu, sinusitis and migraine. In order to understand how these remedies work through their topical application, literatures on the skin barrier structure and function and on the mechanisms of action of some well established skin permeation promoters have been studied carefully.
The skin is considered the largest organ of the body and has many different functions. The skin functions in thermoregulation, protection, metabolic functions and sensation. The skin is divided into two main regions, the epidermis, and the dermis; each provides a distinct role in the overall function of the skin. The dermis is attached to an underlying hypodermis, also called subcutaneous connective tissue, which stores adipose tissue and is recognized as the superficial fascia of gross anatomy Fig. (1)
The epidermis is the most superficial layer of the skin and provides the first barrier of protection from the invasion of foreign substances into the body. The principal cell of the epidermis is called a keratinocyte. These cells stick to one another by proteins known as cell adhesion molecules. These molecules can be thought of as biological glues. They are important in maintaining the integrity of tissues by linking cells to other similar cells. The family of cell adhesion molecules known as the cadherins is responsible for this cell to cell adhesion.
It is known that cadherins are involved not only in maintaining tissue integrity, but also in other physiological events, such as the development of organs and blood vessels, and wound healing. The epidermis is subdivided into five layers or strata, the stratum germinativum (SG), the stratum spinosum (SS), the stratum granulosum (SGR), the stratum lucidum(not seen in this photomicrograph) and the stratum corneum (SC) in which a keratinocyte gradually migrates to the surface and is sloughed off in a process called desquamation Fig (2).
A cross section of the skin showing the three layers of the skin,
(1) the dermis. (2) the epidermis (3) the hypodermis
A cross section showing four layers of the epidermis
(1) stratum germinativum(SG), stratum spinosum(SS),
stratum granulosum(SGR), stratum corneum(SC)
The outermost layer of the skin, stratum corneum (SC), provides an outstanding barrier against the external environment and is responsible for skin impermeability toward most solutes. The barrier function is related to the unique composition of the stratum corneum lipids and their complex structural arrangement. The lipoidal matrix of the stratum corneum, therefore, is a target of permeation enhancer action. Data obtained from electron microscopy and X-ray diffraction reveals that the disordering of the lamellar packing is an important mechanism for increased permeation of topically applied remedies induced by permeation enhancers (1).
Animal skin and skin alternative were used by investigators, as models in order to aid in the screening of transdermal penetration enhancers. The skin alternative consists of a dermal layer containing human fibroblasts dispersed in a collagen matrix and an epidermal layer of differentiated and stratified human keratinocytes (2,3).
Rapid, controlled molecular transport across human skin is of great interest for transdermal medication delivery. The main barrier is the stratum corneum (SC), which consist of the old dead cells, surrounded by multilamellar lipid bilayer membranes.
Small lipid-soluble molecules can partition into the Stratum corneum, and then diffuse across the lipid bilayer membranes, but water soluble molecules, particularly charged molecules, cannot penetrate significantly by this route. Pre-existing aqueous pathways associated with the skin's appendages (sweat gland ducts and hair follicles) admit water soluble molecules, and are believed to provide one major route for iontophoresis, in which low voltage buffers are used to move ions and molecules across the skin. Iontophoresis often provides molecular fluxes which are smaller than needed. However iontophoresis can provide more transdermal flux when combined with other skin permeation enhancers.
Most pharmaceutical companies involved in transdermal product line are focused on contraception, hormone replacement therapy and smoking cessation. However DermaMed Pharmaceutical Inc. , through extensive literature study, dedicated effort and long experience in herbal remedies both in Germany and Canada realized the importance of the skin as important organ for herbal remedy application in many of the common diseases that constitute severe health problems to people and often lead to chronic overwhelming illness.
Topically applied remedies provide controlled release of drugs directly into the bloodstream through intact skin. It provide a number of advantages over conventional methods of drug administration, including:
|•||Greater convenience and improved patient compliance.|
|•||By delivering a steady flow of drugs into the bloodstream over an extended period of time, transdermal systems can avoid the "peak and valley" effect of oral or injectable therapy and can enable more controlled, effective treatment.|
|•||By avoiding first pass metabolism through the gastrointestinal tract and the liver, the therapeutically equivalent dosage for the transdermal delivery of certain compounds can be significantly less than the corresponding oral dosage, potentially reducing dosage related side-effects.|
|•||Easy to terminate dosing if adverse reaction occurs.|
To explain the mechanism of absorption through the skin to reach systemic circulation, The skin can be considered a membrane. Permeability coefficient of the membrane = 1 / Resistance (R).
The skin resistance to permeability, is due to many components which include:
|2.||Stratum corneum (usually the most significant component).|
The resistance occur one after another in series of the same order.
The Total Skin Permeability = 1/R.vehicle + 1/R. Stratum corneum + 1/R epidermis +1/R.dermis
Factors control the rate of therapeutic ingredient passage through the skin:
The therapeutic active ingredients:
|•||Hydrophilic or lipophilic ( lipophilic ingredients penetrate better)|
|•||Size-small molecules penetrate faster.|
|•||The concentration and solubility of the active ingredients: high concentration or solubility penetrate better (high concentration gradient)|
|•||Vehicle viscosity: viscosity reduces diffusion coefficient.|
|•||Vehicle composition: non-aqueous solvents increase penetration.|
|•||Penetration enhancers: disrupt skin surface causing faster penetration.|
|•||Area for absorption: increased area causes increased absorption.|
Physiological conditions in skin:
|•||Dead cells and lipid accumulation in the stratum corneum decreases initial transport of drug.|
|•||Sebum-pH, amount and composition alter passage.|
|•||Hydration of the skin ( differ according to the person's age and skin location): increased hydration usually increases penetration rate.|
|•||Thickness of the skin: Thin skin causes increased penetration rate e.g. the skin behind the ear is very thin while that of palm of hand is very thick.|
|•||Injury- open cuts and grazes increase penetration rate.|
|•||Temperature: Theoretically, a positive relation is expected between skin temperature and the percutaneous penetration of topically applied substances. Studies showed that temperature effect with the highest penetration is at 38.2 degrees C (4).|
Skin Permeation Enhancers
One literature review found more than 275 chemical compounds cited as skin penetration enhancers (5).
Most of those compounds were generally recognized as safe (GRAS) ingredients that would often be considered inert by a formulator. Complete texts concerning pharmaceutical skin penetration enhancement are available and they provide excellent descriptions and critical reviews of this subject (6,7,8).
Although there are many strategies to enhance skin permeation, some of them include the use of chemical skin penetration enhancers. DermaMed Pharmaceutical Inc. uses natural additives that:
|•||Alter the solubility of the active ingredient in the formulation (including supersaturation), to increase its delivery through the skin|
|•||Optimize the ionization state of the active ingredients in the topical remedies (using buffered gel with the proper pH).|
|•||Enhance the skin permeation (adding natural skin permeation enhancers).|
Topical products often contain many components that are considered inert excipients with respect to the pharmacology:
|•||Solvents and cosolvents are used to alter drug solubility or ease of processing.|
|•||Emulsifiers and gelling agents provide the consistency and properties expected of creams, lotions, and gels.|
|•||Antioxidants and preservatives are provided to extend shelf life or ensure quality.|
|•||Skin permeation enhancers are added to the topical remedies to increase skin permeability by reversibly altering the physiochemical nature of the stratum corneum to reduce its diffusional resistance (8).|
DermaMed Pharmaceutical Inc. uses the natural skin enhancers which include:
|•||Iontophoresis: uses electrical potential to carry drug through the skin, by using active ingredients in buffered gel.|
|•||Linoleic acid and alpha-linolenic: It has been found that polyunsaturated fatty acids PUFA--Linoleic (LA), alpha-linolenic (ALA) and arachidonic acids-enhance skin permeation stronger than monounsaturated fatty acids. The enhancement effects of fatty acids on penetration through the stratum corneum are structure-dependent, associated with the existence of a balance between the permeability of pure fatty acids across stratum corneum and the interaction of the acids to skin lipids (9).|
|•||Oleic acid: Oleic acid has been studied as a skin penetration enhancer for topically applied medications, primarily via its action mainly on the stratum corneum lipid structure. It has been found to increase the epidermal permeability through a mechanism involving the stratum corneum lipid membrane. It is incorporated into skin lipid, disrupt molecular packing and alter the level of hydration and allow drug penetrates faster (10).|
|•||Cod-liver-oil: The enhancing effect of the marine products could generally be associated with their content of free unsaturated fatty acids (11).|
|•||Menthol derivatives as potential skin penetration enhancers: Studies showed that the permeation enhancing effect of l-menthol is significantly high with short lag time (12). The promoting activity of the ethyl ether derivative of Menthol is the greatest of all menthol derivatives. Studies showed that it is the most promising compound which has the greatest action and relatively low skin irritancy (13,14). A study has been made to elucidate the mechanism of skin permeation enhancement and it was concluded that the increase in skin flux, to eight times the base line, could be attributed to the effect of menthol on the skin barrier properties (15). The mechanism of permeation enhancement of menthol has been studied by some other investigators and they concluded that it could involve its distribution preferentially into the intercellular spaces of stratum corneum and the possible reversible disruption of the intercellular lipid domain. They suggested the use of menthol as effective penetration enhancer (16).|
|•||Squalene: Squalene was found to be a very effective skin permeation enhancer. 12% of the human sebum is composed of Squalene to which is attributed the natural moisturizing effect of the sebum. Studies also showed the skin soothing effect of Squalene (17).|
|•||Glycerol derivatives: Studies concluded that glycerol monoethers derived from linear saturated fatty alcohols are very effective permeation enhancers (18).|
|•||Herbal ingredients: have the ability to penetrate the skin fast. In vivo skin penetration studies of the Chamomile flavones apigenin, luteolin and apigenin 7-O-beta-glucoside were carried out with nine healthy, female volunteers. During seven hours the decline of flavonoid concentration in a saturated aqueous alcoholic solution filled in application chambers were repeatedly measured by spectrophotometry at fixed time periods. It was concluded, that the flavonoids are not only absorbed at the skin surface, but penetrate into deeper skin layers. This is important for their topical use as antiphlogistic agents (19).
Another study has been done to investigate the permeability of natural herbal compounds of different range of lipophilicity through hairless mouse skin and the effect of certain herbal extract called Senkyu (Ligustici Chuanxiong Rhizome) ether extract (SEE) as permeability enhancer. It has been found that (Senkyu) ether extract (SEE) enhanced the permeability of the herbal ingredient that have moderate permeability rate. The effect of SEE in vivo was similar to that obtained in the in vitro experiment. It was concluded that the natural compounds having high lipophilicity sufficiently permeated into the hairless mouse skin owing to their accumulative property, and the Senkyu ether extract enhanced the permeability of the moderately lipophilic compounds into the skin (20).
DermaMed Pharmaceutical Inc., by using combination of buffered gel and skin permeation enhancer in addition to the easily permeable herbal ingredients, extracted by natural solvents, further increases the flux through the epidermis. It has been concluded after several studies that Iontophoresis in combination with enhancers (e.g. linolenic acid ) transformed the highly compact cells of the Stratum corneum into a looser network of filaments, disrupted the keratin pattern, and resulted in swelling of Stratum corneum cell layers of human epidermis, thus increases the flux of medication through human epidermis (21).
The scientists of DermaMed Pharmaceutical Inc. are and will always be appreciating the trust of their customers all over the world. They will always make use of their unique creative feature in developing the best of the topical herbal remedies to protect their customers from the side effect of the long term use of pharmacological drugs.
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2- Godwin DA. Michniak BB. Creek KE. Evaluation of transdermal penetration enhancers using a novel skin alternative. Journal of Pharmaceutical Sciences. 86(9):1001-5, 1997 Sep.
3- Tompkins, R.G.; Burger, A.; Ponec, M. Clin. Exp. Dermatol. 1994, 19 (1), 16-22.
4- Clarys P. Alewaeters K. Jadoul A. Barel A. Manadas RO. Preat V. In vitro percutaneous penetration through hairless rat skin: influence of temperature, vehicle and penetration enhancers. European Journal of Pharmaceutics & Biopharmaceutics. 46(3):279-83, 1998 Nov.
5- David W. Osborne and Jill J. Henke. Skin Penetration Enhancers Cited in The Technical Literature. Research and Development, ViroTex Corporation, 4200 Research Forest Drive, Suite 350, The Woodlands TX 77381.
6- K.A. Walters and J. Hadgraft, Eds., Pharmaceutical Skin Penetration Enhancement . Marcel Dekker, New York, 1993.
7- D.S. Hsieh, Ed. Drug Permeation Enhancement: Theory and Applications, Marcel Dekker, New York, 1994.
8- V.P. Shah, C.C. Peck, and R.L. Williams. Skin Penetration Enhancement: Clinical Pharmacological and Regulatory Considerations. Pharmaceutical Skin Penetration Enhancement K. A. Walters and J. Hadgraft, Eds. (Marcel Dekker 1993). pp. 417-427.
9- Tanojo H. Bouwstra JA. Junginger HE. Bodde HE. In vitro human skin barrier modulation by fatty acids: skin permeation and thermal analysis studies. Pharmaceutical Research. 14(1):42-9, 1997 Jan.
10- Jiang Shao Jun. Kim Young Koo. Lee Seung Hun [a] The ultrastructural changes of stratum corneum lipids after application of oleic acid in propylene glycol. Annals of Dermatology. 10(3). July, 1998. 153-158.
11- Loftsson T. Gunnarsdottir T. Magnusdottir LM. Frioriksdottir H. Guomundsdottir TK. Olafsson JH. Haraldsson GG. Guomundsson G. Hjaltason B. Effect of various marine lipids on transdermal drug delivery--in vitro evaluation. Bollettino Chimico Farmaceutico. 136(10):640-5, 1997 Nov.
12- Kommuru Thirumala R. Khan Mansoor A. Reddy Indra K [a]. Effect of chiral enhancers on the permeability of optically active and racemic metoprolol across hairless mouse skin. Chirality. 11(7). 1999. 536-540.
13- Takayama and T. Nagai, Drug Dev. Ind. Pharm., 20, 677 (1994).
14- H. Okabe, Y. Obata, K. Takayama and T. Nagai, Drug Design Delivery, 6, 229 (1990).
15- Kaplun-Frischoff Y. Touitou E. Testosterone skin permeation enhancement by menthol through formation of eutectic with drug and interaction with skin lipids. Journal of Pharmaceutical Sciences. 86(12):1394-9, 1997 Dec.
16- Kunta JR. Goskonda VR. Brotherton HO. Khan MA. Reddy IK. Effect of menthol and related terpenes on the percutaneous absorption of propranolol across excised hairless mouse skin. Journal of Pharmaceutical Sciences. 86(12):1369-73, 1997 Dec.
17- A. Aioi, K. Kuriyama, T. Shimizu, M. Yoshioka, and S. Uenoyama. Effects of Vitamin E and Squalene on Skin Irritation of a Transdermal Enhancer, Lauroyl Sarcosine. Int. J. Pharm. 93:1-6 (1993).
18- Loftsson T. Petersen DS. Le Goffic F. Olafsson JH. Unsaturated glycerol monoethers as novel skin penetration enhancers. Pharmazie. 52(6):463-5, 1997 Jun.
19- Merfort I. Heilmann J. Hagedorn-Leweke U. Lippold BC. In vivo skin penetration studies of camomile flavones. Pharmazie. Vol 49(7) (pp 509-511), 1994.
20- Sekiya K. Kadota S. Katayama K. Koizumi T. Namba T. Study on baths with crude drug. III. The effect of ligustici chuanxiong rhizome extract on the percutaneous absorption of some natural compounds. Biological & Pharmaceutical Bulletin. 20(9):983-7, 1997 Sep.
21- Bhatia Kuljit S. Singh Jagdish [a]. Effect of linolenic acid/ethanol or limonene/ethanol and iontophoresis on the in vitro percutaneous absorption of LHRH and ultrastructure of human epidermis. International Journal of Pharmaceutics (Amsterdam). 180(2). April 15, 1999.