IIPTA...A Patent Landscape on Dermal Filler 4 2.1 Dermal fillers: Dermal fillers (soft tissue...

A Patent Landscape onDermal Filler

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A Patent Landscape on Dermal Filler

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Abstract

The demand of dermal filler becomes global. A technology landscape analysis on dermal filler is conducted to find out the recent technology trend of the dermal filler and the future

research scopes on the said field. Several patents on dermal fillers are retrieved from the USPTO, WIPO, EPO, Patent Lens databases and analyzed on the basis of bibliographic and technical data. The analysis includes the bibliographic and technical analysis. The bibliographic analysis incorporates patenting activities over time, the patent distribution with in International Patent Classification, and patent analysis on the basis of applicants/assignees. The applications of the inventions, new products with compositions, and process involved within the dermal filler research arena are mind mapped. It is found that the first invention on the said field was taken place in 1980 and highest number of inventions were filed in 2006. United States is the leading country for the dermal filler though each of Korea, Japan, and Italy share moderate contributions to the global dermal filler market. A61K is the predominant international patent classification for dermal filler although several IPCs are found within the inventions which reflect the wide field of research. A moderate positive correlation (r=0.55) is shown between the number of patents on the basis of priority year and publication year. A strength, weakness, opportunity and threat analysis for the technology is also performed. Dow Corning Corporations, Allergen, Q-Med are considered as potential key players in the field of dermal filler. After the preliminary landscape report, a “white gap analysis” is performed to point out the future research scope on dermal filler.Keywords: Dermal filler, hyaluronic acid, collagen, silicone, hydroxyapatite, polylactic acid, permanent, semi-permanent, temporary, international patent classification, priority year, publication year, assignee, mind map


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TABLE OF CONTENTS

Chapter 1: Introduction ................................................................................................................

Chapter 2: Literature review .........................................................................................................

2.1 Dermal filler .....................................................................................................................

2.2 Types of materials used ..................................................................................................

• Polylactic acid ...........................................................................................................

• Calcium hydroxyapatite ..........................................................................................

• Collagen ....................................................................................................................

• Hyaluronic acid ........................................................................................................

• Silicone ......................................................................................................................

2.3 Mode of Action of dermal filler .....................................................................................

Chapter 3: Methodology ...............................................................................................................

Chapter 4: Result and Statistical analysis ...................................................................................

4.1 Bibliographic Analysis ....................................................................................................

4.1.1 Types of patents .....................................................................................................

4.1.2 Patenting activities over time ................................................................................

4.1.3 Number of patents over geographical scope .......................................................

4.1.4 Number of patents on the basis of applicants .....................................................

4.1.5 Patent analysis according to IPC ..........................................................................

4.2 Technical Analysis ...........................................................................................................

4.2.1 Mind map of applications of inventions ..............................................................

4.2.2 Mind map of final products and compositions ..................................................

4.2.3 Mind map of process involved .............................................................................

Chapter 5: SWOT analysis ............................................................................................................

Chapter 6: Competitive Intelligence ...........................................................................................

Chapter 7: White Gap Analysis ....................................................................................................

Chapter 8: Discussion ...................................................................................................................

References ......................................................................................................................................

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Who does not want to be the Handsome Hunk like Tom Cruise or angle of earth like Angelina Jolie? The fact is- most of the Hollywood stars do not born with handsome appearance; they have to make their appearances attractive to the spectators either by taking the help of non-surgical procedure or by going under scissors; even Mr. and Mrs. Smith start Angelina Jolie went under scissors to give a perfect shape of her lip. Nearly 11.7 million people have undergone cosmetic treatment in 2007 in the United States of America1 which showed a 45% escalation of the demand of cosmetic treatment since 1997. Breast augmentation, nose reshaping, eyelid surgery, liposuction, tummy tuck are the most common surgical cosmetic procedure whereas microdermabrasion, soft tissue fillers, hair removal procedures by external energy emitting device are considered as predominant non-surgical procedures2. According to the very recent data (2012) from the American Society of

Plastic Surgeons, the maximum demand for cosmetic procedure comes from the persons who belong between the age range “40-50” followed by the persons of late fifty3. The recent data also showed that female patients went under scissors than the male candidates in 2012 than in 2011 in the Unites States. The cosmetic treatment is not restricted within the United States of America; the demand also grows in India. The cheap rate and the immense traditional knowledge on Ayurveda lift India in a fifth position in a global tourism chart on the basis of medical cosmetic treatment4. A Bandra, Mumbai based dentist made a shocking comment “The average dentist in the United Kingdom is not qualified for advanced cosmetic procedures. Full mouth rehabilitation with bridgework, crowns and laminates there would cost approximately Rs 20 lakh ($39,000). In India, this will cost Rs 6.5 lakh (US$12,600) with dentists of better caliber”4.

Chapter 1: Introduction


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2.1

Dermal fillers: Dermal fillers (soft tissue fillers) are one kind of medical aesthetic device. Dermal fillers are the biomaterials which are used to address volume loss and contour defects in the lower third of the face. The characteristics of an ideal dermal filler are1:

a) Biocompatibleb) Painless to injectc) Non-immunogenic d) Non infectiouse) Minimal adverse effectf ) Inexpensive

It can complement surgical treatment to give a long lasting greater aesthetic appearance. FDA, USA recorded 930 cases on dermal fillers since 2003 to 2008 (Fig. 1);

Chapter 2: Literature review

Figure 1: Number of cases vs. year5

216

159

3

136

4

130

5

160

6

131

Year

no.

of c

ases

1 2


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The sources of the cases include 877 manufacturers of dermal fillers and 53 voluntary cases among which 739 cases came from the United States5 which meant the United States were the initiator of the dermal fillers in the cosmetic surgery.

In another study, FDA found 763 (94%) female candidates with dermal filler. But to know the prevalence of dermal filler in a specific age-range irrespective of their gender, FDA carried out another study on 533 cases where most of the patients (38%) belonged to the age-range “50-60” (Fig. 2).

Dermal fillers are injected to patients through most 9 common sites5: a) nasolabial, b) lips, c) peri-orbital, d) forehead, e) peri-oral, f) cheeks, g) chin, h) nose, and i) other sites- such as hands, forearm, earlobe, nipple, foot, and neck either through6 linear threading technique, or serial puncture technique or through fan technique. The needle is inserted through the middle of the wrinkle and injected the dermal fillers to the wrinkle in case of linear threading technique6. For

the serial threading technique, multiple injections are placed serially along the length of the treated wrinkle or fold6; the needle is inserted so closely that it merges into smooth continuous line which lifts wrinkle whereas the needle inserted along the periphery of the wrinkle/fold area for fan technique6. A research was performed to evaluate the frequencies of each injection site category (Fig. 3);

Figure 2: Patient demographic5

Age-range

2

10 to 20 20 to 30

14

30 to 40

75

40 to 50

135

50 to 60

203

60 to 70

85

70 to 80

18

above 80

1

no.

of c

ases


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Among 536 cases, nasobial was most preferred injection site (191) followed by lips (145), forehead (79), pre-orbital (78), pre-oral (76), cheeks (47), nose (16), chin (15) and other (10), respectively.

The ideal dermal filler does not create any adverse effect; but FDA, USA conducted a statistical analysis over 930 cases among which adverse effects were taken place

for 823 cases. Device malfunctions were also found for 93 cases. Allergic reaction, swelling, inflammatory reaction, erythema, numbness, migration, bleeding and others- such as tear duct obstruction, blurred vision, heart attack etc were documented as the adverse effects due to the dermal fillers. Figure 4 demonstrates the frequency of each category of events;

Figure 3: Frequency of each injection site category5

Figure 4: frequency of occurrence vs adverse events category5

swellin

g

erythmia

allergy

vascular e

ventspain

lumps/bumps

blister/c

ystother

numbness

bleeding

adverse effects

no.

of c

ases

334

150

15

292

230

39

140

13

275

163

44 22 13

lips chinforehead othernasobial cheeksorbital noseperi

145

15

79

10

191

4778

16

76

site of injection

no.

of c

ases


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Most of the cases showed swelling (334) as the adverse effect of the treatment with dermal fillers. Among the 93 cases of malfunction, 90 cases were related to the syringe5.

Dermal fillers can be temporary, semi-permanent and permanent1 (table 1); the longevity of the fillers depends on the

composition and the biodegradability of the products. The dermal fillers which remain for one to two years in tissues and which persist for more than two years in the tissues are considered as semi-permanent and permanent dermal fillers, respectively . The taxonomy of some standard fillers are listed down in table 2

Generally poly-lactic acid, hyaluronic acid, hydroxyapatite, collagen and silicone are the main constituents of the dermal filler. The brief ideas about the materials are given in the next section;

2.2 Types of materials used

Polylactic AcidPolylactic acid (PLA) is an aliphatic biopolymer which is derived from the natural resources and crude oil. It was discovered by Carothers in 1932 at DuPont. Polylactic Acid (low molecular weight) was produced by heating lactic acid under vacuum replacing the condensed water6. The first application

of PLA was combined with polyglycolic acid and sold under the brand name Vicryl in the U.S.A. in 1974. The single monomer of PLA, lactic acid (2-hydroxy propionic acid), is generated through fermentation or chemical synthesis. Corn starch is used as raw material for lactic acid fermentation production. Lactic fermentation process is generally adopted in the case of industrial lactic acid productions because the chemical synthesis have major drawbacks such as high manufacturing cost and inability to manufacture desirable L-lactic acid stereoisomer6. Since lactic acid has both –OH and –COOH groups, the production of PLA can be taken place by the reaction (figure 1);

Table 1: Classification of dermal fillers by composition1

Temporary (<1 year)

Autologus fat transfer, collagen, cultured

fibroblasts, hyaluronic acid

Semi-permanent (1-2 year)

Calcium hydroxyapatite, Polylactic acid,

Polyvinyl alcohol, Hydroxymethylmethacrylate

Permanent (>2 years)

Collagen implant- porcine, polytetrafluroethylene,

Polyacrylamide gel, Polymethymethacrylate


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PLA has two isomers: L-lactic acid and D-lactic acid (figure 2). Pure L-lactic acid or D-lactic acid are both used for synthesis of PLA6. These two isomers can generate four distinct materials such as Poly D-lactic acid (crystalline material with regular chain

structure), poly L-lactic acid (hemicrystalline with regular chain structure), poly D,L- lactic acid (amorphous) and meso-PL6. Except the fourth distinct material, each of these three materials is soluble in benzene, choloroform and dioxane6 etc.

The physical properties of PLA such as glass transition temperature, melting point, tensile strength, tensile modulus and elongation at break6;

Figure 5: Direct polymerization from lactic acid7

Table 2: Physical properties of PLA

Figure 6: stereoisomers of PLA6

Glass transition temperature (Tg)

Melting point (Tm)

Tensile strength

Tensile modulus

40-70o C

130-180o C

48-53 MPa

3500 MPa


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The applications of PLA in tissue engineering become well-known after the documentation of the drawbacks of the biometals and bioceramics in scaffold. An ideal scaffold is used as dermal filler and must be7;

a) Biocompatibleb) Porous with appropriate pore sizes of the

tissue to permit the cell growths and the removal of the waste

c) Mechanically endured with the local stress from the associated tissues,

PLA is one of most recognized polyesters which are used in tissue engineering for its biodegradable and biocompatible properties. The mechanical strength and the porosity are also favorable to choose PLA as dermal fillers. But, slow hydrolytic degradation and hydrophobicity limit the cell adhesion7. The investigations on the applications of PLA in wound healing process and facial treatment (facial lipoatrophy and scar rejuvenation) have been going on7.

HydroxyapatiteHydroxyapatite (CaHA) is one kind of bioceramic which is mineral form of calcium apatite8. The hydroxyl ion (OH-

) can be substituted by the fluoride ion (F-), choride (cl-) etc. It is not informed about the first commercial application of calcium hydroxyapatite, but currently calcium hydroxyapaptite is used as medical aesthetic material for dermatological treatment8. CaHA can be produced by solid state reactions and by the hydrothermal treatment. Solutions of the compounds containing calcium ions (Ca++) and phosphate ions (PO4---) are mixed together and finally, CaHA is precipitated8. The natural sources

of Ca++ ions can be calcium chloride, calcium carbonate, calcium nitrate etc whereas the sources of PO4--- may be sodium phosphate, potassium phosphate, phosphoric acid etc. Orlovskii and his co-workers recommended a reaction for preparation of CaHA8;

Ca(NO3)2 + KH2PO4 Ca10(PO4)6 (OH)2

The precipitation is collected through a filter and washed by ethanol which is followed by drying at 40-50 oC. The dry process involves the mixing of solutions containing appropriate amounts of Ca++ and PO4--- and calcinated within the temperature range of 1300oC. The source of OH group is found from the application of water vapor8. The application of CaHA in dermatological field is well-known. Radiess, a semi-solid synthetic product of CaHA has been used for last 20 years as an irreplaceable material used in dermal filler. This product is produced by suspending CaHA microspheres of 20-45 microns diameter in a gel carrier of carboxymethylcellulose. Radisse is used to cure facial wrinkles, folds9. The gel is replaced with soft tissue growth and the CaHA remains at the site of injections9. The local histeocytic and fibroblastic actions are started to generate collagen around microspehres. CaHA is degradable material; over time, caHA is broken into Ca++ and PO4-

-- ions and these ions are eliminated through the basic metabolism process. The average cost is US 681 per Radiess injection for facial augmentation whereas the cost of raw hydroxyapatite is varied from US $ 1-1000 per Kg10.


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CollagenCollagen is naturally occurring proteins found in connectives tissues of animals. Collagen extracted from cow, was used as a scaffold. But, the chance of bacterial or viral contamination with the injected site of human body. The researchers of Rice University combined stem cells and collagen-like materials in the laboratory to produce laboratory grown tissues which could be transplanted to patients11 without the risk of bacterial and viral contaminations. The molecular weight of collagen is varied from 1,000- 10,000 and the hydrolyzed collagen is composed of several types of amino acids with their varied concentration; among them, glycine is the most superior amino acid. Collagen also contains additional two amino acids which are not found in other proteins- Hydroxyproline and Hydroxylysine12. Type 1 collagen material has minimal antigenicity, good hemostatic capability, and readily available from natural resources13. Films made from hydrolyzed collagen can be used as a tissue adhesive for suture replacement because of its biodegradable, nontoxic, readily absorbable characteristics13. Hsirao and his co-worker (2010) documented the manufacturing process of collagen membrane; the collagen slurry (a monomer solution) was prepared which was degassed later to form collagen with predetermined concentration, pH, and ionic strength14. The resultant product is added with an absorbent material to remove water which ultimately formed to collagen mat. Finally collagen mat is dried under vacuum by gel drier to produce collagen membrane. The collagen processing technology can provides several products in several forms including

sheets, putties, gels, fibers, powders etc. The liquid collagen is generally used for the beauty products and nutritional supplement. Collagen can also be available in powder form and is sold under the name of beauty collagen. It is manufactured from fish skin by using a complex hydrolysation method. Vitamin C, Vitamin B6 and Copper are necessary for collagen synthesis11,12,13,14. A lack of these important vital nutrients may lead to premature aging of the skin and development of wrinkles.

Hyaluronic AcidHyaluronic Acid (HA) is a natural component found in all natural connective tissue. While the use of HA has increased within the cosmetics community, the vast majority of people remain unaware of its unique history. Hyaluronan was first discovered in 1934 by Karl Meyer and John Palmer through the isolation process of a chemical substance from cow eyes15. In the year 1950, the first application of Hyaluronan in medical sector was found as vitreous replacement during an eye surgery15. It was first isolated as acid, but under physiological conditions, it started to behave like a salt (sodium hyaluronate).Hyaluronan, an extracellular matrix component, is a high molecular weight glycosaminoglycan composed of disaccharide repeats of N-acetylglucosamine and glucuronic acid15. It is found in skin, umbilical cord, synovial fluid, and vitreous humor, lung, kidney, brain and muscle tissues15

D- Glucuronic acid and N-acetylglucosamine are linked together through beta-1,4 and beta-1,3 glycosidic bonds (figure 3);


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HA is naturally synthesized by membrane proteins, called hyaluronan synthases. These enzymes (hyaluronan synthases) synthesize polymers of the repeating disaccharide structure of hyaluronan by alternate addition of glucuronic acid and N-acetylglucosamin15. The hygroscopic nature of Hyaluronan is important for modulating tissue hydration and osmotic balance. Apart from this, Hyaluronan also acts as signaling molecule by interacting with cell surface receptors, migration and differentiation15. HA is not toxic, non-antigenic, non-immunogenic, biocompatible and has high structural homology across species and low interaction with blood15.

SiliconeObserving the similarity with “ketones”, the name “silicone” was provided by Kipping in 1901 to explain new compounds of the formula R2SiO16. The name silicone was adopted by the industry and usually refers to linear polymers such as polydimethylsiloxane16. The presence of “organic” compound with “inorganic” bond gives silicone excellent biocompatibility which is useful for healthcare purpose. Silione was first discovered in 1824 through the reaction of potassium with potassium fluoroslicate16:

4K + K2SiF6 Si + KF

First organic application of silicone was shown in 1863 by the reaction of diethyl zinc with silicone chloride which produced tetraethylsilane16;

Zn (C2H5)2 + SiCl4 Si(C2H5)4 + 2 ZnCl2

The most common silicone are polydimethylsixane (sometimes trimethylsiloxy) compounds

Figure 8: polydimethylsixane

Silicone polymers are obtained by three steps process: a) Cholosilane synthesis; b) cholosilane hydrolysis and, c) polymerization and polycondensation16.

a) Cholorisilane synthesis16: The first step includes

i) the reaction of carbon with silicone metal

SiO2+C Si + CO;

Figure 7: Chemical structure of hyaluronic acid15


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ii) methanol with hydrochloric acid; CH3OH + HCl CH3Cl + H2O; iii) Flow of methanol on a silicone

powder at a temperature 250o to 350o degree and 1 to 5 bars to give dimethyldichlorosilane16;

b) Chlorosilane hydrolysis: Dimethyldichlorosilane is hydrolyzed in the epreence of excess water to give polydimethylsiloxanes16;

c) Polymerisation and polycondensation: The linear & cyclic oligomers obtained by hydrolysis of the dimethyldichlorosilane have too short a chain for most applications16.They must be condensed (linears) or polymerized (cyclics) to give macromolecules of sufficient length16.

The characteristic of silicone are17 1) low thermal conductivity; 2) low chemical reactivity; 3)low toxicity; 4) thermal stability; 5) non-adhesive to substrates but adhesive to metal; 6) high gas permeability. For these useful properties, silicone is known as one of the most common products in healthcare industries. Table 2 shows some standard dermal filler;


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Product name

Evolence

Cymetra

Zyderm I

Zyplast

Cosmoderm I, CosmoDerm II,

CosmoPlast

Restylane

Company

Johnson & Johnson

Lifecell corporation

Allergan Inc., Bay dermatology,

Neiman Joseph B Md Pc etc.

INAMED Corporation

INAMED Corporation

Medicis Aesthetics, Inc

Composition

non-pyrogenic device, porcine

collagen; available in two sizes - 0.5 ml

and 1.0 ml

human skin tissue

35 mg/mL of bovine collagen

and 0.3% lidocaine

35 mg/mL of bovine collagen

that is cross-linked with

glutaraldehyde

human-bioengineered

collagen distributed in a

phosphate-based saline solution and

0.3% lidocaine

biosynthetically produced

by bacterial fermentation;

Medium-sized particles of stabilized

hyaluronic acid

Indication

Facial fillers & wrinkle remover

Nasolabial and radial folds

glabellar frown lines, forehead furrows, crow’s

feet, fine perioral rhytides,

deeper rhytides, deeper skin folds,

atrophic scars

wrinkles and acne scars

facial tissue with moderate to

severe wrinkles and folds or the

lips

Approval status

FDA approval in 2008




FDA approval in March, 2003


Collagen

Hyaluronic Acid


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Product name

Perlane and Perlane L

Juvederm

captique

Hylaform/Hylaform Plus

Prevelle silk

Company

ORTHOFIX, INC

Inamed Corporation

Genzyme Biosurgery

Genzyme Corporation

Genzyme Biosurgery

Composition

Identical to Restylane with

larger gel particles.

Sterile, biodegradable, nonpyrogenic,

viscoelastic, clear, colorless

homogenized gel implant; cross-

linked hyaluronic acid

Hylaform but derived from

a bacterial source through fermentation

a sterile, nonpyrogenic,

viscoelastic, clear, colorless gel

implant composed of cross-linked molecules of hyaluronan

Colorless hyaluronic acid gel

with lidocaine

Indication

Correction of deeper folds, such as nasolabial folds

facial wrinkles and folds

skin contour deficiencies caused by

wrinkles and folds

skin contour deficiencies caused by

wrinkles and folds

Administration to deep dermis for correction of moderate

to severe facial wrinkles and folds

Approval status






Hyaluronic Acid


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Product name

XIAMETER® PMX-200 SILICONE

FLUID 12,500CS


FLUID 30,000CS

XIAMETER® PMX-200 SILICONE FLUID 350CS


FLUID 60,000CS

Q7-9120 SILICONE FLUID 20 CST

SILKY WAX 10

ST - CYCLOMETHICONE

5- NF

ST - ELASTOMER 10

Silikon 1000

Company

Dow Corning

Dow Corning

Dow corning

Dow corning

Dow corning

Dow corning

Dow corning

Dow corning

Alcon Laboratories

Inc

Indication

Skin care, hair care




Skin care

Skin care

skincare and topical & delivery

applications.

skincare and topical

pharmaceutical delivery

applications.

Subdermis

Approval status

Not approved

Not approved

Not approved

Not approved

Not approved

Not approved

Not approved

Not approved

Approval for labeling in 2013

Composition

12,500 cSt, polydimethylsiloxane

polymer


polymer

350 cSt, polydimethylsiloxane

polymer.


polymer.

High-purity non-volatile silicone fluid (NF Dimethicone, EP

Dimeticone)

semi-occlusive silicone wax (melting

point 53°C)

Volatile silicone, decamethylcy-

clopentasiloxane (Cyclomethicone NF)

blend of a unique silicone elastomer

and a volatile silicone fluid

Liquid siliconeInjectable liquid

silicone poly-dimethylsiloxane

Silicone


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Table 3: Branded dermal filler. Coursey http://www/fda.gov.in

Product name

Sculptra

Radiesse

Arte-Fil

Company

Dermik Laboratories

BioForm Medical, Inc

Artes Medical, Inc

Indication

deep dermis or subcutaneous

space

Sub-dermis

subcutaneous tissue

Approval status

Approved by FDA in 2004

Approved by FDA, USA in 2006

Approved in 2006 by FDA, US

Composition

Polyvinylhydroxide particles in

polyacrylamide gel

25-45 µm calcium hydroxylapatite microspheres suspended in cellulose gel

Silicone particles100-600 µm irregular

shaped, solid silicone particles

suspended in polyvinylpyrolidone

carrier

Polylactic Acid

Hydroxyapatite

polymethylmethacrylate


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2.3 Mode of actionBased on mode of action, dermal fillers can be categorized as volumisers (fillers) and stimulators1. Volumisers are of low viscosity and they injected usually to the upper layers of dermis1. When volumisers are administered to skin, they fill out the skin and increase facial volume1. The examples of some volumisers are collagen, silicone, hyaluranic acid (HA)1. Stimulators primarily create foreign body reaction over a definite period which results long term or permanent collagen deposition. Polymethylmethacrylate, calcium hydroxyapaptite, polylactic acid are the common exaplkes of stimulators. Some fillers include both volumising and stimulating components and fall into both classes 1.Based on the biodegradability, dermal fillers can be temporary, semi-permanent or permanent 1. Most biological materials such as collagen, hyaluronic acid etc lasts for less than 12 months before being resorbed in tissues 1. People who does not want permanent look but rather interested

to repeated experimentations with soft tissue augmentation, prefer temporary dermal filler. Slowly resorbable materials such as polylactic acid (PLA), calcium hydroxyapaptite (CaHA) are considered as semi-permanent dermal fillers and these fillers persist for one or two years in tissues 1. In order to maintain the effect of the dermal fillers permanently within tissues, certain materials such as liquid injectable silicone, polyacrylamide gels, polymethylmethacrylate,polytetrafluroethylene are considered as permanent fillers because of their non-resorbable characteristic 1.

The patent analysis incorporates the collection of patent data to determine about growth in particular technology. It proposes technology planning and shows the business opportunity on the particular technology18. The objectives of the study are to analyze the patents on breast ultrasound technology and assess the trend. This study incorporates bibliographical analysis and technological analysis of the patents on said technology which will be useful future researches.


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The first step of patent analysis was to retrieve the patents-both granted and published related to dermal filler. Patents were retrieved from freely available databases of international/national patent offices (The United States Patent and Trademark Office or USPTO, World Intellectual Property Organization or WIPO, European Patent Office or EPO, and a free public resource for global patent systems (Patent Lens). Each database provides several options such as title, abstract, claims, intellectual patent classification code etc., and the keywords are mentioned at least in one or each of these provided options to find out particular patents. The patents were found from the different combinations of keywords mentioned in title, abstract or claims of the databases. Table 1 demonstrates the names of the databases, corresponding search queries and number of patents found on dermal fillers from these databases. Some of the patents which were found in one database were repeated again in other

databases; so, these repeated patents were considered for single time only. Altogether, 324 patents were retrieved for analysis among which 220 patents (& patent applications) from WIPO, 54 patents patents (& patent applications) from USPTO, 33 patents (& patent applications) from PatentLens and 17 patents (& patent applications) from Espacenet were considered (Table 8). No separate patent (or patent application) was found from IPO.

After retrieval, the non-technical and technical information from the patents were collected and the raw data were represented in taxonomical manner. These raw data were analyzed to evaluate the patenting activities over time, the number of patents over geographical scope, types of assignees and international patent classifications. Also, further analysis was carried out to map the application areas, new products, process involved in the arena of dermal filler research.

Chapter 3: Methodology


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Table 4: Search query, database and results

Search query

En_Ti: hydroxyapatite and Cl: skin

En_Ti: methacrylate and Cl: skin

En_Ti: (hyaluronic acid) and Cl: skin

En_Ti: silicone and Cl: skin

En_Ti: dermal filler

En_Ti: collagen and Cl: skin

ttl/ “dermal filler”

Ttl/ “hyaluronic” and aclm/ “skin”

Ttl/ “hydroxyapatite” and aclm/ “skin”

Ttl/ “silicone” and aclm/ ”skin”

Ttl/”methacrylate” and aclm / “skin”

Title: (hyaluronic acid) and abstract: skin

Title: hydroxyapatite and abstract: skin

Title: collagen and abstract: skin

Title: methacrylate and abstract: skin

En_ Ti: (glycolic acid) and Cl: skin

Title: (hyaluronic acid) and abstract: skin

Title: hydroxyapatite and abstract: skin

Title: collagen and abstract: skin

Name of database

WIPO

WIPO

WIPO

WIPO

WIPO

WIPO

USPTO

USPTO

USPTO

USPTO

USPTO

EPO

EPO

EPO

EPO

WIPO

Patent Lens

Patent Lens

Patent Lens

No. of hits

11

12

203

652

102

185

41

48

0

166

6

326

11

500

20

0

193

11

394


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Table 5: patents/patent applications considered from each database

Patents/patent applications

220

54

33

17

Database

WIPO

USPTO

PatentLens

EPO


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4.1Bibliographic analysis

4.1.1Types of Patents:

It is known that there are three types of

patents- product, process and product-process patents. The analysis (Fig. 5) indicated that maximum number of patents were on product patents (54%) followed by product patents (%) and product-process patents (24%), respectively.

4.1.2 Patenting activities over time: Patenting activities are generally evaluated through priority year (filing year where applicable) and publication year. Priority year is the year when inventors first disclose their invention to the government authorized body whereas the publication year is the

year when the contents of the patent come to public knowledge through the database handled by the specific patent offices. Fig. 6 shows the technology trends of dermal fillers on the basis of priority year and publication year. There is no specific trend found on the basis of priority year and publication year.

Chapter 4: Results and statistical analysis

Figure 9: Types of Patents Patents (%)

Types of Patents

54%

24%

22%


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4.1.3 Number of patents over geographical scope:

Maximum inventions were found in United States (15%) followed by Italy (8%), France

(7%), Japan (6%), Korea (4%), Germany (3%), Canada (2%), respectively. Other countries included Great Britain, Spain and Denmark.

Figure 10: Patenting activities over time

Figure 11: Patent distribution over geographical scope

Year

14

no.

of P

aten

ts

12

10

8

6

4

2

0

1975 19801 985 1990 1995 20002 005 20152010

-2

number of patents(on priority year)number of patents

15

6

3

1

8

5

21

7

4

1

United

States Italy

France

Japan EPKorea

Germany

Canada

Great Brit

ainSpain

Denmark

no.

of P

aten

ts %

Countries


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4.1.4Number of Patentson the basis of applicants:

The patent data (Fig. 8) were analyzed on the basis of following categories of applicants: industrial organizations, individual investor, law firm, academic research unit and healthcare research unit. Highest number of patents was registered from industrial organizations (55%) followed by individual investor (9%) and law firm (7%), respectively. The University of British Columbia applied

only one patent on dermal filler. No information about the contribution from any healthcare research unit as the applicant was found.

Dow Corning Corporation, Allergen Inc., Fidia Pharmaceutical S.P.A., Novozymes Biopolymers S.A., Hyal Pharmaceutical Corporation- these industrial organization were considered as major applicants in the field of dermal filler. Fig. 8 demonstrates the analysis on patent applications from individual industrial organizations:

Dow Corning Corporation, the leading assignee filed 15 patents followed by Allergen Inc. (10), Fidia Pharmaceutiocal S.P. (10), Novozymes Biopolymer A/S (8), Hyal Pharmaceutical Corporation (4), Amorepacific Corporation (4), Laboratory Skin Care (2) and Loreal (2), respectively.

Figure 12: Major industrial organizations vs. patent applications

Organization

no.

of P

aten

ts

15

4

10

2

8

10

4

2

Allerga

n, Inc

Novozymes

Biopolymer A/S

Laborat

ory

skin care Lo

real


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4.1.5 Patent analysis according to IPC

A more detailed analysis on the fields of dermal filler was made by analyzing the

patents on the basis of international patent classification (IPC). The analysis (Fig. 9) sorted out major IPCs with number of patents (%);

Table 6: Number of Patents vs. IPC

IPC

A61K

A61Q

A61P

A61L

C08B

A61M

A61F

C08G

C08L

Definition

preparations for medical, dental and toilet purpose

specific use of cosmetics

therapeutic activity of chemical compounds or medicinal preparations

methods or apparatus for sterilising materials

polysaccharides; derivatives thereof

devices for introducing media into, or onto, body

filters implantable into blood vessels; prostheses; orthopaedic, nursing or contraceptive devices; fomentation; treatment or protection of eyes or ears; bandages, dressings or absorbent pads; first-aid kits

macromolecular compounds obtained otherwise than by reactions only involving unsaturated carbon-to-carbon bonds

compositions of macromolecular compounds

Number of Patents (%)

64

22

17

7

6

5

4

4

4

A61K is the most predominant (64%) IPC within the dermal filler patent areas followed by A61Q (22%), A61P (17%), A61L (7%), C08B (6%); A61M (5%), A61F (4%), C08G (4%), and C08L (4%), respectively. Other IPC s included A01N, C12P, C08F, C08J, B23P, C07K, C07H, C07C, B82Y, B32B, G02B, G08K, C07F, C11D, and A61B, respectively.


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Figure 13: patent distribution according to IPC

7%

64%

4%2% 2%

1%

22%

17%

6%4%

2%1%

5% 4%2%

1% 1%1% 1% 1%1% 1% 1% 1%

no.

of P

aten

ts

IPC

A61k

A61Q

A61P

A61L

A61M

A61F

C08B

C08G

C08L

A01N

C12P

C08F

C08J

C07K

C07H

C07C

B82Y

B32B

G02

B

G08

K

C07F

C11D

A61B

B23P


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4.2Technical Analysis

4.2.1Mind map of applications of inventions


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4.2.2Mind map of final products and compositions


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4.2.3Mind map of process involved


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Chapter 5: SWOT Analysis

Table 7: SWOT Analysis

Opportunities

• American market is mature, though European21 and Asian22 market looks promising.

• Current study shows researches on generation cheap dermal fillers with advanced administration process can expand the demand of dermal filler19

Weakness

• Careful and sensitive procedure needed for administrations- Needs expertise people for the treatment with the dermal filler1

• Expensive but the pricing varies depending on the number and types of areas being treated20

Strength

• demand of dermal filler has been continued since tradition and it never ends19

• Wide ranges of materials- animal extract or plant extract are useful to make dermal filler

• Generally biocompatible , non-allergic1

Threats

• Chance and fear of adverse effects from dermal filler20

• Mentality of some people to maintain original looks instead of any artificial appearance

• Regulatory laws or patent laws may discourage the inventions on dermal filler21


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Chapter 6: Competitive Intelligence

Company

Dow Corning

Allergen Inc

Q-Med Esthetics

Bioform medical Inc.

Product range

XIAMETER® PMX-200 SILICONE FLUID 1,000CS; XIAMETER® PMX-200 SILICONE FLUID 12,500CS; ST - ELASTOMER 10; ST - CYCLOMETHICONE 5- NF; SILKY WAX 10;

Q7-9120 SILICONE FLUID 20 CST;

XIAMETER® PMX-200 SILICONE FLUID

60,000CS23

Zyderm I, Zyderm II and ZyPlast; CosmoDerm

and CosmoPlast; Juvederm 24 HV,

Juvederm 30HV and Juvederm 3024

Perlane, Restylane, and Mercolane,

Emervel25

1.5cc Radiesse Volume Advantage

syringe 26

Financial information

Sales $ 6.12 billion; net income income $ 188

million in 201223

$1,391.1 million total product net sales- 6.1 % compared to total product net sales in 2011; revenue $ 5.7 billion (in 2012) with a growth of 9% than

201124

3046300 SEK in 2012 total asset25

336.1 million Euro net earning in 201226

Research and development

Silicone based research on skin care application, topical

delivery process, transdermal drug delivery process23

researches going on facial Aesthetics specially Cheek Augmentation to Correct

Age-Related Volume Deficit in the Mid-Face24

Working on lip enhancement treatment, acne and scar

removal 25

Working in order to smoothen nasolabial folds26


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Table 8: Competitive intelligence

Company

Fidia pharmaceutical

L’oreal

Product range

Genaid; Hyal-System; Hyalogyn; Hyalosilver;

Jaloplast; Jaloplast Plus27

Age perfect glow renewal, Youh code texture perfector;

Revitalift; Ideal Moisture skin tone28

Financial information

Not available

22,5 billion Euros of sales in 2012; €791M

invested in Research and Development28

Research and development

Working on skincare and tissue repair27

Working on skin and hair care, also researching on

stem cell; 20 molecules have been developed over the

last 40 years (among them the Mexoryl™ SX for sun

protection and the Ceramide R rebuilding strong hair

fibers)28


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White Gap analysis is an analysis which is conducted after the preliminary landscape report of a particular technology. It is required to identify the “white gap” of the technology. “White gap” means the problems related to technology which is not solved and landscape analysis is conducted to find out the problems which are needed to be eradicated in the future. This analysis actually shows the scope of future researches of the technology.

After landscape analysis, the following “white gaps” related to the dermal filler found:

a) The treatment with dermal filler is usually expensive; cheap dermal filler products are needed to be invented.

b) Most of the dermal fillers do not exist at the treatment site of the patients;

generally after two months, the dermal fillers products degrade. Starting of degradation means the return of the pre-treatment condition of the patients. So, non-biodegradable dermal fillers are needed to be produced.

c) The injection site sometimes show redness, inflammation for some cases; so the injections technique should be improved

d) Some dermal filler can not permanently cure problems such as wrinkles and scars; so the choice of fillers before administration is necessary.

e) Dermal fillers can create problem for some patients- such as patients who are pregnant or breastfeeding; so before treatment- each and every detailed should be informed to the physicians.

f) Gender differences to the responses from dermal filler

Chapter 7: White Gap Analysis


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Chapter 8: Discussion

The demand of dermal filler is showing promising trend29,30. The history of dermal filler started from 1840, but those dermal fillers were not available in the non-allergic or bio-compatible form. Zyderm products are the first biocompatible non-allergic medicines which have been started to be commercialized by Allergen Inc.- the leading company of dermal filler from 1980. The present study showed 3 patents were filed in the year 1984 that meant the researches were started from 1984 which shared the similar evidence with Allergen’s product commercialization history24.

The patenting activities over time (Fig. 6) showed that no specific trend was found for either the number of patents on the basis of priority year or publication year. The importance of priority year (filling year if applicable) reflects the performance activities from the technologies whereas from the same date of the publication year, the inventors or the applicants can start to commercialize the patents; so the timeframe between the priority date/year and the publication date/year is necessary to estimate the time taken by the inventors/applicants to complete the research which reflects the performance of the company/inventor. A correlation analysis between the number of patents on the basis of priority year and publication year was conducted

and the result showed that there were moderate positive correlation (r=0.55) between the number of patents on the basis of priority year and publication year. The correlation coefficient concluded that there was a tendency of increasing the number of patents on the basis of priority year with the number of patents on the basis of publication year (or vice versa).

The maximum number of inventions was documented in the year 2006 though a downward slope of invention on dermal filler was shown after the year 2006; only 9 patents were filed in 2008. The market saturation and the reduction of consumer spending were considered as the reason for decreasing trend of inventions31. However, Moheito and Prather (2007), two American researchers found the same information from their work- according to them, the worldwide market for dermal filler was increased 19% in 2006 and the US market was expected to increase further 20% to 25%32. The expectation from the American market was not new in the document of Moheito and Prather (2007)32.

The analysis of patent data on the basis of geographical scope (Fig. 7) demonstrated that the highest number of invention (15% of en tire inventions) on dermal filler came from the United States. The country which


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makes significant number of inventions, also faces a noteworthy growths- the dermal filler market within the United States of America has faced a major growth (20%) throughout the world30. Apart from the United States and European countries, Japan and Korea also made significant contribution in the market of dermal filler31. According to Sahoo (2011), the downsizing of American and European market has given an opportunity to grow the Asian market31. Japan represented the single largest Asian territory for aesthetic products and accumulated $168.1 million in total sales followed by South Korea followed ($93.2 million), China ($73.2 million), Australia ($53.3 million), Taiwan ($18.6 million) and India ($10.1 million), respectively31. A document on global dermal market pointed out non-animal hyaluronic acid products as the popular dermal filler product. The introduction of Q-Med’s Restylane with “non animal stabilized hyaluronic acid (NASHA)” technology has opened a new era in dermal research25. New semi-permanent and permanent fillers have entered into the market to fulfill the patient’s demands. Fig. 14 and 15 will demonstrate the revenue and sales of the global dermal fillers (study conducted from 2005 to 2011)33. The data (Fig. 14) showed the continuous growths of revenues of dermal fillers especially a hike in a case of hyaluronic acid. The demand of the dermal fillers from the patients also grows up since the 2005 which is reflected from the statistical analysis of global sales market of dermal filler (Fig. 15).

A patent can be categorized under more than one international patent classification. From the present work, it was found that there

is maximum number of patents registered under A61K which covers medical and dental preparations (Fig. 9). This was followed by A61Q and A61P. The wide breadth of field gave the opportunity for broad patent coverage.

The inventions on dermal filler have been going on for the applications of dermal fillers such as cleansers, moisturizers, volumizers, wrinkle or scar removers, sunscreen product, and the protector for ultraviolet radiation. Dermal filler is also used as the patients who do not want to keep the evidence of aging on their skin. Silicone, hyaluroniuc acid hydroxyapaptite (sintered macroporous hydroxyaapatite) are indicated as the valuable constituents for the dermal filler. Along with these main constituents, anti-microbial agent, anti-inflammatory agents are used to make the product safe for the patient. Also, vitamins (especially vitamin c and vitamin e) are incorporated with the dermal filler to improve the skin condition. Botulinum neurotoxin is targeted to use to remove the wrinkle from skin whereas the combination of peptide component with the collagen products and enzyme based component are incorporated to make a special cream for only night time. Tissue augmentation is another important application of dermal filler where the ceramic biomaterials with less than 30 % surface porosity are usually suspended over water. The delivery system of the dermal filler is also targeted to be improved. The patent data showed that the cross-linked hyaluronic acid is commonly considered for the manufacturing of dermal fillers. The cross-linked hyaluronic acid is


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homogenized, neutralized and mixed with calcium salt would make dermal filler. Also, a pharmaceutical composition with the autologus growth factor was mentioned to improve the skin condition. The enzymatic hydrolysis of hyaluronic acid polymer followed

by derivation of hyluronic acid oligomer would prepare conjugate composition. The administration procedure of high viscosity dermal filler and the synthesis process of dermal macromolecules were also focused within the research areas of inventions.

Figure 14: Dermal Filler revenue (2005-2011)

Year

$322

$55 $67

2005

$476

$49$94

2006

$613

$58

$131

2007

$749

$75

$181

2008

$861

$84

$241

2009

$1026

$94

$278

2010

$1110

$105

$306

2011

Rev

enue

HACollagen

Particle


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Figure 15: Dermal Filler sales (2005-2011)

$441

$1,345

$594

$1,473

$959

$761

$1,138

2005 2006 2007 2008 2009 2010 2011

Sale

s gr

owth

Year


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References

1. L Sturm et al. (2009). Permanent and Semi-Permanent Dermal Fillers. ASERNIP-S Report No. 55. Adelaide, South Australia: ASERNIP-S. Available online

http://www.surgeons.org/asernip-s Last access 17th Sept., 2013

2. Cosmetic Procedures Increase in 2012, Available Online http://www.surgery.org/media/news-releases/cosmetic-procedures-increase-in-2012 Last Access 25th Nov., 2013.

3. 2012 Plastic Surgery Procedural Statistics. AMERICAN SOCIETY OF PLASTIC SURGEONS. Online Available http://www.plasticsurgery.org/news-and-resources/2012-plastic-surgery-statistics.html Last access 17th Sept. 2013

4. A Ghaswalla. (2009). Travel trends: Cosmetic surgery in India. CNN Travel. Available online http://travel.cnn.com/mumbai/life/boob-talk-land-bollywood-123207 Last Access 17th Sept., 2013

5. L Lim. (2008). Executive Summary- Dermal Filler Devices. FDA General and Plastic Surgery Devices Panel. Available Online http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4391b1-01%20-%20FDA%20Executive%20Summary%20Dermal%20Fillers.pdf Last access 17th Sept., 2013.

6. Jamnshidan et al. (2010). Poly-Lactic Acid: Production, Applications, Nanocomposites, and Release Studies. Comprehensive Reviews in Food Science and Food safety. 9(5):552-571.

7. Xiao et al. (2012). Poly (Lactic Acid)-Based Biomaterials: Synthesis, Modification and Applications. Biomedical Science, Engineering and Technology, Prof. Dhanjoo N. Ghista (Ed.), ISBN: 978-953-307-471-9, InTech. Available online http://www.intechopen.com/books/biomedical-science-engineering-and-technology/poly-lactic-acid-based-biomaterials-synthesis-modification-and- applications Last Access 17th Sept., 2013.

8. VP Orlovskii, VS Komlev, and SM Barinov. (2002). Hydroxyapatite and Hydroxyapatite-Based Ceramics. Inorganic Materials. 38(10): 973-984.


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9. P Jacovella. (2008). Use of calcium hydroxylapatite (Radiesse®) for facial augmentation. Clin Interv Aging. 3(1):161-174.

10. Available Online http://www.radiesse.com/ Last Access 19th Nov., 2013.

11. Lesley et al. (2011). Multi-hierarchical self-assembly of a collagen mimetic peptide from triple helix to nanofibre and hydrogel. Nature Chemistry. 3:821-828

Available Online http://www.faqs.org/patents/app/20100098924 Last Accecss 17th Sept., 2013 12. NF Estrin, PA Crosley, CR Haynes. (1982). The CTFA Cosmetic Ingredient Dictionary, 3rd

ed. Washington, DC. The Cosmetic, Toiletry and Fragrance Association 1982. Available Online http://www.hymed.com/wp-content/themes/atahualpa351/pdfs/COLLAG1.pdf Last Access 17th Sept., 2013

13. G Petito. Concepts of Dietary Peptides: Collagen Hydrolysates. Online available http://www.hymed.com/wp-content/themes/atahualpa351/pdfs/dietpep.pdf Last access

17th Sept, 2013

14. T Hsiao, Y Lin. (2010). Collagen membrane for medical use and method for manufacturing the same. Patent application no: 20100098924.

15. J Necas, L Bartosikova, P Brauner, J Kolar. (2008). Hyaluronic acid (hyaluronan): a review. Veterinarni Medicina. 53 (8): 397–411.

16. A Colas. (2005). Silicones: Preparation, Propertiesand Performance, Dow Corning Corporation. Available Online http://www.dowcorning.com Last Access 26th Nov., 2013.

17. H Morreto, M Schulze, G Wagner. (2000). Silicones, Ullmann’s Encyclopedia of Industrial Chemistry, DOI: 10.1002/14356007.a24_057.

18. K Sastry, HB Rashmi, NH Rao. (2010). Nanotechnology Patents as R & D Indicators for Disease Management Strategies in Agriculture, Journal of Intellectual Property Rights, 15: 197-205.

19. FS Brandt, A Cazzaniga. (2008). Hyaluronic acid gel fillers in the management of facial aging, Clin Interv Aging, 3(1): 153–159.

20. Bauman et al. Dermal Fillers. Available Online http://www.mhprofessional.com/downloads/products/0071490620/BaumannCh23.pdf Last Access 17th Sept., 2013


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21. Injectable dermal fillers, Available Online http://www.asstech.com/en/downloads/newsletter_Dermal_Fillers_engl.pdf Last Access 17th Sept., 2013

22. S Pitman. (2011). China and India show great promise in dermal filler treatments, Available Online http://www.cosmeticsdesign-asia.com/Market-Trends/China-and-India-show-great-promise-for-dermal-filler-treatments Last Access 17th Sept., 2013.

23. Available Online http://www.dowcorning.com. Last Access 28th Nov., 2013.

24. Available Online http://www.allergan.com/index.htm Last Access 17th Sept., 2013

25. Available Online http://www.q-med.com/ Last Access 17th Sept. 2013

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27. Available Online http://www.fidiapharma.us/en/ Last Access 17th Sept., 2013

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29.Dermal Fillers. Global Aesthetic Market V: A Market Evolution. Available Online http://www.pharmatree.in/pdf/reports/Global%20Aesthetic%20Market%20Study%20V%20062608%20Dermal%20fillers.pdf last Access 16th Sept., 2013.

30.Hyaluronic Acid Dermal Filler Market Skyrockets. Available Online http://www.prnewswire.com/news-releases/hyaluronic-acid-dermal-filler-market-skyrockets-57024492.html Last Access 26th Nov., 2013.

31.A Sahoo (2011). Asian Aesthetic Market Report. The Aesthetic Guide — November/December 2010. Available Online http://digital.miinews.com/article/Asian_Aesthetic_Market_Report/555365/53062/article.html Last Access 16th Sept., 2013

32. GD Monheit, CL Prather. (2007). Juvéderm: a hyaluronic acid dermal filler. J Drugs Dermatol. 6(11):1091-5.

33. Available Online http://www.miinews.com/exec_summaries/Global%20Market%20for%20Dermal%20Fillers%20Executive%20Summary%20-%20022106%20SK.pdf Last Access 28th Nov., 2013.

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