EP1534241A1 - Transdermal aerosol compositions - Google Patents
Transdermal aerosol compositionsInfo
- Publication number
- EP1534241A1 EP1534241A1 EP03732114A EP03732114A EP1534241A1 EP 1534241 A1 EP1534241 A1 EP 1534241A1 EP 03732114 A EP03732114 A EP 03732114A EP 03732114 A EP03732114 A EP 03732114A EP 1534241 A1 EP1534241 A1 EP 1534241A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- composition according
- skin
- agent
- penetration enhancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to transdermal aerosol compositions for topical application, a spray device for transdermal delivery of aerosol compositions and to a method of transdermal delivery of therapeutic agents.
- Transdermal delivery of therapeutic agents offers several inherent clinical and patient advantages over traditional oral tablet and capsule formulations, especially for drugs that:
- transdermal drug delivery has received increased attention because it not only provides a relatively simple dosage regime but it also provides a relatively slow and controlled route for release of a physiologically active agent into the systemic circulation.
- transdermal drug delivery is complicated by the fact that the skin behaves as a natural barrier and therefore transport of agents through the skin is a complex mechanism.
- the skin consists of two principle parts, a relatively thin outermost layer (the 'epidermis') and a thicker inner region (the 'dermis').
- the outermost layer of the epidermis (the 'stratum corneum') consists of flattened dead cells which are filled with keratin.
- the region between the flattened dead cells of the stratum corneum is filled with lipids which form lamellar phases that are responsible for the natural barrier properties of the skin.
- the agent For effective transdermal delivery of a physiologically active agent that is applied to the surface of the skin ('topical application'), the agent must be partitioned firstly from the vehicle into the stratum corneum, it must typically then be diffused within the stratum corneum before being partitioned from the stratum corneum to the viable epidermis, dermis and into the bloodstream.
- physiologically active agents can be formulated with incorporation of one or more drug penetration enhancers.
- aqueous ethanol can be used as a vehicle in formulations for topical application.
- Ethanol can act as a penetration enhancer that can increase the flux of an active agent across the skin due to a solvent drag effect (Berner et al., 1989, J. Pharm. Sci, 78(5), 402- 406).
- Octyl salicylate and AzoneTM are further examples of penetration enhancers that have been shown to improve percutaneous absorption (U.S Patent Number 6299900).
- PCT/AU00/01419 describes a propellant free spray on skin patch composition, which forms a flexible porous skin patch to improve wound healing and drug administration, however the composition is limited to water soluble compounds.
- transdermal aerosol drug delivery system has the potential to overcome the limitations of existing transdermal drug delivery devices, such as transdermal patches.
- the potential to avoid skin irritation offers a significant advantage over existing patch and nasal delivery methods, both of which have been shown to cause application site reactions in up to 50% of patients using these types of dosage forms (Lopes et al., 2001 , Maturitas 38, S31 -39).
- U.S Patent No. 6325990 relates to a film forming composition for spraying on the skin comprising a physiological active, a polysiloxane adhesive, an absorption promoter, a solvent, a volatile silicone and a propellant.
- a physiological active a physiological active
- a polysiloxane adhesive an absorption promoter
- a solvent a volatile silicone
- a propellant a propellant
- the adhesive In transdermal systems where both a drug and an enhancer are incorporated, it is important that the enhancer is released at a rate that will result in an optimal effect upon drug permeation through the skin. Therefore, in a film-forming system, the adhesive must show effective permeability for the drug and the enhancer, defined by the delivery profile of the drug under consideration. If the solubility of either the drug or the enhancer is not optimised, then the permeation profile will be affected (Venkatraman ⁇ t al., 1998). Drug-in-adhesive systems are more recent second-generation systems wherein the drug is dispersed in the adhesive itself. The saturated solubility for many compounds in adhesives is low, thus the tendency for the drug to precipitate is even greater, leading to stability issues. (Kotiyan et al., 2001).
- Liquid excipients (including the drug) will 'plasticise' the adhesive to some degree; which would lead to an undesirable residue on the skin. This "plasticised” residue is often sticky, collecting dirt and lint, and is therefore cosmetically unacceptable.
- the present invention arises from the inventor's studies of finite dose formulations which contain penetration enhancers that enhance the percutaneous absorption of a therapeutic agent.
- the present invention arises, at least in part, from the realisation that an improvement in percutaneous delivery can be achieved by the appropriate selection of a hydrofluorocarbon propellant dissolved in a lower alcohol such as ethanol or isopropyl alcohol or a combination thereof, and which can also exist as a single-phase solution with the penetration enhancer of choice.
- the aerosol composition may initially contain water in an amount up to 50% w/v preferably up to 10% w/v water, and more preferably may initially contain up to 5% w/v water without impacting upon the capacity of the volatile vehicle to dissolve the desired amount of the therapeutic agent and penetration enhancer used in said metered-dose transdermal aerosol compositions in their most preferred form as single-phase solutions.
- the present invention provides a composition including:
- a volatile pharmaceutically acceptable solvent comprising a lower alcohol and a hydrofluorocarbon propellant, and optionally up to 50% w/v water wherein the physiologically active agent, dermal penetration enhancer, volatile pharmaceutically acceptable solvent and propellant combine to preferably form a single-phase solution.
- compositions with a relatively higher water content of up to 50% w/v water may be used in a topical vehicle that can be applied to irritated skin, broken skin or mucous membranes, wherein the composition may exist as a single phase solution, emulsion or micro-emulsion in which the active agent and/or penetration are either completely dissolved within one of the aforementioned vehicle phases or are alternatively dispersed within one of these vehicle phases, or a combination thereof, such as the physiologically active agent being dissolved in the composition and the dermal penetration enhancer being dispersed in the same composition.
- compositions comprising water in an amount of up to 10% w/v are preferred.
- composition of the present invention may overcome at least some of the disadvantages of the composition described in the aforementioned U.S Patent No. 6325990, which can result in a two phase solution or emulsion, as opposed to the single phase solution of the present invention.
- the present invention also provides a metered dose spray applicator containing the above composition for transdermal administration.
- the present invention further provides a method of treatment of a subject with a physiologically active agent comprising applying a transdermal composition as hereinbefore described to an area of skin of a subject.
- a physiologically active agent comprising applying a transdermal composition as hereinbefore described to an area of skin of a subject.
- the composition of the invention comprises a hydrofluorocarbon propellant.
- the hydrofluorocarbon propellant is preferably a hydrofluoroalkane such as HFC-134a or HFC 127.
- the most preferred hydrofluorocarbon propellant is HFC-134a.
- HFC-134a is particularly advantageous in compositions to be administered transdermally as compositions of the invention applied to the skin , with HFC-134a produce more saturation of the drug when compared with other propellants such as dimethyl ether.
- HFC-134a rapidly providing high saturation of the active and penetration enhancer on the skin increases partitioning of the drug and penetration enhancer into the skin rapidly providing a reservoir of active and penetration enhancer within the skin.
- incorporation of HFC-134a provides for a faster drying time which allows the physiological active and the penetration enhancer to form an amorphous deposit upon evaporation of the volatile carrier.
- the volatile solvent evaporates and the composition becomes touch dry within 2 minutes, more preferably within 1 minute, leaving no residue or film on the skin.
- the amount of propellant in the composition of the invention is preferably 15 to 50% v/v and more preferably 20 to 40% v/v.
- composition of the invention contains a penetration enhancer.
- penetration enhancers for use in the composition of the invention are sunscreen esters of formula (I):
- R 1 is hydrogen, lower alcohol, lower alkoxy, halide, hydroxy or NR 3 R 4 ;
- R 2 is a C 8 to C-18 alkyl
- R 3 and R 4 are each independently hydrogen, lower alkyl or R 3 and R 4 together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclic ring
- n is 0 or 1
- q is 1 or 2 wherein when n is 0 and R1 is NR 3 R 4 , the NR 3 N 4 is para-substitued.
- sunscreen esters are those selected from the group consisting of C 8 to C ⁇ 8 alkylcinnamate, C 8 to C ⁇ 8 alkylmethoxycinnamate, C 8 to C ⁇ s alkyl salicylate and mixtures thereof. More preferably the penetration enhancers are selected from padimate O and octyl salicylate.
- the amount of penetration enhancer present in the composition of the invention is preferably in the range of 0.1 to 10% w/v and more preferably 2 to 8% w/v.
- the composition of the invention contains a lower alcohol, preferably ethanol, propanol (including isomers thereof) or a mixture thereof.
- the volatile solvent comprises at least 60% w/v of one or more lower alcohols. More preferably the volatile solvent component consists essentially of an ethanol, isopropanol or mixture thereof. It is present in an amount sufficient to provide a single phase with the penetration enhancer and propellant. Typically the alcohol will be present in an amount of from 40 to 80% v/v and more preferably 50 to 70% v/v.
- the choice of solvent used in a composition can be selected on the basis of the desired transdermal delivery profile as measured by percutaneous penetration in order to achieve the desired pharmacological effect. Combinations of volatile solvents could be used to obtain the desired pharmacological effect; for example on a weight basis:
- the composition of the invention may contain water.
- the decision on whether water is to be present and the amount of water will depend on the active physiological agent and its stability and interaction with water and whether the composition is to be applied to irritated skin, broken skin or mucous membranes. In some instances water may be a useful solvent whereas in other circumstances instability of the active in the presence of water may dictate that water be omitted. Indeed in some cases special precautions against the presence of water such as the use of desiccants may be desirable.
- composition of the invention includes a physiologically active agent.
- suitable physiologically active agents include steroid, hormone derivative, non-steroidal anti-inflammatory drug, opioid analgesic, antinauseant, antioestrogen, aromatase inhibitor, 5-alpha reductase inhibitor, anxiolytic, prostaglandin, anti-viral drug, anti-migraine compound, antihypertensive agent, anti-malarial compound, bronchodilator, anti-depressant, anti-alzheimer's agent, neuroleptic and antipsychotic agent, anticholinergic agent, anti-parkinson's agent antiandrogen or anorectic agent.
- the preferred physiologically acceptable agents include testosterone, oestradiol, ethinyloestradiol, levonorgestrel, progesterone, norethisterone acetate, ibuprofen, ketoprofen, flurbiprofen, naproxen, diclofenac, fentanyl, buprenorphine, scopolamine, prochlorperazine, metochlopramide, ondansetron, tamoxifen, epitiostanol, exemestane, oxybutynin, darifenacin, tolterodine, ropinirole, granisetron, rivastigmine, buspirone, rizatriptin, zolmitriptan, lacidipine, tropisetron, olanzapine and methyl phenidate, 4-hydroxy- androstenedione and its derivatives, finasteride, dutasteride, turosteride, LY
- physiologically acceptable agents include apomorphine, oxybutynin, ropinirole, fentanyl, granisetron, rivastigmine, buspirone, rizatriptin, zolmitriptan, lacidipine, tropisetron, olanzapine and methyl phenidate or a pharmaceutically acceptable salt or derivative of any one of the aforementioned.
- One aspect of the invention provides a metered dose spray applicator containing a composition for transdermal administration.
- the composition of the invention will generally be retained under pressure within the container so that a significant proportion of the propellant is in liquid form.
- the spray applicator may comprise a nozzle and means for providing a metered dose of spray from the nozzle.
- the spray applicator may further comprise spacing means for spacing the application nozzle at a predetermined distance from the skin of the subject onto which the spray is to be delivered.
- An aerosol composition for transdermal delivery of an analgesic was prepared from the following composition.
- An aerosol composition for transdermal delivery of an anti-cholinergic drug was prepared as a single phase solution from the composition described below.
- composition for transdermal delivery of an anti-anxiety drug to the skin was prepared as a single phase solution from the following composition:
- An aerosol composition for transdermal delivery of an anti-Parkinson agent was prepared as a single phase solution from the composition described below.
- Example 7 is described with reference to the attached drawing.
- Figure 1 is a graph showing skin penetration of buspirone over time.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Pain & Pain Management (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Psychology (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPS317102 | 2002-06-25 | ||
AUPS3171A AUPS317102A0 (en) | 2002-06-25 | 2002-06-25 | Transdermal aerosol compositions |
PCT/AU2003/000784 WO2004000275A1 (en) | 2002-06-25 | 2003-06-24 | Transdermal aerosol compositions |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1534241A1 true EP1534241A1 (en) | 2005-06-01 |
Family
ID=3836730
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03732114A Withdrawn EP1534241A1 (en) | 2002-06-25 | 2003-06-24 | Transdermal aerosol compositions |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1534241A1 (en) |
JP (1) | JP2005533795A (en) |
KR (1) | KR20050071373A (en) |
AU (1) | AUPS317102A0 (en) |
BR (1) | BR0312004A (en) |
CA (1) | CA2490325A1 (en) |
EA (1) | EA007351B1 (en) |
NZ (1) | NZ537435A (en) |
WO (1) | WO2004000275A1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004000263A1 (en) * | 2002-06-25 | 2003-12-31 | Acrux Dds Pty Ltd | Transdermal delivery rate control using amorphous pharmaceutical compositions |
JP2007511544A (en) * | 2003-11-19 | 2007-05-10 | アクルックス・ディ・ディ・エス・プロプライエタリー・リミテッド | Compositions and methods for prevention or treatment of amyloidosis |
US20060263421A1 (en) | 2005-05-18 | 2006-11-23 | Abeille Pharmaceuticals Inc | Transdermal Method and Patch for Nausea |
CN101883556B (en) * | 2007-11-02 | 2013-05-29 | 艾克若克斯Dds有限公司 | Transdermal delivery system for hormones and steroids |
BR112013020775A2 (en) * | 2011-02-15 | 2016-10-11 | Lilly Co Eli | processes to control pain in dogs using a fentanyl transdermal solution |
CA2827488C (en) * | 2011-02-15 | 2020-07-07 | Amy Louise Marr | Methods for controlling pain in equines using a transdermal solution of fentanyl |
GB2571696B (en) | 2017-10-09 | 2020-05-27 | Compass Pathways Ltd | Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced |
CN114206349A (en) | 2019-04-17 | 2022-03-18 | 指南针探路者有限公司 | Methods for treating neurocognitive disorders, chronic pain and reducing inflammation |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5082866A (en) * | 1988-06-01 | 1992-01-21 | Odontex, Inc. | Biodegradable absorption enhancers |
AUPN814496A0 (en) * | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
US6004969A (en) * | 1996-04-15 | 1999-12-21 | National Science Council | Transdermal delivery of buprenorphine preparations |
ID30353A (en) * | 1999-02-05 | 2001-11-22 | Cipla Ltd | TOPICAL SPRAY MEDICINE |
IN191090B (en) * | 2000-08-29 | 2003-09-20 | Ranbanx Lab Ltd |
-
2002
- 2002-06-25 AU AUPS3171A patent/AUPS317102A0/en not_active Abandoned
-
2003
- 2003-06-24 WO PCT/AU2003/000784 patent/WO2004000275A1/en active Application Filing
- 2003-06-24 KR KR1020047020967A patent/KR20050071373A/en active Search and Examination
- 2003-06-24 JP JP2004514437A patent/JP2005533795A/en not_active Withdrawn
- 2003-06-24 BR BR0312004-0A patent/BR0312004A/en not_active IP Right Cessation
- 2003-06-24 EA EA200500082A patent/EA007351B1/en not_active IP Right Cessation
- 2003-06-24 CA CA002490325A patent/CA2490325A1/en not_active Abandoned
- 2003-06-24 EP EP03732114A patent/EP1534241A1/en not_active Withdrawn
- 2003-06-24 NZ NZ537435A patent/NZ537435A/en unknown
Non-Patent Citations (1)
Title |
---|
See references of WO2004000275A1 * |
Also Published As
Publication number | Publication date |
---|---|
KR20050071373A (en) | 2005-07-07 |
EA200500082A1 (en) | 2005-06-30 |
NZ537435A (en) | 2006-02-24 |
AUPS317102A0 (en) | 2002-07-18 |
EA007351B1 (en) | 2006-10-27 |
BR0312004A (en) | 2005-03-29 |
WO2004000275A1 (en) | 2003-12-31 |
JP2005533795A (en) | 2005-11-10 |
CA2490325A1 (en) | 2003-12-31 |
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