GB2487764A - Composition including ciclopirox olamine and VEGF - Google Patents
Composition including ciclopirox olamine and VEGF Download PDFInfo
- Publication number
- GB2487764A GB2487764A GB1101877.7A GB201101877A GB2487764A GB 2487764 A GB2487764 A GB 2487764A GB 201101877 A GB201101877 A GB 201101877A GB 2487764 A GB2487764 A GB 2487764A
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- United Kingdom
- Prior art keywords
- preparation
- agents
- vegf
- copper
- mimetics
- Prior art date
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- 229960004375 ciclopirox olamine Drugs 0.000 title claims abstract description 23
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- YUZJJFWCXJDFOQ-UHFFFAOYSA-K manganese(3+);2-methoxy-6-[2-[(3-methoxy-2-oxidophenyl)methylideneamino]ethyliminomethyl]phenolate;chloride Chemical compound [Cl-].[Mn+3].COC1=CC=CC(C=NCCN=CC=2C(=C(OC)C=CC=2)[O-])=C1[O-] YUZJJFWCXJDFOQ-UHFFFAOYSA-K 0.000 description 1
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Abstract
A pharmaceutical preparation comprises ciclopirox olamine, and one or more of: vasco-epithelial growth factor (VEGF), a VEGF biomimetic, and/or a VEGFR2 receptor agonist, in a physiologically acceptable medium. The composition may also comprise one or more catalases or mimetics thereof, superoxide dismutases or mimetics thereof, one or more antioxidants, one or more 5 alpha reductase inhibitors, one or more nitric oxide synthases, a UV protective material, and/or a penetration enhancing ingredient, such as salicylic acid. The composition may be for use in: autologous growth factor therapy; the prevention of hair loss; for improving skin blemishes; or treatment of damage to skin cells associated with accumulation of reactive oxygen or nitrogen specifies. It may also be used for soaking follicular grafts prior to implantation; for improving survival rates of implanted hair follicles, to improve wound healing times; or to prepare grafts for removal prior to hair transplant surgery.
Description
Synergistic Growth Factor Composition The present invention relates generally to a synergistic growth factor composition and finds particular, although not exclusive, utility in improving hair and skin condition.
The process of new hair growth, whether as part of the natural hair cycle or as a result of a treatment to encourage hair growth, relies on numerous cross-talking signal pathways to bring about the processes necessary for hair growth. These principal processes are: cell proliferation of the dermal papilla, cell migration to form the appropriate structures, and angiogenesis to form blood supply routes to the new hair follicle.
The three steps are also vital for healthy skin condition. In normal skin and normal hair growth cycling, these stages take place without any pharmaceutical or cosmetic intervention. However, in people with various forms of alopecia, hair loss, or a slowing of hair growth, one or more of these processes might not happen at a normal rate, and can stop altogether. Similarly these processes often occur at a reduced rate in UV damaged skin and scar tissue.
VEGF is a well-documented signal to activate these processes via the VEGFR2 receptor. VEGF leads to downregulation of Bad, TGF-f31 and caspase expression through the Akt/PKB and calcium ion dependent pathways. This brings about the end of apoptosis and the telogen phase. Secondly it acts via the MAPKinase pathway to increase cell proliferation. Via the same Akt/PKB and calcium ion dependent pathways, VEGF also stimulates NO production and cell migration. Interestingly, all of these pathways excepting the Akt/PKB are calcium ion dependent.
It is already known that ciclopirox olamine causes an upregulation of VEGF production; this increase will cause an increase of all of the downstream effects of VEGF discussed previously. Ciclopirox olamine may act as a sodium and potassium ion channel antagonist, which in turn may increase cellular calcium ion concentration. This increase in calcium will undoubtedly improve the intracellular signalling potential of the calcium dependent pathways, therefore having a potentiating affect on the intracellular signals.
Whilst the effects of ciclopirox olamine alone are statistically significant, they do not make enough of a difference for visual evaluation on in vivo test subjects. Therefore for use in pharmaceutical and cosmetic preparations an additional compound is necessary to improve the result until a visible difference was achieved.
Human VEGF has not vet been widely legahsed for cosmetic or pharmaceutical use, however it is available as a variety of synthetic and recombinant forms. More widely available are VEGFR2 receptor agonists, and several different biomimetic peptides that may act as VEGFR2 receptor agonists or act in a similar way downstream of the \TEGFR2 receptor to stimulate and/or potentiate the calcium ion dependent, MAPKinase, or Akt/PKB pathways, among other pathways naturally stimulated by VEGF. Any of these are considered suitable for inclusion in a composition with ciclopirox olamine to improve the effects of either individually.
This synergy between VEGF, VEGFR2 agonists and/or VEGF bioniimetic peptides and ciclopirox olamine occurs in two ways. Firstly ciclopirox olamine increases cellular calcium ion concentration, this will potentiate the intracellular signals stimulated not only by the VEGF that ciclopirox olamine produces, but also any additional receptor stimulation by VEGF, VEGFR2 agonists and/or VEGF biomimetic peptides included in the composition. Secondly, VEGF, VEGFR2 agonists and/or VEGF biomimetic peptides will stimulate the VEGFR2 receptor in any set of conditions. This is not the case for the action of ciclopirox olamine, which upregulates VEGF production more significantly in hypoxic conditions. Therefore in well oxygenated areas ciclopirox olamine may not have a significant upregulating effect on VEGF, and the presence of VEGF, VEGFR2 agonists and/or VEGF hiomimetic peptides in the composition xvill ensure reliable results in all areas. Additionally, ciclopirox olamine has limited \vater solubilitv. Whilst the considered pharmaceutical and cosmetic compositions may he based in oils, water, alcohols, propylene glycol or many other media, water based solutions have a variety of advantages. However a water based solution of ciclopirox olamine would not create enough VEGF via upregulation to have a significant effect, and so adding VEGF, VEGFR2 agonists and/or VEGF biomimetic peptides would allow for significant results in water based solutions.
Incorporation of ciclopirox olamine may have another benefit as it is known to be an anti-fungal agent, and so can be used to prevent and cure dandruff, and infections by Malesse7ia furfur and other fungi. As infections may also be treated by electromagnetic radiation-either IJV or a cold-beam laser, it is considered that this composition could be used with sources of electromagnetic radiation, particularly UV, blue and/or red visible light. These could be emitted by light sources such as LEDs or laser emitters. Laser emitters are also thought to have a positive effect on skin and hair condition, and so the possibility of using this composition with regular laser therapy is also considered.
As the cell migration action of VEGF partially relies on nitric oxide production, a favourable embodiment may also include any of a catalase, a superoxide dismutase, or a mimetic of either. These molecules act together to remove reactive oxygen and nitrogen species, prolonging the duration of the nitric oxide signal. Possible superoxide dismutases are any of, hut not limited to, the following: Cu/Zn Superoxide Dismutase, Mn Superoxide Dismutase, Lipochroman-6, EUK-134, copper (II) 3,5- diisopropylsalicvlate, copper CII) 3,5-dibromosalicylate, copper 3,5-ditertiarybutvlsalycilate. Possible antioxidants are either of, hut not limited to, green tea extract and vitamin C or derivative thereof. Possible catalases or catalase mimetics are any of, but not limited to, copper PCA, zinc PCA, Catalase.
An alternative or additional embodiment may comprise an antioxidant to prevent free radical degradation of nitric oxide, or a TJV protective material to reduce UV damage and free radical formation. Embodiments including UV protective materials would have the additional benefit of preventing further skin blemishes such as hyperpigmentation, which alopecia sufferers and those with scar tissue may be more susceptible to. Various UV protective materials are considered, including but not limited to any of the following: propanediol, quaterium-95, polyacrylate-1 5, titanium dioxide, zinc oxide, ethvlhexvl methoxycinnamate, butyl methoxydibenzoylmethane, octyl methoxycinnamate, menthyl anthranilate, homosalate, benzophenone-3 and benzophenone-4.
Similarly, other forms of increasing nitric oxide \vould have a beneficial effect, therefore embodiments including nitric oxide synthases, nitric oxide donators, and nitric oxide mimetics such as any of eNOS, iNOS, minoxidil, tempo, molsidomine and 5-nitrosoglutathione are also considered.
The anti-apoptotic action of VEGF, VEGFR agonists and VEGF biomimetic peptides occurs largely downstream of extracellular apoptotic signals. Whilst this has the benefit of being more specific, targeting the apoptotic pathway prior to the intracellular signals does increase the possible amplitude of the effect. Due to this, a beneficial embodiment may include one or more 5 alpha reductase inhibitors for reducing dlihydrotestosterone levels such as zinc PCA, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF 105,111, saw palmetto extract, green tea extract and hydrolysed lupine extract, and/or another means for reducing the effects of dihydrotestosterone such as caffeine.
Stimulation of VEGFR2 receptors and increasing signal transduction may increase circulation, and therefore have a beneficial effect as part of many cosmetic preparations when included with other cosmetically active agents. Cosmetically active agents (defined as a compound (natural or synthetic) that have a cosmetic or therapeutic effect on the skin, hair or nails including but not limited to lightening agents, darkening agents, and-acne agents, shine control agents, anti-microbial agents, anti-inflammatory agents, anti-mycotic agents, and-parasite agents, external analgesic, sunscreens, photo-protectors, andoxidants, keratolytic agents, detergents or surfactants, moisturisers or humectants, nutrients, vitamins, energy-enhancers, growth factors, anti-perspiration agents, astringents, deodorants, hair-removers, firming agents, anti-callous agents and agents for hair, nail and/or skin conditioning.) Of particular interest are curcumin, taurine, plant sterols, pine bark extract, red tea, white tea, horsetail extract, marine cartilage, kieslerde, melatonin and mimetics, copper peptides, other growth factors and growth factor inimetics, spironolactone, f3-glucan, vitamins C, A, E, B, F, H, K (and derivatives), bacterial filtrates, glucosamine sulphate, or any combination of these.
Ciclopirox olamine penetrates skin, hair, and nail layers readily, however VEGF, VEGFR2 agonists and VEGF biomimetic peptides wiLl penetrate somewhat more slowly. To improve this performance VEGF, VEGFR2 agonists and/or VEGF biomimetic peptides may be included in the preparation in an encapsulated form to increase penetration, or the preparation may additionally comprise a penetration enhancing ingredient such as salicylic acid. Alternatively or additionally ciclopirox olamine penetration may be reduced to equate that of VEGF, VEGFR2 agonists and/or VEGF biomimetic peptides, for example by encapsulating ciclopirox olamine in a large micelle. Another alternative method for alteting the absorption rate of the preparation has already been disclosed, wherein the preparation is applied as part of a procedure including an array of microneedles.
The vasodilatory effects of VEGF pathway stimulation may also be useful as part of growth factor therapies. Autologous growth factor therapies are becoming increasingly popular for alopecia treatment, skincare, and surgical purposes. Any of the embodiments discussed previously would have beneficial effects when applied as part of an autologous growth factor treatment. Non-autologous growth factors are currently not widely legalised and used, but any of the embodiments discussed previously may be beneficial as part of these potential future treatments. A specific biomimetic peptide and recombinant or synthetic sources of VEGF are considered in detail herein, however any biomimetic peptide fulfilling this function may also he considered in addition or as an alternative to either of those described herein.
In one aspect, the invention provides a cosmetic or pharmaceutical preparation comprising ciclopirox olamine and one or more of VEGE, a VEGF biomimetic, and/or a VEGFR2 receptor agonist in a physiologically acceptable medium.
In this preparation the VEGF, a VEGF biomimetic, and/or a VEGJFR2 receptor agonist may he one or more of: Copper Ascorhyl Phosphate Succinoyl Tripeptide-34; the peptide: Glycine Histadine Lysine-Cu; the peptide: R-Glycine Histadine Lysine-Cu, \vhere R is any amino acid or peptide chain; Octapeptide-2; Decapeptide-8; Synthetic Human VEGF; Recombinant Human VEGF; Human VEGF from any human source.
The ciclopirox olamine may comprise between 0.000 1 % and 50% of the preparation.
The VEGF, VEGF biomimetic, and/or VEGFR2 receptor agonist may comprise between 0.00001% and 45% of the preparation.
Ciclopirox olamine may be included to stimulate VEGF production. The ciclopirox olamine may increase intracellular VEGF signal transduction. It may also act as an antifungal agent. It may also act as a sodium/potassium ion channel antagonist.
The preparation may additionally comprise one or more superoxide dismutases or superoxide dismutase niimetics. Alternatively, or additionally, it may comprise one or more catalases or catalase mimetics. The preparation may also comprise one or more antioxidants.
The antioxidant may be one or more of ETJK-134, copper (II) 3,5- diisopropylsalicylate, copper (II) 3,5-dibromosalicylate, copper (II 3,5-ditertiarybutylsalycilate, green tea extract and vitamin C or derivative thereof.
The preparation may additionally comprise one or more S alpha reductase inhibitors.
The inhibitor may be any of zinc PCA, tinasteride, dutasteride, turosteride, bexiosteride, izonsteride, ECE 28260, SKF 105,111, saw palmetto extract, green tea extract and hydrolysed lupine extract.
The preparation may additionally comprise one or more natural or synthetic nitric oxide donators or mimetics.
The nitric oxide donators or mimetics may be any of minoxidil, tempo, molsidomine and S-nitrosoglutathione.
The preparation may additionally comprise a TJV protective material.
The UV protective material may be any of propanediol, quaternium-95, polyacrylate-l5, titanium dioxide, zinc oxide, ethylhexyl methoxycinnamate, butvl methoxydibenz oylmethane, oc tyl methoxycinnamate, menthyl anthranilate, homos alate, benz ophenone-3 and benzophenone-4.
The preparation may be for use with a microneedle array. In another aspect, the invention provides a microneedle array including the preparation described herein. In another aspect, the invention provides a kit for applying the preparation, in which the kit comprises an array of microneedles and the preparation.
The preparation may be for use as part of an autologous growth factor therapy.
In a further aspect, the invention provides a method of treating or preventing hair loss, which comprises topical application of a preparation as described herein.
In a yet further aspect, the invention provides a method of maintaining or improving hair growth, which comprises topical application of a preparation as described herein.
In a different aspect, the invention provides a method of improving skin blemishes such as hyperpigrnentation and scarring, which comprises topical application of a preparation as described herein.
In a further different aspect, the invention provides a method of treating or preventing damage to skin cells associated with accumulation of reactive oxygen or nitrogen species such as free radicals, which comprises topical application of a preparation as described herein.
In another aspect, the invention provides a method of using a preparation, as described herein, to prepare possible implantation sites before hair transplant surgery.
In yet another aspect, the invention provides a method of using a preparation, as described herein, to soak follicular grafts before implantation as part of hair transplant surgery.
In an additional aspect, the invention provides a method of using a preparation, as described herein, after implantation of hair follicles to improve their survival rates and/or to improve wound healing times.
Finally, in another different aspect the invention provides a method of using a preparation, as described herein, to prepare grafts for removal prior to hair transplant surgery.
The use of the preparation described above may he topical application and/or injection, or in other \vays.
It is possible to utilise the angiogenic properties as well as the hair growth inducing properties of the discussed VEGF containing solution before, during or after surgery. This could be hair transplant surgery, and the solution could be used to soak follicular grafts before implantation, or used after implantation to improve survival rates and wound healing times. The solution may be beneficial before surgery to prepare grafts for removal, or prepare possible implantation sites.
Claims (26)
- CLAIMSI. A pharmaceutical preparation comprising ciclopirox olarninc and one or more of VEGF, a VEGE biomimetic peptide, and/or a VEGFR2 receptor agonist, in a physiologically acceptable medium.
- 2. A preparation as claimed in claim 1, in which the one or more of VEGF, a VEGF biomimetic, and/or a VEGFR2 receptor agonist is selected from the group Copper Ascorbyl Phosphate Succinoyl Tripeptide-34; the peptide: Glycine Histadine Lysine-Cu; the peptide: R-Glycine Histadine Lysine-Cu, where R is any amino acid or peptide chain; Octapeptide-2; Decapeptide-8; Synthetic Human VEGE; Recombinant Human VEGE; Human VEGF from any human source.
- 3. A preparation as claimed in either of claims 1 and 2, in which the ciclopirox olamine is present in an amount of between O.000I% and SO% of the preparation.
- 4. A preparation as claimed in any one of claims I to 3, in which the VEGE, VEGF biomimetic, and/or VEGFR2 receptor agonist is present in an amount of between 0.00001% and 45% of the preparation.
- 5. A preparation as claimed in any one of claims I to 4, in which the preparation further comprises one or more catalases, catalase mimetics, superoxide dismutases or superoxide dismutase mimetics.
- 6. A preparation as claimed in claim 5 in which the superoxide dismutases are selected from the group comprising Cu/Zn superoxide dismutase, Mn superoxide dismutase, Lipochroman-6, EUK-I 34, copper (II) 3,5- diisopropylsalicylatc, copper (II) 3,5-dibromosalicylate, and copper JI) 3,5-ditertiarybutylsalicylate.S
- 7. A preparation as claimed in claim 5, in which the catalases or catalase mimetics ate selected from the group comprising copper PCA and zinc PCA.
- 8. A preparation as claimed in any one of claims I to 7, in which the preparation further comprises one or more antioxidants.
- 9. A preparation as claimed in claim 8, in which the one or more antioxidants are selected from the group comprising ETJK-134, copper (II) 3,5- diisopropylsalicylate, copper (II) 3,5-dibromosalicylate, copper (II) 3,5-ditertiarybutylsalycilate, green tea extract and vitamin C or derivatives thereof.
- 10. A preparation as claimed in any one of claims I to 9, in which the preparation further comprises one or more 5 alpha reductase inhibitors.
- 11. A preparation as claimed in claim 10, in which the one or more S alpha reductase inhibitors are selected from the group comprising zinc PCA, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF 105,111, saw palmetto extract, green tea extract and hydrolysed lupine extract.
- 12. A preparation as claimed in any one of claims I to 10, further comprising one or more nitric oxide synthases, nitric oxide donators or nitric oxide mimetics.
- 13. A preparation as claimed in claim 12, in which the nitric oxide synthases, nitric oxide donators or nitric oxide mimetics are selected from the group comprising eNOS, iNOS, minoxidil, tempo, molsidomine and S-nitrosoglutathione.
- 14. A preparation as claimed in any one of claims I to 13, further comprising a UV protective material.
- 15. A preparation as claimed in claim 14, in which the UV protective material is selected from the group comprising propanediol, quaternium-95, polyacrvlate- 15, titanium dioxide, zinc oxide, ethylhexyl methoxycinnamate, butvl methoxvdibenzoylmethane, octyl methoxvcinnamate, menthyl anthranilate, homos ala te, benzop henone-3 and Benz op henone-4.
- 16. A preparation as claimed in any one of claims I to 15, further comprising one or more cosmetic agents selected from hghtening agents, darkening agents, anti-acne agents, shine control agents, anti-microbial agents, anti-inflammatory agents, anti-mycotic agents, and-parasite agents, external analgesic, sunscreens, photo-protectors, antioxidants, keratolytic agents, detergents or surfactants, mois turis ers or humectants, nutrients, vitamins, energy-enhancers, growth factors, and-perspiration agents, astringents, deodorants, hair-removers, firming agents, anti-callous agents and agents for hair, nail and/or skin conditioning.
- 17. A preparation as claimed in claim 16, in which the one or more cosmetic agents are selected from the group comprising curcumin, taurine, plant sterols, pine bark extract, red tea, white tea, horsetail extract, marine cartilage, kieslerde, melatonin and mimetics, copper peptides, other growth factors and growth factor mimetics, spironolactone, 3-glucan, vitamins C, A, E, B, F, H, K (and derivatives), bacterial filtrates, glucosamine sulphate, and any combination thereof.
- 18. A preparation as claimed in any one of claims I to 17, in which one or more of the ciclopirox olamine, the VEGF, VEGFR2 agonists and/or VEGE biomimetic peptides are present within the preparation in encapsulated form.
- 19. A preparation as claimed in any one of claims I to 17, further comprising a penetration enhancing ingredient.
- 20. A preparation as claimed in claim 19, in which the penetration enhancing ingredient is salicylic acid.
- 21. A kit for applying the preparation, in which the kit comprises an array of microneedles and the preparation as claimed in any one of claims I to 20.
- 22. Use of a preparation as claimed in any one of claims 1 to 20 for autologous growth factor therapy.
- 23. Use of a preparation as claimed in any one of claims I to 20 for the prevention or treatment of hair loss, for improving hair growth, for improving skin blemishes, or for the prevention or treatment of damage to skin cells associated with accumulation of reactive oxygen or nitrogen species.
- 24. Use of a preparation as claimed in any one of claims 1 to 20 for soaking folhcular grafts prior to implantation.
- 25. Use of a preparation as claimed in any one of claims I to 20 after implantation for improving survival rates of hair follicles and/or to improve wound healing times.
- 26. Use of a preparation as claimed in any one of claims I to 20 to prepare grafts for removal prior to hair transplant surgery.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1101877.7A GB2487764A (en) | 2011-02-03 | 2011-02-03 | Composition including ciclopirox olamine and VEGF |
| US13/173,894 US20120003300A1 (en) | 2010-06-30 | 2011-06-30 | Composition Comprising Vascular Endothelial Growth Factor (VEGF) for the Treatment of Hair Loss |
| GB1111182.0A GB2481712B (en) | 2010-06-30 | 2011-06-30 | Composition comprising vascular endothelial growth factor (VEGF) for the treatment of hair loss |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1101877.7A GB2487764A (en) | 2011-02-03 | 2011-02-03 | Composition including ciclopirox olamine and VEGF |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB201101877D0 GB201101877D0 (en) | 2011-03-23 |
| GB2487764A true GB2487764A (en) | 2012-08-08 |
Family
ID=43836159
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB1101877.7A Withdrawn GB2487764A (en) | 2010-06-30 | 2011-02-03 | Composition including ciclopirox olamine and VEGF |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2487764A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20040016089A (en) * | 2002-08-14 | 2004-02-21 | 김기연 | Production of human vascular endothelial growth factor(VEGF) protien by plant cell system there of |
| WO2006026617A2 (en) * | 2004-08-30 | 2006-03-09 | Iken Tissue Therapeutics, Inc. | Compositions and methods of promoting hair growth |
| EP2275104A2 (en) * | 2009-06-17 | 2011-01-19 | Valetudo S.r.l. | Pharmaceutical and cosmetic composition including lactoferrin, ciclopirox and etidronic acid |
-
2011
- 2011-02-03 GB GB1101877.7A patent/GB2487764A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20040016089A (en) * | 2002-08-14 | 2004-02-21 | 김기연 | Production of human vascular endothelial growth factor(VEGF) protien by plant cell system there of |
| WO2006026617A2 (en) * | 2004-08-30 | 2006-03-09 | Iken Tissue Therapeutics, Inc. | Compositions and methods of promoting hair growth |
| EP2275104A2 (en) * | 2009-06-17 | 2011-01-19 | Valetudo S.r.l. | Pharmaceutical and cosmetic composition including lactoferrin, ciclopirox and etidronic acid |
Non-Patent Citations (4)
| Title |
|---|
| Cobbledick, T., "Hair Growth Factors - A Nanogen briefing for the scientific community", available online at http://www.nanogen.co.uk/documents/hair-growth-factors.pdf [date accessed 15 April 2011]. * |
| KR 20040016089 A (KIM) See EPODOC English abstract, and WPI English abstract accession no. 2004-428126/40. * |
| Linden, T., et al., "The antimycotic ciclopirox olamine induces HIF-1alpha stability, VEGF expression, and angiogenesis", FASEB, 2003, Vol. 17 (6), pp. 761-763. * |
| Medline abstract NLM7197541 & Kellner, H. M., et al., "Pharmacokinetics and biotransformation of the antimycotic drug ciclopiroxolamine in animals and man after topical and systemic administration", Arzneimittel-Forschung, Vol. 31 (8A), pp. 1337-1353. * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB201101877D0 (en) | 2011-03-23 |
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| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |