CN105682667A

CN105682667A - Novel skin care formulation

Info

Publication number: CN105682667A
Application number: CN201480055211.3A
Authority: CN
Inventors: 保罗·里德
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-09-02
Filing date: 2014-09-02
Publication date: 2016-06-15
Also published as: HK1219872A1; SG11201602332RA; WO2015031903A1

Abstract

Formulations and methods for the treatment and care of skin, especially to the treatment of dehydrated and damaged skin associated with environmental exposure and disease are described. The inflammation associated with dermatological or immunological conditions, viral and bacterial infections, and burn lesions may also respond to treatment with the present invention. The formulations comprise a mixture of cobra venom and orthosilicic acid and an acceptable excipient. The disclosed formulation may be orally or topically administered.

Description

New skin care formulation

The cross reference of related application

This application claims the U.S. Provisional Application US61/872 that denomination of invention is " novel skin care formulation " of JIUYUE in 2013 submission on the 2nd, the priority of 784, the document is incorporated herein reference.

Technical field

The physical trait of many consumers its skin of concern. Such as, the consumer with wrinkle, dry speckle or sun damage it is generally desirable to the minimizing of this category feature. The mass part of application on human skin constantly occurs the exposure interacting and being subject to environmental factors such as daylight and wind to be encroached on outside stimulus. This exposure may result in the physics to skin and visible change. Additionally, some physical conditions such as disease can cutaneous outward appearance.

Background technology

Cobra venom (cobravenom) has been widely used as and has been mainly used in lenitive therapeutic agent. Clinical research from nineteen thirties to the fifties discloses, and cobra venom is the effective analgesic that activity is better than morphine, and does not have known opiates untoward reaction. In the U.S., the cobra venom for medical usage only obtains with homeopathic therapeutic method's product form, and it comprises the activated product of extremely low concentration. In homeopathic therapeutic method, it is preferred that cobra venom diluent is 1:10,000 diluent, but, change completely with the actual volume used that elapses in age. Current guideline as provided in American Pharmacopeia homeopathic therapeutic method (HomeopathicPharmacopoeiaoftheUnitedStates) (USHP) lists 10^-6-10^-8The recommendation dilution factor of scope.

Cobra venom is used for the research after nineteen thirties of the purposes of the Therapeutic Method of pain and disease and starts application in clinical research, and it discloses cobra venom and has extremely effective analgesic activity. But, during this period, cobra venom is only used by injection. Although being successfully and safety clinically, but need nonetheless remain for frequently being injected by clinicist and decline by the end of the pouplarity of nineteen seventies this application process.

Silicon is teleorganic composition. It had both had the structure function of the composition as the protein-glycosaminoglycan complex found in connective tissue matrix, had again growth and to osteogenetic metabolism (silicon is conducive to bone mineralization process). Silicon is with silicon dioxide (SiO₂), free orthosilicic acid (H₄SiO₄), be naturally occurring in food in conjunction with silicic acid and the silicate patterns of some nutrients. In order to effectively be adsorbed, silicon must with orthosilicic acid (H₄SiO₄) form aquation. Orthosilicic acid is polymerized under neutral pH (7.0-8.0) and remains monomer molecule under low and high pH. As polymer, it is water insoluble and is thus difficult to be adsorbed. In host, orthosilicic acid keeps monomeric form, and presumption is this is because it is in conjunction with other plasma fraction, for instance protein and carbohydrate. Protein mainly through its amino in conjunction with orthosilicic acid, but be likely to and involve auxiliary key, for instance hydrogen bond and Van der Waals force. Have been found that orthosilicic acid has anti-wrinkle effect, it is prevented that moisture content is produced by skin deficiencies and stimulation collagen.

Summary of the invention

As required, this document describes detailed embodiment;It will be appreciated, however, that disclosed embodiment is only the example of the disclosure implemented in different forms. Therefore, the detailed description of exact functionality disclosed herein is not construed to finite form, and only as the attached claim awaited the reply basis and as instruction those skilled in the art each comfortable actual any applicable when change use the representative basis of the disclosure.

The disclosure relates generally to treatment and nursing skin, especially treatment and environmental exposure and the dehydration of disease association and the compositions of damaged skin and method. Infecting to dermatosis or immune disorders, rheumatoid arthritis, virus and antibacterial and damage relevant inflammation can also to using this preparation for treating have response. Described preparation is made up of with the mixture orally or topically using acceptable excipient cobra venom and orthosilicic acid (OSA). Cobra venom and OSA is formerly application of already by multiple injection. These are injected the pain and sense of discomfort that cause experimenter and need lasting medical monitoring. The oral and topical formulations of the disclosure eliminates these defects.

Term used herein " about " refer to approximate, in certain interval, almost or about. When term " about " is combined use with numerical range, it is by extending above and changing this scope lower than the border of meant numerical value. Generally, described numerical value is varied above and difference lower than 20% by term used herein " about ".

Term used herein " is used " and is referred to and be delivered to by the skin care formulation of the disclosure or be applied to experimenter. Such as, described preparation is used including, but not limited to oral consumption or local application to experimenter.

Term used herein " substrate " refers to pharmaceutically acceptable carrier, and it does not disturb the effectiveness of preparation, and for its use to experimenter's avirulence. This kind of substrate can include lotion, cream or aqueous solution.

" dosage (dose) " used herein or " dosage (dosage) " refer to the concrete consumption of the preparation of the disclosure provided in single administration or concrete time limit. Dosage can be determined based on the recommendation that health care professionals and research worker provide.

Term used herein " excipient " refers to the additive that the final dosage form carrier of skin care formulation includes. Excipient provides the formulation delivered physics to the dosage form carrier of target site interested and/or aesthetic. Excipient can be included, it is therefore intended that fill preparation (and being also referred to as " filler ", " filler " or " diluent ") or give final dosage form treatment potentiation, for instance being conducive to drug absorption or dissolving.

Term used herein " preparation " refers to the preparation being suitable for orally or topically being applied to experimenter.

Term used herein " experimenter " refers to any and all of organism. " experimenter " can refer to people or other animal any.

Technology used herein and scientific terminology have the implication that technical field those of ordinary skill described in the disclosure is generally understood, except defined otherwise. Present document relates to well known to a person skilled in the art various method and material. Well known to a person skilled in the art that any applicable material and/or method may be incorporated for implementing the disclosure. But. Preferred material and method can be described.

Many factors can facilitate beautifying skin outward appearance to change. These factors can include, for instance damage, disease, the age, environmental exposure, hormonal readiness change, externally applied or take in material such as medicine, genetic condition or their combination and other factors.The change of skin appearance can be considered irregular or abnormal, for instance dry, wrinkling, sagging or pigmentation changes.

The preparation of the disclosure includes cobra venom. Elaps (Naja) is to be called to include 28 kinds of elapid poisonous Elaps. The member of Elaps is distributed the most extensively and the Naja being widely recognized that most. Several other belongs to the kind including so-called Elaps. One example is that ophiophagus hannah (Ophiophagushannah) is planted, so-called Ophiophagus hannan (Cantor).

Various Naja kinds are throughout the region in Africa, South-West Asia, South Asia and Southeast Asia. In an embodiment of the disclosure, cobra venom can be isolatable from Elaps and ophiophagus hannah kind. Other type of cobra venom may be used for other embodiment. In one embodiment, the cobra venom of the disclosure demonstrates pain relieving and anti-inflammatory property. In another embodiment, the preparation of the disclosure includes natural origin in the nonsynthetic peptides of Ophiophagus hannan (Cantor) venom and neuropeptide.

The preparation of the disclosure also includes orthosilicic acid. It turned out orthosilicic acid and promote that the collagen protein in cartilage is formed. In one embodiment, the orthosilicic acid of the preparation of the disclosure is hydrated form (H₄SiO₄) and thus effectively absorbed by experimenter.

In one embodiment, it is possible to the cobra venom of the disclosure/OSA preparation is configured to various Orally administered dosage form. Orally administered can be the form of tablet, coated tablet, lozenge, hard capsule and soft capsule, solution, Emulsion, syrup or suspension.

In the present embodiment, Orally administered usually easy-to-use application program every day carries out, and it can according to the response adjustment of the degree of sufferer and experimenter. The cobra venom of the disclosure and OSA and one or more conventional excipient can be made pharmaceutical composition and unit dosage forms. Preparation can be used with solid (such as tablet or filling capsule), semi-solid, powder or slow releasing preparation. In another embodiment, it is possible to by preparation with the liquid such as solution, suspension of oral application, Emulsion, elixir or the suppository form use filling capsule, rectum or vaginal application.

Cobra venom and the OSA oral formulations of the disclosure can be used individually, but the pharmaceutical practice generally according to intended route of administration and standard is used with the form of mixtures with one or more excipient being suitable for. This kind of excipient can include, for instance diluent or filler, binding agent, disintegrating agent, lubricant, coloring agent, correctives, solubilizing agent, suspending agent and preservative. In one embodiment, the excipient used together with this oral formulations includes water, sweeting agent, preservative and pH adjusting agent. The concentration of these compositions is to well known to a person skilled in the art.

In one embodiment, the preparation of solid form can include one or more materials at (include powder, tablet, pill, capsule, cachet, suspensoid and dispersible granule), and described material is also used as diluent, correctives, solubilizing agent, lubricant, suspending agent, binding agent, preservative, tablet disintegrant or coating material. Powder can include as the solid fines with the mixture of active component fine powder.

In another embodiment, the liquid cobra venom/OSA pharmaceutical formulation of the disclosure can comprise Emulsion, syrup, elixir, aqueous solution and aqueous suspension. These preparations can include the preparation of solid form, for exactly converting it into the preparation of liquid form before use. ?s the tip got over ? Chinese torreya woods ticket and is composed the fan onion sea ? ? ? ? ? prostitute ? onion Hang Chishao garden ? ? hazel ? grain ? ? plaited straw aphid word ? that relaxes and (9) castrate ? and chew and handsome condemn jealous PVC and move back the Adeps seu carnis Rhiopithecus roxellanae セ legendary small dragon with horns 16. ? ? Gu bones of the body? the tip wine ü ? ? fatigued Dao of staring at Jing Qian SA is dissolved in coloring agent that applicable excipient (including water) and adding is suitable for, correctives, stabilizer and thickening agent prepare aqueous solution.

In another embodiment, for being locally applied to epidermis, it is possible to the preparation of the disclosure to be configured to ointment, cream or lotion or transdermal patch. It is, for example possible to use excipient (also referred to as " substrate ") preparation ointment and cream, for instance with the addition of the water of applicable thickening agent and/or gellant or oil matrix. Excipient (such as water or oil matrix) can be used to prepare lotion, and generally also comprise one or more emulsifying agents, stabilizer, dispersant, suspending agent, thickening agent or coloring agent. The preparation being suitable for local application in the oral cavity includes: active component is included in the lozenge in the substrate (being generally sucrose and Radix Acaciae senegalis or Tragacanth) of taste masking; Active component is included in the pastille in inert base (such as gelatin and glycerol or sucrose and Radix Acaciae senegalis); With collutory active component being included in applicable liquid-carrier.

In one embodiment, the preparation of the disclosure can be configured to suppository to use. First low melt wax (such as the mixture of fatty acid glycerine esters or cocoa butter) is melted, and, for instance by the dispersion of active ingredients that stirs. Then the homogeneous mixture of fusing is poured into the mould of convenient size so that it is cooling and solidification.

In another embodiment, it is possible to prepare the preparation of the disclosure for vaginal application. Pessary, tampon, cream, gel, paste, foam or spray are known in the art as applicable.

The preparation of the disclosure can be prepared for nasal administration. Solution or suspension are directly applied to nasal cavity by (such as dropper, suction pipe or aerosol apparatus) by conventional methods. Preparation can provide with single dose form or multiple dose form. When using dropper or suction pipe below, it is possible to used the solution of applicable predetermined by experimenter or suspension completes this and operates. When aerosol apparatus, for instance, it is possible to complete this behaviour by metering atomising atomizing pump. In another embodiment, it is possible to use the preparation of the preparation disclosure for aerosol, especially for respiratory tract and include intranasal administration.

If it is required, then the enteric coating being suitable for slow release or controlled release cobra venom and OSA can be used to prepare preparation. For example, it is possible to the preparation of the disclosure to be prepared into transdermal or subcutaneous delivery device. These delivery systems are advantageous for when to need the compliance of slow release cobra venom and OSA and patient for treatment's scheme be key.

Such as, it is easy to improving the preparation of the disclosure by less change (salt pref, esterification etc.) so that they are more soluble in water or other vehicle, these are well known to the skilled person. Those skilled in the art also fully know the route of administration changing concrete preparation and dosage, in order to the pharmacokinetics of manipulation disclosure preparation, thus reaching maximum beneficial effect in patients.

Term used herein " therapeutically effective amount " refers to the consumption needed for alleviating the condition symptoms of experimenter. Each concrete case adjusts this dosage according to individual need. This dosage can change within the tolerance, and this depends on many factors, for instance the seriousness of disease to be treated, the age of experimenter and the route of administration of general health situation, other the medicament used together with treatment experimenter and preparation and form.

For Orally administered, every daily dose of cobra venom is about 35 μ g-about 300 μ g cobra venoms/sky and about 0.1mg-is about 1.5mgOSA/ days. In one embodiment, this every daily dose comprises about 70 μ g cobra venoms and about 200 μ gOSA/ days, for Orally administered, and said preparation comprises about 10 μ g/ml-and is about 1.0mg/ml cobra venom and about 200mg/ml-is about 2.0mg/mlOSA. In another embodiment, the concentration of cobra venom is about the concentration of 50 μ g/ml and orthosilicic acid and is about 1.0mg/ml. The application rate (i.e. the application times of every day) of oral formulations can change according to the difference of the seriousness of disease to be treated. For local application, said preparation comprises about 5.0 μ g-and is about the cobra venom/gram substrate of 1.0mg and about 2 μ g-are about the OSA/ gram of substrate of 0.2mg. In one embodiment, the concentration of said preparation is 10-30 μ g cobra venom/gram substrate and about 50 gOSA/ gram of substrate of μ. The number of times that every day, dosage was used and use the time limit (natural law namely using oral dose) and depend on the seriousness of disease to be treated and the effectiveness of preparation. Those skilled in the art can not need excessively experiment and according to individual knowledge and disclosure herein scheme in treating disease as herein described, it is determined that for specifying the therapeutically effective amount of the preparation of the disclosure of disease and experimenter.

The disclosure provides the method for treating skin, inflammation or autoimmune disorder, including the cobra venom as herein described/OSA preparation to subject in need's administering therapeutic effective dose. In one embodiment, the method includes Orally administered said preparation. In another embodiment, the method includes locally executing said preparation. In another embodiment, described disease is rheumatoid arthritis.

The disclosure also provides for the method for the treatment of skin, inflammation or autoimmune disorder, including the cobra venom as herein described/OSA preparation to patient in need's administering therapeutic effective dose. In one embodiment, the method includes Orally administered said preparation. In another embodiment, the method includes locally executing said preparation. In another embodiment, described disease is rheumatoid arthritis.

The disclosure provides cobra venom as herein described/OSA preparation to be used for the purposes treating in the medicament of skin, inflammation or autoimmune disorder in preparation. In one embodiment, the method includes Orally administered said preparation. In another embodiment, the method includes locally executing said preparation. In another embodiment, described disease is rheumatoid arthritis.

Specific embodiments

Provide following preparation and embodiment is to enable those skilled in the art to be more clearly understood that and implementing the disclosure. Should not treat them as restriction the scope of the present disclosure, and be only used as its example and representative. Preparation embodiment

Zooscopy

Experiment 1

Take tolerance studies to observe the anaphylaxis of the Cavia porcellus topical gels to preparing with cobra venom. This animal model attempts to make host to test product sensitization within 2 week time limit, then attacks after 2 weeks. Will depilation and processing by local application test substances repeatedly when the 1st, 7 and 14 days on test animal (Cavia porcellus) 3X4cm region on its backside: natural cobra venom, modified cobra venom, gel without active component and 0.1%2,4-dinitro-chlorobenzene solution. When the 28th day, prepare the opposite flank of 3X4cm epilating area processes every animal wherein with 1%2,4-dinitro-chlorine benzole solns.Observe anaphylaxis and 0,24,48 with 72 little records together with anaphylaxis intensity constantly.

The data obtained during this research confirm that local cobra venom preparation and excipient all will not bring out the anaphylaxis of locality.

Experiment 2

Test gel preparation in Mice Formalin pawl is tested, in order to the pharmacodynamic activity of checking local cobra venom. This test is as the model of pain relieving and inflammation, in order to evaluate the local action of medicine. Herein, mice is divided into matched group and 10 animals for the treatment of group (often group >). Cobra venom gel is directly applied to the right rear solid end of mice 3 days, every day 1 concentration 20 μ g/g substrate. When the 4th day, 1.5% formalin solution was injected the right rear solid end of mice in 5 hours after administration. Observe that mice licks pawl as the reaction to pain. The pawl time licked in record, and within 0-5 minute, as 1 phase, 15-30min is as 2 phases. Carry out similar seminar to evaluate the systemic activity of cobra venom gel. In the method, cobra venom preparation is applied to the epilating portion on back part of animal.

By poor at 1 interim topically and systemically cobra venom composition cobra venom preparation effectiveness, and 2 interim using, there is remarkable activity. But, although local and far-end mode of administration are effective astoundingly, but analgesic activity is not clearly dose response (response) property. This result shows that venom can affect the approach feeling relevant to pain and inflammation.

Experiment 3

Take adjuvanticity (adjuvant) arthritis model to determine whether the antiinflammatory of the cobra venom of report and disease modifying activity can by Orally administered realizations. Rule of thumb it is chosen as the dosage that this research selects, in order to simulate the oral dose (6.5mg) used for basic homeopathic therapeutic method (homeopathic) of maximum tolerance clinical administration dosage (2-4mg) by injecting and report. Additionally, test high dose, it is approximately equal to 30mg/kg, 90mg/kg and 270mg/kg the weight of animals wherein interiorly. Selecting the experimental group of 8 rats to include untreated matched group, i.e. the matched group of only CFA, the dosage of cobra venom is 30,90 and 270 μ g/kg. Animal passes through every day at 9AM intranasal administration acceptance test material. Then to acutely inflamed inhibitory action in test animal model. 0.1mlCFA is subcutaneously injected into right rear solid end brings out edema by being administered in the morning latter 6 hours when the 5th day. Animal 9am of the 11st day after bringing out started every day acceptance test material until the 28th day, in order to the extended period (i.e. long term) of role of inspection.

These results prove that Orally administered cobra venom is effective in this RA arthritis animal model completely, given play to report by injecting the identical dose dependent immunomodulating of cobra venom and joint protective effect. With research formerly conversely, there exist protein (i.e. nonsynthetic peptides and neuropeptide) in cobra venom solution by Orally administered be that biology is effective.

The studies above supports the application of the preparation of the cobra venom/OSA combination of oral and topical form, namely exceedes the major progress of the injectable product being formally referred to as Nyloxin. These preparations eliminate the demand to injection, and also avoid the sense of discomfort relevant to parenteral administration and medical monitoring.

Human research

Experiment 1

Preparation is by 0.02mg cobra venom/gram substrate and 0.05mgOSA/ gram of substrate composed topical formulations. Said preparation is supplied to several experimenter to evaluate the effect when being applied to face and cervical region.

Experimenter 1. there is the female subjects of ageing skin

The women of 55 years old, evaluates the topical formulations of experience some months process.Do not report untoward reaction. This product of subject perception is maintained on its skin, feels aquation, and the little fine rule around her eyes and oral cavity obviously reduces.

Experimenter 2. there is the female subjects of ageing skin

The women of 63 years old, evaluates the topical formulations of experience some months process. She is the person of frequently using of other skin-protection product, but finds that they are unsatisfactory. Do not report untoward reaction. She finds after a few weeks, and the numerous little fine rule of its lip and around eyes starts to disappear. She also uses said preparation on its cervical region, and deep wrinkle starts to significantly reduce. When extending use, her continuous skin becomes evenly with smooth. Said preparation extension is used to its back of the hand portion by she.

Experimenter 3. there is the female subjects of ageing skin

The women of 51 years old, evaluates the topical formulations of experience some months process. She is also the person of frequently using of other skin-protection product, but unsatisfactory. Do not report untoward reaction. She notices change positive in the elasticity of its skin, elasticity, outward appearance and general health. The circulation that she feels in its skin strengthens, thus keeping skin feeling soft. Fine rule around her eyes and oral cavity is substantially less, and dark areas is very inconspicuous. Flexibility and compliance that interruption use said preparation causes having reached in advance for 2 weeks are significantly degenerated.

Experimenter 4. there is the female subjects of normal skin

The women of 26 years old, evaluates the topical formulations of experience some months process to determine the potential of its protection skin. Using said preparation about after 1 month, not to be noted untoward reaction. But, she notices that the elasticity of skin and texture significantly change. Experimenter suffers from rosacea, can change in its seriousness, and it is accidentally can cause embarrassed red patch. Rosacea is almost wholly absent, thus eliminating the demand using other cosmetics to cover this region. There is also reports that the fine rule on forehead reduces.

Claims

1. the orally available pharmaceutical preparation used, comprises: Ophiophagus hannan (Cantor) (kingcobra) venom, orthosilicic acid and excipient.

2. the preparation of claim 1, wherein cobra venom comprises ophiophagus hannah (ophiophagushannah) venom.

3. the preparation of claim 1, wherein said preparation is the preparation of solid form.

4. the preparation of claim 1, wherein said preparation is liquid preparation.

5. the preparation of claim 1, wherein the concentration of cobra venom is about 1.0mg/ml for about 10 μ g/ml-, and the concentration of orthosilicic acid is about 2.0mg/ml for about 200mg/ml-.

6. the preparation of claim 1, wherein the concentration of cobra venom is about 50 μ g/ml, and the concentration of orthosilicic acid is about 1.0mg/ml.

7. can the pharmaceutical preparation of local application, comprise: cobra venom, orthosilicic acid and excipient.

8. the preparation of claim 7, wherein cobra venom comprises ophiophagus hannah venom.

9. the preparation of claim 7, wherein said preparation is lotion.

10. the preparation of claim 7, wherein said preparation is gel preparation.

11. the preparation of claim 7, wherein the concentration of cobra venom is about 1.0mg/ gram of substrate for about 5.0 μ g-, and the concentration of orthosilicic acid is about 0.2mg/ gram of substrate for about 2 μ g-.

12. the preparation of claim 7, wherein the concentration of cobra venom is about 20 g/ gram of substrate of μ, and the concentration of orthosilicic acid is about g/ gram of substrate of 50 μ.

13. the method for the treatment of skin, inflammation or autoimmune disorder, including the preparation of the claim 1 to subject in need's administering therapeutic effective dose.

14. the method for claim 13, wherein cobra venom comprises ophiophagus hannah venom.

15. the method for claim 13, wherein said disease is rheumatoid arthritis.

16. the method for claim 13, wherein said preparation is the preparation of solid form.

17. the method for claim 13, wherein said preparation is liquid preparation.

18. the method for the treatment of skin, inflammation or autoimmune disorder, including the preparation of the claim 7 to subject in need's administering therapeutic effective dose.

19. the method for claim 18, wherein cobra venom comprises ophiophagus hannah venom.

20. the method for claim 18, wherein said disease is rheumatoid arthritis.

21. the method for claim 18, wherein said preparation is lotion.

22. the method for claim 18, wherein said preparation is gel preparation.