GB2338413A

GB2338413A - Composition for enhancing transdermal absorption

Info

Publication number: GB2338413A
Application number: GB9813093A
Authority: GB
Inventors: Gursharan Singh Moonga
Original assignee: Individual
Current assignee: Individual
Priority date: 1998-06-18
Filing date: 1998-06-18
Publication date: 1999-12-22
Anticipated expiration: 2018-06-18
Also published as: GB9813093D0; GB2338413B

Abstract

The invention relates to the development of multi -micro dilution technology (MMD) which facilitates the topical and transdermal delivery of nutrients and Active Pharmaceutical ingredients(APhl) e.g. minerals, vitamins and Topical analgesics ,antiseptics and Non steroidal anti-inflammatory drugs(NSAID). A major benefit is the ability to significantly reduce irritation associated with certain APhl. The active substance is diluted based on invention of multi-micro dilution technology and this assists in trandermal delivery to provide nourishment or therapy for healthy skin.

Description

2338413 TOPICAL AND TRANSDERMAL DELIVERY BY MULTIMICRO DILUTION TECHNOLOGY

1 /1- - 1 Inventor: Dr Gursharan Moonga, BritHealth Limited, Weltech centre, Ridgeway,Welwyn Garden City,Herts.,AL7 2AA England Patent Application

BACKGROUND TO THE INVE?sTION:

Phosphoresces and iontrphoresis are means of enhancing skin transport of selected molecules. Chemical absorption enhances are still actively studied. Liposorne-mediated delivery is more of a reality than once it appeared as paradigms are shified and formulation development continues. Submicrron (1 00-30ONMI) oil in water creams have been formulated which deliver high levels of lipophilic drugs such as diazepam than conventional preparations as reported by Schwartz and Friedman in pharmaceutical research, 1995 patent WO 93/18752. A patent application for topical suspension of solid submicron particles also exists (European patent application number EP 0 506 197 AI (30.9.92). Despite of barrier properties of skin, it is still an attractive organ for local administration of certain systemically active drugs and vaccines. It is easily accessible and highly immunoreactive. In addition to well known transdermal products now in the market many other drugs and biotechnological including large molecular weight proteins and peptides are under investigation for possible dermal delivery.

IvEHODS OF PREPARATION ANDIlvIMI) TEC OLOGY: PREPARATION OF ADDITIVE PF2800A AND PF2803A CARRIER SYSTEMS FOR INCORPORATION N1 VARIOUS FORMULATIONS SOLUTION 1. B, Ferr Phos in conc HCl C. Kali Mur in H20 D. Kali Sulph in H2 E. Nat Mur in H20 F. Silica in conc. NaOH TOTAL 121ng in 1 00mi. Note. Solution F needs to be filtered before use.

SOLUTION 2.

A. Calc sulph in dilute HCl B. Ferr Phos in dilute HCl C. Kali mur in H20 D. KaIi sulph in H20 E. Nat mur in H20 F. Silica in dilute NaOH.

1,2g in 1 0OrnI and filter and 1 Orril of A x in 1 00nil PF2800A 5 LITRE:

1. Take 1OmI of each 2x solution AB,QD,E&F make up to 10On-A with water 2. Add to 1 litre of water containing 25gm Germal 115 containing 1 Og of Sodium nipagin. 3. Make upto 3 litres with water. 4. Check pH(Iimits 637.5) adjust if necessary. 5. Make upto 5 litres with water. 6. Filter into a plastic container.

PF2803A 10Litre 1. Take 25mi of each 2x solutions &B,C,1),E E& F and make upto 25OmI with water 2. Add to 4 litres of water containing 50gm Germal 115 containing 20gm of sodium Nipagin. 3. Check pH (limits 63- 7.5) adjust if necessary. 4. Make upto 10 litres with water. 5. Filter into plastic containers.

For preparations of skin care products and OTC medicines, 0.025% W1W of Additive Carrier System PF2800A was used in all formulations. However, Additive Carrier System PF2803A (0.025%) was used in Hair care/Scalp preparations and Formulations evaluated included those listed in Annexe 1 and others e.g. NSAID, Topical analgesics etc. The formulations listed were validated according to BPlEP OR USP standards and are shown to have stability and shelf life of three (3) years. Trials were conducted using listed formulations and involved 65 patients with skin problems, Clinical Trials Investigators confirmed that 60 patients reported healthy epithelium layer and smooth skin after applying the creams containing (Excluding any other Active ingredients) Additive Carrier Systems. However in case of creams containing actives e.g. Tea tree oil or Tretinoin or Analgesics, no irritation was reported. CARRIER SYSTEM BASED ON BIOCHEMICAL MINERALS: The skin is made up of the thin upper layer of cells called the epidermis and the lower layer consisting of fibrous network of blood vessels called the dermis. Separating these is a fine layer of skin cells known as basal layer. Kali sulph is found in external layer of epithelium, Ferr Phos is also found in red blood cells and other tissues. Kali mur and Nat mur is found in fibrin. Calc sulph and Silica is also found in tissues. The inventor used the formulation tools such as theoretical and experimental models or predicting skin penetration rate, solubility analysis, and a wide variety of vehicles and penetration enhancement methods, which included the solvents, surfactants, and lipophilic enhancers 3 The inventor has found that these biochemical minerals act as transport systems for vital nutrients and therapeutics for delivery across the dermal layer.

ANNEXUEL 1. ANTISEPTIC CREAM FOR CUTS, WOUNDS, NAPPY RASRMINOR BURNS AND FOR SLOW HEALING SKIN:

INGREDIENTS W/W % Cosmolloid wax BDH 6.00 White Beeswax substitute 2.50 White soft paraffin 20.00 Technical white oil 23,46 Propyl paraben 0.10 Methyl paraben 0.10 Cetal 3.00 Crill 6 4.00 Propylene glycol 5.00 Germall 115 0.30 Additive PF2800A 0.25 Terpeniol 0.10 Tea tree oil and lavender oil 1.00 Purified water 30.59 METHOD AND EQUIPMENT: Stainless steel bucket 15 litre, Stainless steel spatula and scoop, Stainless steel steam jacketed pan 200 and 400 litre, thermometer, Egh speed stirrer, Scales 50Kg capacity, Flexifiller with electric mantle to hopper. a) Raise steam to 15 psi, weigh the cosmolloid wax, beeswax substitute, cetal and prpyl paraben and place in the 200 litre pan, open steam valve. Weigh the white soft paraffin in convenient lots eg 10Kg and add to the 200 litre pan.. Weigh the technical white oil into a bucket. Add to 200 litre pan. Drain bucket thoroughly. Weigh the crill into a bucket. Add to 200 litre pan. Drain bucket thoroughly. Stir contents of pan occasionally until contents are melted then close steam valve. Collect about 40 litres of purified water in the 400 litre pan. Open steam valve and heat until water reaches 85-90 degree centigrade. Close steam valve. Weigh Methyl paraben and dissolve it in hot purified water. Weigh propylene glycol by the bucket, pour into 400 litre pan, drain bucket thoroughly and rinse with a small portion of liquid ladled out from pan. Weigh the additive PF2800A and Germall 115 and add to 400 litre pan. Stir to dissolve. Allow the oily phase in the 200 litre pan to cool to 70 degree centigrade. Bring the acueous to same temperature by admitting steam to the jacket of 400 litre pan if necessary. b) Suspend the high-speed stirrer with emulsifying head fitted above the 200-litre pan with the mixing head well below the surface of the liquid. Operate the mixer and add the aqueous phase by ladling into dried, tarred, buckets weighing each bucket as filled, In this way the total weight of the aqueous phase transferred can be ascertained and losses due to evaporation made good by adding more purified water to 400 litre pan so as to bring the total weight transferred to the 61.25 Kg. Admit steam to the jacket for 30-60 seconds if signs of solidification appear on the surface of emulsion. Weigh the terpineol, tea tree oil and lavender oil and add to the emulsion while mixing. Continue mixing for 15 minutes. When approved by the quality control, heat the bulk emulsion to 60-65 degree centigrade if necessary with mixer operating to avoid overheating at the sides of pan.

c) N_ Assemble the filling machine with electric mantle surrounding the hopper and thermostat set at about 50 degree. Transfer the emulsion by means of a warm dry bucket to the hopper and adjust filling volume to deliver the required dose. Then fill into the containers as specified.

e) Check weigh of filled container every 10 minutes or from every 200 filled. Check temperature of product inside hopper from time to time and adjust thermostat as required.

f) Safety aspects: Risks of bums from hot surfaces- steam pipes, interior of vessels, splashes of hot oils. Avoid contact. Steam pressure gauge to read 15 psi maximum.

2. MOISTURISING FLUID FOR DRY SKIN:

INGREDIENTS W/W% Methyl Paraben(Nipagin M) 0.11 Carbopol 934 0.09 Sodium Hydroxide Pellets 0.03 Additive PF2800A 0.25 Collone NI 1.90 Technical White oil 4.76 Propyl Paraben (Nipasol M) 0.11 Umordant P 2.38 Eppicol LZ 0.48 Perfume @ellmay 1- 1098 1 A) 0.09 Germall 115 0.47 Purified water 89.83 3. CLEANSING MILK WITH VITAMIN E:

INGREDIENTS W/W% Methyl 0.09 paraben[nipagin M] Propyl 0.04 paraben[nipasol Nfl Additive PF2800A 0.25 Solution Cetal 1.19 Srearic acid 3,69 Technical white oil 14.28 Tdethanolamine 2.56 Perfume Bellmay 0.09 10912A Allantoin 1.19 Purified water 76.62 Natural vitamin E 0.05 is 11,-.

4. CLARNYING SKrN FRESHNERISMOOTHER:

INGREDIENTS W/WO/0 Ethaol B Denatured 95 20.00 Extrapone complex 2 0.24 Propylene glycol 1.20 Triton x 100 0.48 Witch hazel 8.84 Additive PF2800A 0.25 Perfume B11may 10912A 0.09 Colour -green 0.04 Purified water 68.86 5. VITAMIN E CREAM NOURISIUNG..

INGREDIENTS W/W% Methyl paraben 0.11 Propyl paraben 0.05 Carbopol 934 0.09 Additive PF2800A 0.25 Sodium hydroxide pellets 0.03 Collone NI 1.79 Technical white oil 4.76 dl-alpha Tocopherol acetate 0.38 Pro.. lene glycol 4.75 Empicol LZ 0.47 Anstead red 2 0.01 Anstead yellow 6 0.009 Germall 115 0.47 Bellmay 1-10912A 0.09 Purified water 86.69 6. LOTION FOR EXTRA DRY BODY:

Methyl paraben 0.11 Propyl paraben 0.04 Carbopol 940 0.01 Collone NI 1.90 Technical white oil 24.00 MonopropyIene glycol 14.76 Additive PF2800A 0.25 Sodium hydroxide pellets 0.03 Empicol LZ 0.4 Bellmay 1-10912A 0.09 Germal 1115 0.21 Purified water 58.00 7. ASTRINGENT COLOGNE:

Denatured Ethanol B96 65.00 CremophorR160 1.50 Perfume Magnum 36775 4.00 Propylene Glycol 3.00 Purified water 26.50 Additive PF2800A 0.25 8. AFTER SHAVE CREAM:

Methyl paraben 0.13 Propyl paraben 0.04 Carbopol 934 0.11 Collone N 1 0.19 Technical White Oil 5.55 Additive PF2800A 0.25 Sodium Hydroxide Pellets 0.03 Empicol LZ 0.05 Anstead brown 13452 0.01 Perfume magnum 36775 1.00 Germall 115 1,00 Purified water 91.64 9. HERBAL BATH ESSENCE INGREDIENTS W/WO/0 Sodium chloride 2.00 Methyl paraben 0,13 Propyl paraben 0,04 Germall 115 0.30 Texapon N25 60.00 Comperlan vod 5.00 Celiol HE 2,50 Perfume HB 1844 1.20 Additive PF2800A 0.25 Extrapone complex 2,50 Anstead green 5 0.25 Purified water 25.83 10. ANTI DANDRUFF SHMPOO:

INGREDIENTS W/WO/0 Methyl paraben 0.13 Propyl paraben 0.04 Germall 115 0.30 Texapon 25 35.00 Comperlan KI) 4.25 Sodium hydroxide 1A Herbasol complex 1.1 Vee gum HV 0.5 Propylene glycol 1,5 Zinc pyrithione 48% 1,0 Perfume BB 1844 0.075 Blue dye VRS 0.02 Additive PF2803 A 0.25 Purified water 58.19 CONCLUSION: The invention offers opportunity for skin care, personal care and OTC manufacturers to develop products which offer new route of transport across the dermal layer which is irritant free.

2 CLALMS OF P1WENTOR:

The invention relates to the development of Multi-micro dilution (IVM) technology which can be used by manufacturers of skin care products, hair care products and OTC medicines for dermal Applications. 1. The inventor claims the use of technolog in the formulation of skin care products e.g.

cy moisturisers, dry skin conditions and problem skins. (FORNWLATIONS LISTED IN Annexe A) The inventor claims anticipated use of technology in tretinoin formulation for acne as tretinoin is highly effective but also highly irritating, melanin formulation for sun screen, 5-Flurouracil for treating actinic keratosis, a precancerous skin condition caused by excessive exposure to Sun. However currently available 5-Fluorouracil creams are highly irritating which leads to poor patient compliance. The inventor also claims anticipated use of delivery system for peptides, vaccines and other biotechnological products. The inventor claims the use of technology in antiseptic creams (formulation listed in Annexe B), NSAID and Analgesic creams and wound healing creams etc.

4. The inventor claims the irritancy free delivery of molecules across dermal layer for improved therapeutic and healing effects. The inventor claims the use of technology for personal care products for irritancy free delivery of actives (including vitamins & minerals)across dermal layer for healthy skin.

6. The inventor claims use of technology in formulations for treatment of scalp conditions and Shampoos e..c,. anti-dandruff shampoos and lotions or creams 7. Inventor claims the process of preparation of Additive Carrier Systems as deliverv systems.

2.

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