WO2004019920A1

WO2004019920A1 - Transdermal delivery system

Info

Publication number: WO2004019920A1
Application number: PCT/IB2002/003449
Authority: WO
Inventors: Carol Choi Fung Yuen
Original assignee: Carol Choi Fung Yuen
Priority date: 2002-08-27
Filing date: 2002-08-27
Publication date: 2004-03-11
Also published as: AU2002329530A1

Abstract

This Transdermal Delivery System (TDS) is a 'bead-on-adhesive' invention, with essential features as follows: 1) 'Bead-on-adhesive' -Encapsulated core actives which can be natural therapeutic substances, herbal prescriptions, or botanical extracts, or appropriate drugs form 'bead' which performs a template function, 2) A technique that enables a full range of production scale, from small batches for customized individual conditions to over-the-counter mass production for common aliments, 3) Controlled release transdermal delivery, 4) Masking of odor or color that core substances may have, 5) Resilient support function, 6) Self-sealant without any auxiliary fixing device. This TDS is a resilient supporting substrate, e.g. textiles, elastomers etc., [1a3, 1b2] with a self-sealant adhesive coated [1a3, 1b2] on its whole surface. Beads, which are embedded with controlled release encapsulated core actives, are either stuck at the foremost tip end surface as a 'compress' for the wrapping model or on the wrong-side [1b2] central zone [1b1] for the tubing model. Core actives are customized natural prescriptions, like Chinese herbal prescriptions, aromatherapy blends, vegetable oil blends or botanical extracts, or drugs to treat individual conditions or to heal common aliments. The encapsulated beads [1a2, 1b1], in which the core actives are embedded, are shelled with a membrane. With the membrane, all undesirable odor is masked and all possible residue colour-stains is avoided. (Figure 1a and b is a schematic representation of the bead-on-adhesive TDS invention.)

Description

DESCRIPTION

Transdermal Delivery System

This new product is inspired by the traditional compresses adopted by many people in traditional cultures for wound healing. Originally, medicinal herbs were gathered and made into a paste, which was placed onto a piece of textile and pressed onto the wound locally. This kind of drug delivery device is still in use in many places, and is often referred to as a transdermal delivery system (TDS).

The invention relates to a TDS of the type, which includes microcapsules (or encapsulated beads) dressing (or 'compress') 'stuck' with pressure sensitive adhesive or the like onto, either the foremost free end of a strip of or the wrong-side central zone of a tubular resilient textile, which acts as a backing layer. The microcapsules are spherical in shape as a bead in which core actives are encapsulated. The core actives used can be natural substances, prescriptions, essential oil blends, vegetable oil blends, aromatherapy blends, botanical extracts, or drugs that are of therapeutic effect. The resilient textile acts as a support like a regular bandage and may be wrapped conveniently without using any hooks or fixtures of any kind to hold it in position. In brief, the invention step of this product is a 'bead-on-adhesive' system for a TDS.

Traditional herbal compresses are one of the well-known TDSs in the world. Chinese 'External Medicine' ( y

often uses compresses to achieve transdermal delivery results. This kind of topical application has long been known as an effective remedial measure for patients. The method has worked well- for thousand of years; however, it has a disgusting odor when worn, and color stains and residues of paste are left behind when unwrapped, and the 'juice' from the mashed paste of herbal substances on the skin may cause an unpleasant feeling. These problems have limited this topical application, in traditional Chinese medicine particularly, because they are unacceptable to many people.

This TDS tackles these problems by converting the 'paste' into a form, either aqueous or suspension or the like, into core actives, which are then microencapsulated into 'beads'-like microcapsules. The encapsulation is to mask undesired odors and color pigments. This masking function is one of the key devises in the product design.

Although nowadays there exist some TDSs that are of the kind for pain relieving or fever cooling, etc., these devises can only relieve one specific symptom. If health practitioners or pharmaceutical manufacturers want to use the same technology to produce another TDS to tackle other symptoms, they must launch some other mass production lines. Because one production line only produces one product, change to other lines is expensive for the manufacturer. From a production engineering point of view, there can be rooms to improve the cost effectiveness by means of some innovative steps in group technology.

The concept of embedding different kind of natural core actives, as described above, into different microcapsules, enables the possibility of customized prescriptions to meet various individuals needs. Applying existing microencapsulation technologies, it is possible to handle customized prescriptions for either a particular individual or a group of patients with similar conditions, like chronic pain, inflammation or wound healing, etc. Because of using the 'bead' as a template for embedding various possible active ingredients as mentioned, group technology in TDSs production becomes possible on this TDS production, i.e. customized as well as mass production becomes a matter of choice in production batch. The new TDS using this 'bead-on-adhesive' concept make possible a larger range of natural prescriptions to treat different conditions. The flexibility of various 'prescription-in-bead' of this TDS devise is another key innovation in this product.

Another problem is that TDS is usually worn for a certain period of time leaving active substances in contact with the skin. That means a steadily and long lasting controlled release of core actives is desirable. However, substances in a paste form, as mentioned above, lack release control. Many commercially available TDSs are not controlled-release either. The encapsulation process for the core actives in this invent TDS tackles this problem. A controlled release mechanism of core actives is another key devise in this product design.

There are many bandages or plasters in the market today. Most of them have very competitive features. However, many of the bandages are either in patch forms that are tacked onto the target site as a disinfectant or protection for wound healing; or they are in roll form that performing a supporting function only. A few of them do combine the support and healing functions together. However, those are primarily with core actives in hydrogel form to make a patch take effect on a local target site, without incorporating the controlled-release element. And/Or some of them are just patches designed to wear with a tubing support, yet still without any release control function. A few of them do have a drug release control function, yet they are commonly in patch form and do not serve a supporting function. None of them yet are made into a wrapping or tubing form bandage with a cluster of microcapsules simply produced in a 'bead-on-adhesive' model. By this, the TDS combines all the desirable functions to perform healing, controlled release and a resilient supporting function. This is another key devise in this new product.

Apart from this, many of the wrapping bandages in the market required some of kind of auxiliary fixing device like hooks. Such fixing devices are not very convenient to wrap and sometimes restricts the necessary movement. To tackle this problem, this invention is configured with a self- sealant supporting wrapping or tubing devise; no undesirable auxiliary parts are employed to fix the free end. This is the last but not the least devise for this invention.

To sum up, this TDS is a 'bead-on-adhesive' invention, with essential features listed as follows:

1) 'Bead-on-adhesive' -Encapsulated core actives of natural therapeutic substances, herbal prescriptions, or botanical extracts or drugs form the 'bead' performs a template function,

2) A technique that enables a full range of production scale, from small batches for customized individual conditions to over-the-counter mass production for cornmon aliments,

3) Controlled release transdermal delivery,

4) Masking of odor and colour of core substances that may have,

5) Resilient support function,

6) Self-sealant without any auxiliary fixing device

A preferred embodiment of the invention will now be described with reference to the accompanying drawing in which:

• Figure 1 (a and b) show a plan and elevation view of the whole wrapping model of the TDS;

• Figure 2 is a cross section of the microcapsules showing the membrane of the encapsulated beads and the inner space in which various customized core actives are embedded.

• Figure 3 (a and b) show an example of the self-sealant wrapping model of the TDS as worn on a finger joint, performing a resilient supporting function.

• Figure 4 (a and b) show another example of the tubing model of the TDS as worn on a knee cap, performing a resilient supporting function.

• Figure 5 is a section to show how the TDS works on the skin.

As shown in Figure la, the wrapping model of this TDS is the type of a resilient support, with a certain self-sealant material [3] laminated on its whole surface [1], and a coating of encapsulated core actives [2] at the foremost tip end surface performing a dressing function for healing of various conditions. As shown in Figure lb, the tubing model of this TDS is the type of a resilient support, onto which encapsulated core actives, i.e. the 'beads' were stuck [2] on the wrong-side central zone in the tubing textile performing a dressing function for healing of various conditions.

Figure 2 is a schematic representation of the cross section of the microcapsules or 'beads', with which the core actives [1] are embedded in a membrane [2], The core materials [1] can be in gaseous, liquid or solid state as well as in emulsion or suspension, such as vegetable oil base essential oil blend or various traditional Chinese herbal prescriptions or drugs, which have therapeutic effects like anti-inflammatory, analgesic, spasmolytic, etc. This results in a versatile TDS devise.

The beads, produced by microencapsulation technology, are shelled with a polymeric membrane. The material of the membrane must be non-toxic, non-irritable and biodegradable, like beta tricalcium, sodium alginate and chitosan, etc. The polymer membrane is designed to perform a controlled release function of core actives as well as odor-masking and colour stain avoiding functions. The controlled release function is dependent on some sorts of physical, chemical or biological phase changes, like a change of body temperature, moisture, or enzymatic activities, etc. during the time that the microcapsules are in contact with the skin. The microcapsules produced are stuck with a layer of adhesive, e.g. pressure sensitive adhesive (PSA), etc. and stuck onto a resilient fabric, like polypropene or any appropriate medical textiles, suitable for use as a self-sealant compress. The adhesive model is preferably of a medical or surgical grade, tacky yet non-stringy, easy to fix and peel and yet comfortable to wear, e.g. polyisobutylene (P_B) based PSA.

The dimensions of the 'bead' zone on the backing layer are dependent on the applied site. No specification on bead zone dimension should be stated here. The TDS can be either in a wrapping model [Drawing la and 3a,b], or in a tubing model [Drawing lb and 4a,b]. Beads are stuck with pressure sensitive adhesive or the like onto, either at the foremost free end of the strip in the wrapping model of or on the wrong-side central zone in the tubing model.

As shown on Figure 3, the TDS is in virtue a self-sealant one that does not require any fixtures to set it in position when worn, like on a finger joint [3a]. The microcapsules are hidden underneath the wrapping and contact directly onto the target site to effect. When worn with this wrapping model, its resiliency enables the finger joint to move freely with the TDS well in position [3b].

Figure 4 is a section showing another example of the resilient support function of the TDS. When freely with the TDS well in position [4b].

Figure 5 is a schematic representation of how the customized TDS works on the skin.

A wrapping model of this new TDS was produced in a laboratory scale trial basis. Details of materials, formulation and manufacture are cited in the Appendix I and II, given as an example of how this 'Bead-on-adhesive' TDS can be customized produced.

APPENDIX I

An Investigation into the Methodology to Manufacture a 'Bead-on- Adhesive' Pain-relieving Transdermal Delivery System

(University of Manchester Institute of Science and Technology 2002 by Carol C F YUEN)

MATERIALS

Materials of the Microcapsules

The Core Materials — Aroma Formulation as the Therapeutic Active

The first stage of the investigation is to determine the physiochemical properties of the 'would-be' core substance if it is to enter the skin smoothly. It should be effective when delivered steadily over a relatively long period. Interestingly, skin does permit passive absorption of lipophilic, low- molecular-weight chemicals to cause local effects.

Vegetable oils

Vegetable oils are well-known to be lipophilic in nature, and have long been used as skin emollients. Chemically, they are referred to as triglycerides. Glycerides are esters of glycerol and fatty acids. Glycerol is a common component in almost all of the vegetable oils, the only differences among them being found in their different fatty acids components. There are many different fatty acids. They feature a long hydrocarbon backbone attached to the carboxyl group (- COOH). Figure I shows the generic reversible chemical reaction of triglycerides, glycerols and fatty acids.

Figure I Reversible Chemical Reactions of Triglycerides, Glycerol and Fatty acids As shown, the long-chain fatty acids (2) react with glycerol (3) resulting in very large triglycerides (1) molecules that cannot easily penetrate the skin, but nevertheless are good emollients. Triglycerides are characterised by low volatility, high viscosity and insolubility in ethanol. However, triglycerides blend well with pure natural volatile oils, commonly known as essential oils. These have comparatively smaller molecules, generally in the molecular weight range from 120 to 260. This enables them to slowly penetrate the skin.

Vegetable oils were thus selected as the base for the aroma formulation embedded in the microcapsules. A selection of vegetable oils was blended for their richness in nutrients and because they act as a good skin emollient. ^[6] Apart from this, the vegetable oils in the base were chosen for their known 'carrying' function. The vegetable oil mixture was further blended with the essential oils, with which they were miscible, to complete the core active material. This facilitated the diffusion process for better skin absorption as described previously in this section. In fact, the vegetable oils are always referred to as carrier oil in aromatherapy for their 'carrying' function, which means they act as a vehicle for 'transporting' essential oils into the human body via the skin. Cold-pressed vegetables were used in this study to avoid the risk of peroxidation of the oil, causing free radical cell damage. ^[7] Many of these natural vegetable oils, e.g. coconut oil, are used as skin surfactants. They are generally non-toxic, but can easily be oxidised to a malodorous form. This unpleasant property caused them to be replaced by their synthetic counterparts. Microencapsulation of the natural vegetable oils masks their tendency to smell, and makes them more acceptable as ingredients for personal care.

Essential Oils

Pure essential oils have relatively low molecular weights and melting points, and possess versatile, yet potent, therapeutic effects. In fact, essential oils were chosen as a core active material in that they:

1. Consist of relatively small and lipophilic molecules which can penetrate into skin;

2. Do not irritate skin, if species are selected carefully;

3. Possess many synergistic therapeutic effects;

4. Are, in general, economical and with good availability.

All these characteristics make them good candidates to be core ingredients within the microcapsules in a TDS. In order to achieve the pain-relieving effect, a blend of essential oils was prepared with constituents providing analgesic, spasmolytic and anti-inflammatory effects. The Polymeric Wall (membrane/shell)

A mixture of beta-tricalcium phosphate [Ca₃(PO )₂] solution of 10% dilution in a 2% sodium alginate solution was prepared for the manufacture of the polymeric wall in the encapsulation process. The chemicals were selected for their non-toxic properties and biocompatibility. Beta- tricalcium phosphate was added to the sodium alginate to insolubilise the membrane, thus making it stronger and not as tacky as if sodium alginate were used alone. Calcium alginate is used in wound dressings.

The Adhesive — Polyisobutylene based Pressure Sensitive Adhesive (PSA) Model

Since TDS products are devices for external application on the skin, they have to provide good skin contact on the target sites over a certain period to ensure adequate drug delivery. It is necessary to take into consideration the following aspects when choosing an adhesive for the purpose:

1. Cohesive properties ;

2. Adhesion properties;

3. Compatibility of the adhesive with the drug adhered;

4. Health and safety factors for human use.

Unfortunately it is difficult to find a compatible adhesive system for the formulation. However, recent investigations into pressure sensitive adhesives (PSAs) reported positively on their ease of use and good stability. Many reported that PSAs were a possible choice for medical bandages and hospital tapes.¹-⁸'⁹'¹⁰'¹¹-¹ In his recent paper Trenor pointed out that, "Medical PSAs must be biologically inert, non-irritating to the skin, cause no system toxicity and be compatible with the active ingredients and any other excipients." Health and safety considerations are crucial and determining factors in any personal care or medical products. For this reason, most TDSs include a skin surfactant in the excipient. In the same paper, Trenor noted that the addition of skin surfactants reduces the peel strength of the adhesive. He stated, there exists "... a trade-off between better transport of the drug and better adhesion of the PSA..." and this trade-off may become a limiting factor in the future development of TDSs.^[11]

In considering whether surfactants should be included in the adhesive in this study, it was interesting to notice that in many cases, amphoteric surfactants were used for personal care amphoteric surfactants "... primarily contain betaines, which occur in many vegetables oils. Interestingly, betaines have been long used to treat muscle weakness medically, with no known toxicity... "^[12]. Since the formulation of the core materials in this study was primarily a vegetable oil, it was assumed that no surfactant would be needed in the adhesive formulation. The limiting factor of the TDS mentioned by Trenor might therefore be avoided. The vegetable oils in the core are good skin emollients. It was therefore expected that the core formulation would play a dual role in this case.

The properties of polyisobutylene (PIB) that make it suitable for use in medical grade PSAs, as quoted in Trenor 's recent paper, are:

1. it is highly paraffinic and non-polar and can be used with substances that have a low solubility parameter and low polarity;

2. it is of low toxicity, and is FDA (of the United States) favourable;

3. it is light in colour, aesthetically pleasing;

4. it is the medical grade adhesive selected for surgical tape and oval bandages;

5. it has a critical surface tension of 30 to 32 mNm^"1.

It is synthesised by cationic polymerisation in the presence of a Lewis acid at -80°C. The most important reason Trenor suggested PIB would be a suitable TDS adhesive was its critical surface tension. In order for an adhesive to wet a substrate, as he noted, "The surface energy of the adhesive must be equal or less than that of the adhered. For skin, the critical surface energy varies between 38 and 56 mNm^"1, depending on the temperature and the relative humidity of the skin.^[13]" When comparing skin with PIB, its critical surface tension varies between 30 and 32 mNm^"1, which is well below that of skin. This makes it a good candidate for the adhesive formulation.

Chemically speaking, PIB is a paraffinic hydrocarbon polymer, composed of long, straight-chain macromolecules containing only chain-end olefinic bonds. Figure II shows one repeat of the chemical structure of PIB. .^[14]

FΪPiirp TT T_._> Str_.cτ1.t_ l- _.n rYn_*mi t* <ϊ. ι _ιrt nrp nf PTB This molecular structure leads to chemical inertness and resistance to chemical or oxidative attack, and solubility in hydrocarbon solvents.

PIB softens substantially as the temperature is increased, and breaks down and depolymerises when severely kneaded or milled in contact with air or oxygen. That is, PIB is subject to simultaneous degradation by oxidation, heat and mechanical shear. It is highly resistant to penetration by water i vapour and gases, and is often added to other polymers to reduce their permeability. For these reasons, PIB was adopted as the adhesive system for this trial production.

The solvents used in the fabrication process should be environmentally friendly. PIB -based PSA t generally are dissolved in hydrocarbon solvents and, thus heptane was used as the solvent. Resins are Dften added to adhesives containing PIB to improve the balance between tack and internal strength.

The Backing Layer — To Compare among three-selected Textiles Samples

The backing layer is also one of the crucial components of a TDS product. It may affect the drug's diffusion rate and the adhesion of the TDS to the skin.

n ideal backing layer should be of the following features:

Good tensile strength Appropriate elasticity Soft hand Easy to fix High coverage

However, in this trial an attempt was to make an easy-to-fix bandage with a self adherence function, i.e. double faces adhesive were applied, the coverage of the bandage was thus not taken into account as a major concern.

Samples were made of 100% polyprolene, 25grams per square metre non-woven elastic bandage and an over-the-counter woven elastic bandage. APPENDIX II THE MANUFACTURE

The Components

Every textile sample was coated with adhesive, and a layer of MCs was applied to the end of the bandage as a medical dressing for chronic pain relief. The trial TDS was assembled with the following three components:

1) The MCs, see Figure III, which contained a dose of natural essential oil in vegetable oil blend which are embedded as core active ingredients,

2) A PTB-based PSA, and

3) The textile-backing layer as mentioned in Appendix I.

Polymeric wall of sodium alginate/calcium phosphate Core shelled with natural vegetable oil blend

Figure III Microcapsules The Configuration

The design of the TDS was structured on a simple basis. The textile substrates were coated with adhesive, with the end of the bandage coated with a dose of MCs dressing. The schematic configuration is shown in Figure IN

The significance of this design is of three-fold: firstly, the configuration of the bandage will be in its simplest form, with only three components. Secondly, the strength of adhesion will not be sacrificed, although the bandage is designed to be easy to peel without discomfort. Thirdly, the bandage will have the special feature of including a cluster of beads at its tip, functioning as a dressing.

3

_ __ _to_s_____ ~ *

Figure IN Schematic Configuration of the Transdermal Delivery System The Manufacturing Process

Aromatherapy Blending— Essential Oils blended with a blend of Vegetable Oils

An aromatherapy blending with the following formulation was prepared for the trial on pain relieving function:

Vegetable oils

Calendula oil 150

Jojoba oil 250

Lime Blossom oil 100

Comfrey oil 150

Borage oil 150

Hemp seed oil 200

Natural Essential Oils (1% of vegetable oil mix)

Ginger oil 3

Roman Chamomile 2

Frankincense 5

Myrrh 5

Juniper Berries 5

Microcapsules Production — Extrusion method of Encapsulation

The extrusion method is a physical process of microencapsulation involving nozzle devices.

The solution used to prepare the outer wall of the microcapsules consisted of 20 parts of beta- tricalcium phosphate, Ca₃(PO )₂ , per 100 of a 2 % solution of sodium alginate. Precise details are not available as this procedure had to be carried out at a Swiss company, Biotech Encapsulation AG, that specializes in this technology. The polymer-wall mixture was pumped into the outer concentric nozzle of the encapsulator. The aroma blend formulation was syringe-pumped through an inner concentric nozzle so as to be embedded in the polymeric-wall mixture. A membrane of wall material was formed across a circular orifice at the end of the vibrated concentric nozzle and the aroma blend flowed into the membrane, causing extrusion of a rod of material. Droplets broke away from the rod to form the spherical beads. The beads formed were then dropped into a 1% buffered calcium chloride bath to form cross-linked MCs. Figure V shows a schematic representation of the process.

The MCs used in this study were produced with a 750 microns concentric nozzle. The encapsulation process used a frequency range of 596 to 614 Hz., with a syringe pump speed of 320 to 340 ml per hour, and pump pressure of 0.75 to 0.90 bar. A net weight of 92.57 grams of MCs was produced. The diameter of the core was produced with a size of one half of the polymeric wall, which implied a core-to-wall volume ratio of 1 to 8. That means approximate 10.29 grams of core active material was encapsulateded. Theoretically, if a 10 mm x 10 mm piece of textile were fully and evenly coated with 100 μg MCs, there should be a dose of approximately 11 μg of aroma formulation.

Preparation of the Adhesive Model

Having reviewed the literature¹-¹⁵¹ provided by the PIB supplier, the following surgical tape adhesive formulation was prepared:

Vistanex PIB LM MH 100

Zinc oxide 50

Alumina Trihydrate 50

Parapol 950 75

Terpene-phenolic resin 25

Hydrocarbon solvent (Heptane) 600

This surgical adhesive formulae was prepared according to the following procedure:

1. Charge a clean mixer with heptane solvent.

2. Add Polyisobutylene and PAR 950. Mix for 3.5 hours.

3. Add Zinc oxide. Mix for 30 minutes.

4. Add Alumina trihydrate. Mix for 15 minutes.

5. Add resin. Mix for 30 minutes.

As PIB is a tacky solid that is difficult to handle, specialized equipment is required for its dissolution, and this was kindly made available by Itac Ltd. The Coating Process

Generally speaking, the process of fabricating a TDS requires special equipment for the casting solution and for coating, drying and laminating the products. Adhesives are applied in a liquid form by techniques such as brushing, coating or spraying. In this study, a simple coating technique was employed in a laboratory-scale trial. Samples were first coated with a K-bar (a wire-wrapped metal bar - number 1, the finest wire, was used). As the fabrics were fairly open the adhesive penetrated to the reverse side, which produced a self-sealant surface for easy fixing. The MCs were then stuck on the textile samples with a blade, at the end of the adhesive surface of the bandages.

REFERENCES

U.S. Food and Drug Administration Centre for Drug Evaluation and Research, FDA Concept Paper:

Drug Products That Present Demonstrable Difficulties for Compounding Because of Reasons of

Safety or Effectiveness

Abe, A. et al. Ed. 2002. Advances in Polymer Science: Filled Elastomers Core material Delivery

System. Springer: Berlin.

Deasy, P.B. 1984. Microencapsulation and Related Core material Processes. Marcel Dekker: New

York and Basel.

Salamone, J. C, Concise Polymeric Materials Encyclopeodia, CRC Press "Microencapsulation

(Core material Release) by Shinzo Omi.

Schaefers, U. 2002. Presentation Paper on Controlled Release Systems in Cosmetic and Personal

Care: Skin Morphology, Function and Models. BRG: Lyon

Coverdale, B. 2001. The Base Oil Manual. Naturecare:London

Buckle, J., 1997. Clinical Aromatherapy in Nursing. Arnold: London.Davis, J.R., 2001. ASM „ Material Engineering Dictionary. ASM:U.S.

' Tan, H., Pfister, W 2,2 (1999). Pharmaceutical Science and Technology Today _, Venkatraman, R. Gale 19(1998). Biomaterials

') Satas, D, ed. (1998); Handbook of Pressure Sensitive Adhesive Technology: Hospital and First Aid _, Productss; New York: Van Nostrand Reinhold

') Trenor, S. R.; An Examination of Transdermal Core material Delivery Using a Model Polyisobutylene Pressure Sensitive Adhesive, htt ://scholar. lib . vt. edu/theses

;) Winter, Ruth. 1999. A Consumer's Dictionary of Cosmetic Ingredients. New York: The Three Rivers ; Press

') Quernin, M. et al. 709 (1998). Journal of Chromatography B. -) http://www.mit.edU/afs/athena/course/3/3.063/www/3.063PS 1.pdf ) Exxon Mobil Corporation. 2001. Vistanex Polyisobutylene Properties and Applications. )Mark, J., ed. 1999. Polymer Data Handbook: "Polyisobutylene, butyl rubber, halobutyl rubber". _, New York: Oxford University Press (Nelson, G. 21(1991). Rev. Prog. Coloration: Microencapsulates in textile coloration and finishing.

SDC: U.K. ¹ ) Johnson, M. 1996. Adhesives and Sealants Industry: Ways to Differentiate Tackiness of Pressure

Sensitive Tapes. BNP: US )Moore, E., 1975. Vegetable oils and fats: Their production & commercial extraction.

Unilever: London.

FKIURE^" E Schematic Representation of single nozzle Encapsulator Research IE-50R gend:

Syringe 2 Pressure bottle 3 Pulsation head Vibration unit 5 Single nozzle 6 Electrode

Reaction vessel 8 Bypass-cup 9 Liquid filter Air fitter 11 Dispersion control unit 12 Control unit

LED / Stroboscope 14 Filtration disc 15 Capsules collection flask Magnetic stirrer S Syringe pump

Claims

1. The transdermal delivery system (TDS) as a 'Bead-on-adhesive' model includes core active substances which can be either natural therapeutic substances, or herbal prescriptions, or botanical extracts or drugs, that are shelled in a polymeric membrane by microencapsulation to form 'bead-like' microcapsules which are then used to stick on an adhesive backing layer to give topical healing effect.

2. A TDS as claimed in Claim 1 includes a group technology innovation that allows a full range of production scale, from small batches for customized individual conditions to over-the-counter mass production for common aliments, by taking advantage of the template function of the 'Bead-on-adhesive' concept.

3. A TDS as claimed in Claim 1 and Claim 2, which is in virtue a versatile medical devise where the core actives can be natural prescriptions, like aromatherapy blends, essential oil blends, vegetable oil blends, or Chinese herbal prescriptions, or natural plant extracts, or drug prescriptions and the like. Including one of the aromatherapy formulation as indicated:

Vegetable oils

Calendula oil 150

Jojoba oil 250

Lime Blossom oil 100

Comfrey oil 150

Borage oil 150

Hemp seed oil 200

Natural Essential Oils (1% of vegetable oil mix)

Ginger oil 3

Roman Chamomile 2

Frankincense 5

Myrrh 5

Juniper Berries 5

4. A TDS as claimed in any proceeding claims includes a controlled release of core actives, and a masking of odor and color functions.

5. A TDS as claimed in any proceeding claims includes microcapsules (beads) with core actives, stuck on either the foremost tip end for the wrapping model or the wrong-side central zone for the tubing model of the resilient supporting fabrication.

6. A TDS as claimed in any proceeding claims which is made from a combination of, either natural, or elastomeric, or polymeric materials, or resilient textiles (like elastic woven, ors non-woven, or knitted fabrics, etc.), or pressure sensitive adhesive (like a PIB based one) or the like.

7. A TDS substantially as herein described above and illustrated in the accompanying drawings.