WO2006119598A2

WO2006119598A2 - Transdermal device for the slow delivery of an omega-3-fatty acid, optionally in combination with a hmg coa reductase inhibitor

Info

Publication number: WO2006119598A2
Application number: PCT/BR2006/000090
Authority: WO
Inventors: Jean Marc Millet
Original assignee: Jean Marc Millet
Priority date: 2005-05-10
Filing date: 2006-05-10
Publication date: 2006-11-16
Also published as: BRPI0501708A; WO2006119598A3

Abstract

Device for slow liberation via transdermal process of a medicine for reducing an excess of cholesterol and method of production of a transdermic device, which is characterized by a bi-laminate device comprising a flexible macromolecular matrix (2) providing a thickness from 0,15 to 0,6 cm and a surface from 10 to 100 square cm and a posterior coating (1) on one side which allows a considerable reduction (more than 15 times) of the doses to be administered in the treatment of an excess of cholesterol; the macromolecular matrix contains and liberates in a continuous way for a period between 1 to 4 months from 0,05 to 0,18% per day of its total weight of Omega-3 follyocid and / or statin by its surface in contact with the patient's skin without being necessarily the device to be adhered in a fix and permanent way to his / her skin.

Description

"DEVICE FOR SLOW LIBERATION

VIA TRANSDERMIC PROCESS OF A MEDICINE FOR EXCESS OF CHOLESTEROL AND METHOD OF PRODUCTION OF A TRANSDERMIC DEVICE" . The present patent of invention refers to a device for slow liberation via transdermic process, which can be used for liberation of Omega 3 and/or Omega 3 and statin in the treatment for excess of cholesterol and its consequences, which allows to diminish more than 15 times the daily doses of statins or Omega 3 for the same therapeutic result and presents a practical use.

The present state of technique comprises of a treatment for excess of cholesterol, together with hypolipidic diets and physical activities, with the long-term usage of:

- Specific polyunsaturated fatty Acid and particularly the

Acids: Omega 3 (EPA) "Eicosapentaenoic Acid" - Omega 3 Acid

(DHA) "Docosahexaenoic Acid" - Omega 3 Acid "Alpha- linoleric-Acid" .

Product from statins group, the most used class of molecules in order to make cholesterol LD to decrease, for instance: Atorvastatin, Pravastatin, Rosuvastatin, Fluvastatin, Lovastatin, Simvastatin, also known under the trademarks like: Lipitor, Mevacor, Prevacol, Zocor .

In a long-term treatment, the observance of the treatment by the patient is first importance. What happens is that in practice, it is difficult to respect the prescription of taking pills regularly 1 to 3 times a day for months.

On the other hand, these two groups have side effects that may also make them to abandon the treatment temporarily or permanently.

Omegas 3, for instance, are not indicated in cases of problems in pancreas, coagulation or associated to a product like aspirin. They also leave a bad smell in the patient's mouth. Statins are known for provoking skeletal muscles problems (rhabdomyiolysis) that may be severe: Bayer laboratory was recently obliged to withdraw one of its most sold products from the market: Cerivastatin, which caused several people to death. It is interesting to observe, that one of the effects of the statins is exactly to reduce Omega 3 metabolism in the organism decreasing around 20% of the seric concentration of the polyunsaturated fatty acid.

It has been proved that the administration of such medicines from statin group in more than ¹A of the cases has no desired results especially in patients who need most of such medicines. In a study with 3700 people, 73% have achieved the expected result and 27% have not. In such cases increasing in the posology raises the risks of non-desirable effects.

In this context, the inventor proposes a device that allows decreasing the posology and guarantees the perfect observance of the treatment. It refers to a bi-laminate device that allows slow transdermic liberation of active principle (s) (Omega 3 and/or Omega 3 and statin) , which comprises of a flexible macromolecular matrix whose thickness may vary from 0,15 to 0,6 cm and the surface from 10 to 100 square cm and presents a posterior coating on one side which allows a considerable reduction (more than 15 times) of the doses to be administered in the treatment for excess of cholesterol and releases the patient from obligation, which is not always respected, of taking such medicines from 1 to 3 times a day for months since the device, easily used, works from 1 to 4 months liberating Omega 3 and/or Omega 3 and statin for this period.

Posterior coating and impermeable coat prevents against liberating Omega 3 and/or statin on the side that is not in contact with the skin and guides and concentrates such liberation on the side that is in contact with the skin.

There already is in the market dermic "Patches" that liberates substances like nicotine, but such "Patches" that liberate one daily dose the same as the oral doses has to adhere and then has to be glued to the skin and work only for some hours or even some days .

In the present case, the macromolecular matrix contains and liberates in a continuous way for a period between 1 to 4 months from 0,05 to 0,18% a day of its total weight in Omega 3 or Omega 3/statin by its surface in contact with the patient's skin, without being necessary the device to be adhered in a fixed and permanent way to the his/her skin. In the case of the device having Omega 3 with statin, the Omega 3 and statin liberation is done in the same speed and relative proportion since in the manufacturing process, the statin is solubilized inside Omega 3.

The following table shows the percentage of the Omega 3 elimination during 3 months of device usage:

The present device is indicated in the corrections of the consequences of the deficiency of Omega 3 and in the treatment of the cholesterol excess .

Another characteristic of the proposed device is to be able to be embodied as a laminated that may have several forms like a square that may be put in contact to the skin inside clothes such as: socks, underwear, underpants, bra, etc or a bracelet that is possible to be used by the patient in a way that the material of it keeps in contact with the skin allowing, then, the transdermic transfer of the active principle. The device herein depicted may have other ways to be suitable to the proposed usage. The present device is produced in such a way its molecular matrix can be produced by extrusion or injection, having as a base the plasticized PVC having from 16 to 28% of plasticizer and/or EVA base

(Expanded Vinyl Acetate) and or Polyethylene and/or polyurethane and has 8 to 18% of Omega 3. The procedure of manufacture is characterized by preparation of a humid powder obtained from hot mixture (60 to 70°) of polymer, possibly plasticizer and adjuvant, and the OMEGA 3. The obtained mixture is extruded or injected inside a mold adapted to a temperature between 75 and 120°.

When it is used in the device associated to Omega 3 with a component of the statin group, for example Atorvastatin, Simvastatin, Pravastatin, Rosuvastatin, Fluvastatin, Lovastatin and also others, the present device is manufactured in a way that occurs statin micronization and then its solubilization up to a concentration of 10 to 40% in the OMEGA 3, before incorporating such Omega 3 containing solubilized statin to the molecular matrix. The posterior laminate prevents the active principle to leave and concentrates such elimination by the other side being in contact to the skin.

The posterior laminate may be manufactured simultaneously to the polymolecular by co- extrusion and co-injection of a laminate of a plastic that may be PVC little plasticized or another resin.

The posterior laminate may be placed in a second stage by application of a varnish

(primer) : may be an acrylic resin, for example, or by lamination with or without solvent of a resin, or by collage

(may be used a glue such as base of 70% of monomer of polyvinyl chloride, 10 to 12% of ethyl acetate and the rest: polyvinyl acetate) or by thermosealing of a resin like polyethylene or EVA.

When embodied as a bracelet, the device presents, preferably, width from 0,3 to 3 cm, thickness 1,5 to 6 mm and length 6 to 25 cm. In case the bracelet is not already a closed circle, but a band with a system of closing, it can be adjusted to the wrist size, the excess is discarded by the user providing then a dose of Omega 3 and/or statin proportional to the diameter of the wrist and, consequently, to the weight of the individual. The present device, according to an alternative embodiment does not present discomfort in its use, because it is applied under the watch and its wristlet, or even another alternative embodiment even may be embodied as a wristwatch, thus substituting the wristlets of the usual watches .

The present patent of invention refers to the proposed device as well as to the method by which is produced and will be depicted with reference to the drawing presented in the figure 1, wherein the proposed device is schematically depicted in its essence as being a bi-laminate part.

In a more objective way, in the present patent of invention, the inventor has made and tested the elimination of Omega 3 and the anti-cholesterol activity from samples from the Invention in several sizes and shapes, representing several doses in a polymeric matrix containing 15% of Omega 3. The product now proposed has been tested and has the appearance and shape of a laminate of thickness 0,3 cm and surface varying from 14 to 100 square cm, where surface determines the dose.

In the effective tests the following samples are contemplated:

We remember the usual recommended Omega 3 posology is from 0,5 to 1,5 g a day, being from 45 g to 135 g for 90 days.

SAMPLE 1: 10 x 10 cm with thickness 0,3, weight: 44 g containing 6,7 g of Omega 3 (that is, from 5% to 15% of the oral dose for 90 days) ;

SAMPLE 2: 8 x 8 cm with thickness 0,3, weight: 28 g containing 4,2 g of Omega 3 (that is, from 3,2% to 9,6% of the oral dose for 90 days) ; SAMPLE 3: 6 x 6 cm with thickness 0,3, weight: 16 g containing 2,4 g of Omega 3 (that is, from 1.8% to 5,4% of the oral dose for 90 days) ;

SAMPLE 4: 5 x 5 cm with thickness 0,3, weight: 11 g containing 1,67 g of Omega 3 (that is, from 1,23 to 3,7% of the oral dose for 90 days) ;

SAMPLE 5: 2 x 2 cm with thickness 0,3, weight: 1,8 g containing 0,27 g of Omega 3 (that is, from 0,2% to 0,6% of the oral dose for 90 days) ;

SAMPLE 6 (placebo): 6 x 6 cm with thickness 0,6, weight: 16 g containing 0 g of Omega 3.

The test was made with 120 male volunteers, all of them with excess cholesterol, divided into 6 groups of 20. All of them were instructed to put de device inside the underwear, tied to the superior part .

The clinical results obtained after 3 weeks of use may be visualized in the table above. These results were kept during the three months the tests lasted.

Thus, it was discovered that the device liberating posologies of Omega 3 via transcutaneous, by observing, for instance, lot 4, being more than 25 times inferior than the oral recommended posologies were so efficient in reducing the cholesterol levels than these oral doses. Increasing such doses does not change the results in a significant way.

Based on the positive results from such test, another similar test has been made but with a device of thickness 0,4 mm weighting 12 g whose manufacturing was characterized by the solubilization of 26,5% of Atorvastatin (lipitor) in the Omega 3 and such solution incorporated in the polymeric matrix to a concentration of 17%; then the device has 540 mg of Atorvastatin .

The study of eliminating the

Atorvastatin from matrix has showed that it follows the elimination of Omega 3 confirming the carrier paper of them. After 90 days, elimination of Atorvastatin is 82% of the initial amount, which is 440 mg, which is 4.9 mg a day, representing half of the minimum average recommended dose of Lipitor that, according to literature, is 10 mg of Atorvastatin a day. The test results with 100 volunteers, wherein 50 using invention from SAMPLE 4: 5 x 5 cm with thickness 0,3, weight 11 g containing 1,67 g of Omega 3, being only Omega 3 for Group B and 50, the invention with Omega 3 and Atorvastatin according to described above (Group A) .

Group A had an average LDH-C reduction of 58%. The decreasing of the rates appears from the third week of carrying it and it keeps during ate least 90 days. This level of rate reduction id usually obtained with oral doses of Atorvastatin of more than 70 to 80 mg a day (very high doses with more frequent side effects) that is more than 15 times than with the proposed device.

It is obvious that one considerable reduction of the secondary non-desirable effects may be expected. It is the conception and the way of application specific and new in this invention that allows such surprising results.

Other tests were made in a different way from the device. Instead of being a Patch- shaped plaque, the device was embodied as a bracelet of width 15 by 1 cm and thickness 0,3. The advantages of this shape and the usage simplicity are the self-doser character: the excess, depending on the size of the bracelet is discarded. A clinical test was made comparing the devices with posterior coating and without posterior coating. The absence of a posterior coating makes the diffusion of the active principles to happen on the side opposite to the skin and they are wasted in the environment: clothes. Also, diffusion is the fastest, because the liberation surface is bigger.

It was demonstrated that, in the absence of the posterior coating, it must have a dose of active principles inside the device at least two times bigger in order to have the same activity.

Whatever is the drawing, in the absence of the posterior coating: Omega 3, statins migrate to the non-protected surface by the posterior coating indicated as item 1 in figure 1 and from there, when in contact with the skin they cross it. Figure 1 includes also item 2, which represents the macromolecular matrix.

Different from the known patches glued to the skin, if the device of the invention does not keep in contact with the skin for a while, the active principles accumulate on the surface and will be absorbed by the skin during next contact, compensating the temporary non-contact. The present patent also refers to a manufacturing process of the device in question, which employs as active principles : omega 3 and/or statins . As to Omega 3 :

Chosen polyunsaturated Fatty

Acids are Omega-3, a like a mix of DHA and EPA, for example 75% DHA and 25% EPA.

Technique of manufacturing takes into account the fragility of such acids . As to Statins :

It may be used Atorvastatin, Pravastatin, Rosuvastatin, Fluvastatin, Lovastatin, Simvastatin, and others.

Molecular matrix 2 may be manufactured by extrusion or injection, the base of plasticized PVC containing 20 to 28% of plasticizer and/or EVA base (Expanded Vinyl Acetate) and or Polyethylene and/or polyurethane and/or poly-metacrilates and contains 12 to 30% of Omega 3.

Manufacturing procedure is characterized by preparation of a humid powder obtained from hot mixture (60 to 70°) of polymer, possibly plasticizer and adjuvant, and the Omega 3 with statin. The mixture is obtained by solubilization under slow agitation to a temperature of 30 to 40 degrees Celsius in a statin micronized way that is, little by little, taken into the Omega 3. The present method contemplates a first formula - Formula 1 :

EFA: 15% (0,72Og) divided as it follows

EFA 20%

DHA 61%

Other unsaturated F. A. ethyl, ester 9%

Excipients: 85%

Perfume 1,0%

Epoxide soy oil 2,0% (PVC stabilizer)

Calcium estereato 2,9%

Butyl Phthalate 24,0% (plasticizer)

Acrylonitrile butadiene 5,0% (spreading buffer)

Polyvinyl chloride 50,0% Formula 2 :

Unsaturated acid Omega 3 (like esters ethyl) containing 30% of Atorvastatin 15 g

Polyvinyl chloride 55,93 g

Butyl Phthalate (plasticizer) 18 g

Epoxide soy oil 2 g

Calcium estereato 4 g

Co-polymer Acrylonitrile butadiene (plasticizer) 5 g

Pigments 0,07 g

Total 100 g The obtained mixture is extruded or injected in a mold adapted to a temperature between 80 and 120 degrees Celsius.

Claims

1. "DEVICE FOR SLOW LIBERATION

VIA TRANSDERMIC PROCESS OF A MEDICINE FOR EXCESS OF CHOLESTEROL", which is characterized for contemplating a bi-laminate device for slow transdermic liberation comprising a flexible macromolecular matrix (2) of thickness 0,15 to 0,6 cm and the surface from 10 to 100 square cm and presents a posterior coating (1) on one side which allows a considerable reduction (more than 15 times) of the doses to be administered in the treatment for excess of cholesterol and/or the deficiency of Omega 3 and its consequences, the macromolecular matrix contains and liberates in a continuous way for a period between 1 to 4 months from 0,05 to 0,18% a day of its total weight in Omega 3 by its surface in contact with the patient's skin without being necessary the device to be adhered in a fix and permanent way to the his/her skin.

2. "DEVICE FOR SLOW LIBERATION VIA TRANSDERMIC PROCESS OF A MEDICINE FOR EXCESS OF CHOLESTEROL", according to claim 1, characterized by solubilization of Omega 3, before incorporating them to the molecular matrix, from 10 to 40% of an active principle from the group of Atorvastatin, Pravastatin, Rosuvastatin, Fluvastatin, Lovastatin, Simvastatin and others, that will be liberated in the same speed than Omega 3 by the surface in contact to the skin corresponding to a daily dose of at least 15 times less than oral doses usually recommended.

3. "DEVICE FOR SLOW LIBERATION VIA TRANSDERMIC PROCESS OF A MEDICINE FOR EXCESS OF CHOLESTEROL", according to claims 1 and 2, characterized by the fact that the molecular matrix may be manufactured by- extrusion or injection, plasticized PVC base having from 16 to 28% of plasticizer and/or EVA base (Expanded Vinyl Acetate) and or Polyethylene and/or polyurethane and has 8 to 18% of Omega 3; being the procedure of manufacture characterized by preparation of a humid powder obtained from hot mixture (60 to 70°) of polymer, possibly plasticizer and adjuvant, and the OMEGA 3. The obtained mixture is extruded or injected inside a mold adapted to a temperature between 80 and 120° .

4. "DEVICE FOR SLOW LIBERATION VIA TRANSDERMIC PROCESS OF A MEDICINE FOR EXCESS OF CHOLESTEROL", according to claims 1, 2 and 3, characterized by the fact of constituting a self-doser device in the shape of a bracelet, width from 0,3 to 3 cm, thickness 1,5 to 6 mm and length 6 to 25 cm that can be adjusted to the wrist size, the excess is discarded by the user providing, then a dose of Omega 3 and/or Omega 3 and statin proportional to the diameter of the wrist and, consequently, to the weight of the individual .

5. "DEVICE FOR SLOW LIBERATION VIA TRANSDERMIC PROCESS OF A MEDICINE FOR EXCESS OF CHOLESTEROL", according to claims 1, 2, 3 and 4, characterized by the fact that it causes no discomfort with the usage, because it is designed and adapted to be applied under the watch and its wristlet.

6. "DEVICE FOR SLOW LIBERATION

VIA TRANSDERMIC PROCESS OF A MEDICINE FOR EXCESS OF CHOLESTEROL", according to claims 1, 2, and 3, characterized by the fact that it causes no discomfort with the daily usage since it presents the shape of a wristwatch, thus substituting the usual wristwatch.

7. "METHOD OF PRODUCTION OF A

TRANSDERMIC DEVICE" which is used to produce a device for slow liberation via transdermic process, which is characterized for employing Omega 3.

8. "METHOD OF PRODUCTION OF A

TRANSDERMIC DEVICE" according to claim 7, characterized by the fact of employing Omega 3 and statin such as: Atorvastatin, Pravastatin, Rosuvastatin, Fluvastatin, Lovastatin, Simvastatin and others.

9. "METHOD OF PRODUCTION OF A

TRANSDERMIC DEVICE" according to claims 7 and 8, characterized by the fact that the molecular-matrix (2) may be manufactured by extrusion or injection having as a base the plasticized PVC having from 20 to 28% of plasticizer and/or EVA base (Expanded Vinyl Acetate) and or Polyethylene and/or polyurethane and/or polyurethane and/or poly- metacrilates and contains 12 to 30% of Omega 3; the procedure of manufacture comprises a preparation of a humid powder obtained from hot mixture (60 to 70°) of polymer, possibly plasticizer and adjuvant, and the Omega 3 or a mixtures of the Omegas 3 with statin, being this mixture Omega 3/Statin obtained by solubilization under slow agitation to a temperature of 30 to 40 degrees Celsius in a statin micronized way that is, little by little, taken into the Omega 3; the obtained humid powder is extruded or injected inside a mold adapted to a temperature between 80 and 120°; the posterior laminate may be manufactured simultaneously to the polymolecular matrix by co-extrusion and GO- injection of a laminate of a plastic that may be PVC little plasticized or another resin; the posterior laminate may be placed in a second stage by application of a varnish (primer) : may be an acrylic resin, for example, or by lamination with or without solvent of a resin, or by collage or by thermosealing of a resin like polyethylene or EVA.