MXPA05010940A - Method and apparatus for in-situ leveling of progressively formed sheet metal - Google Patents

Abstract

A stretch-forming press (10) for stamping continuously fed sheet metal (32) includes a ram (14), a base member (44), and a feed mechanism (20) configured to advance a strip of sheet metal through the stretch-forming press. A forming station (58) has a die (59) configured to form a desired pattern in the strip of sheet metal. A leveling station (86) has a pair of opposed jaws (88, 90) slidably received in corresponding recesses (92, 102) of the stretch-forming press, with the jaws oriented at an angle with respect to a direction of travel for the strip of sheet metal as it passes through the leveling station (86).

Description

COMPOSITION OF TRANSDERMAL INSULIN FREE OF ALCOHOL AND PROCESSES FOR ITS MANUFACTURE AND USE FIELD OF THE INVENTION This invention relates to an insulin composition in combination with an alcohol-free dermal delivery system for transdermal application, and to processes for its manufacture and use.

BACKGROUND OF THE INVENTION Insulin is a hormone of natural origin secreted by the beta cells of the Langerhans Islands in the pancreas, in response to increased levels of glucose in the blood. The hormone acts to regulate the metabolism of glucose and the processes associated with the intermediary metabolism of fat, carbohydrates and proteins. Insulin lowers glucose levels in the blood, and promotes the transport and entry of glucose into muscle cells and other tissues. Due to the chemical nature of insulin molecules, the traditional route of insulin administration in diabetic patients who require multiple daily doses of insulin is intradermal or subdermal injection. , The efforts of previous techniques to develop a Insulin supply system for the treatment of diabetes have not been successful to date. While insulin can be systematically delivered to a patient by topical application of a vehicle containing insulin, the systemic levels of insulin in the blood that can be achieved using this delivery method have generally proven inadequate to meet the demands of the diabetic patient. . Various methods have been developed to improve the transdermal delivery of insulin, including improved passive diffusion carriers, to increase epidermal permeability, sonophoresis, iontophoresis and ionosonic transport. Passive diffusion through the outer layer of the skin has been successfully used for the delivery of low molecular weight lipophilic drugs such as scopolamine, estradiol and nitroglycerin, but has been very unsuccessful for the transdermal delivery of hydrophilic peptides such as insulin, due to the low permeability of the skin to these peptides. Thus, vibrational mechanical energy and / or iontophoresis are used to increase the permeability of the skin and to facilitate the supply of transdermal insulin. Sibalis and co-inventors, in U.S. Patent No. 4,940,456, present an apparatus and method for the transdermal delivery of insulin, mediated iontophoretically. Henley, in U.S. Patent Nos. 5,667,487 and 5,658,247 describes an ionosonic apparatus suitable for iontophoretically mediated ultrasonic transport of therapeutic agents through the skin. Insulin has a tendency to form dimers and hexamers in pharmacological compositions, which are considered too large for the transdermal delivery. Brange, in U.S. Patent No. 5,597,796, appears to chemically modify insulin to produce insulin analogs that resist intermolecular association and allow for improved iontophoretic delivery. Jang and co-inventors, in U.S. Patent No. 5,681,580, discloses a patch containing insulin formulated in a gel for the transdermal delivery of iontophoretically activated insulin. Despite advances in the methods for transdermal insulin delivery previously written, transdermal insulin delivery in an amount sufficient to achieve a therapeutic level in the blood of diabetic patients has not been possible until now. The clinical use of the transdermal drug supply has been limited because very few drugs are capable, at least by passive diffusion alone, of penetrating the skin at a sufficient rate to produce a systemic drug concentration useful in the patient. The outer layer of the skin, the stratum corneum, is a main barrier for the diffusion of low molecular weight drugs, and especially high molecular weight, through the skin into the bloodstream. A drug for which an effective transdermal delivery system has been used for a long time is insulin, a useful therapeutic agent for the control of type I (juvenile onset) and type II (onset in the adult). Insulin, unfortunately, is an example of molecules that do not diffuse easily through the stratum corneum at a therapeutically useful rate. While there have been attempts in the prior art to develop transdermal "patches" containing a particular amount of insulin, which can be transferred at a particular rate, these patches have numerous limitations. A specific limitation is that insulin users must frequently calibrate their requirements in relation to physical activity and carbohydrate ingestion. Additionally, there are different types of insulin, for example, long-acting and short-acting, and the patient must develop skills to mix both types and amounts of insulin in order to adequately control their blood sugar levels. The use of multiple patches with varying drug concentrations and insulin response characteristics is therefore problematic. Thus, there is a long-felt need for a dermal delivery system for insulin in a convenient format, for example, a gel or cream, which can be formulated with insulin compounds having varied release characteristics, and wherein the dose may be be determined as a function of the volume applied.

DESCRITION OF THE PREVIOUS CA U.S. Patent No. 6,416,772 teaches a topical dermal anesthetic composition for pain relief, which contains alcohol in an amount by weight from about 57 to about 91 percent; glycerin in an amount by weight of from about 1 to about 12 percent; an analgesic agent in an amount by weight of from about 2 to about 28 percent, the analgesic agent contains a derivative of salicylic acid; methylisulfonylmethane in an amount by weight of about 0.02 to 5 percent; and emu oil in an amount by weight of about 0.01 to 3 percent. The composition provides transdermal pain when the analgesic agent is applied directly to an area of pain. It is taught that alcohol, preferably ethyl or isopropyl, is necessary to effectively dissolve the analgesic in such a way that it can be absorbed through the skin. In turn, glycerin is required to act as a stabilizer for the licit acetyl acid, triethanolamine salicylate, or other analgesic agent, such that the alcohol does not significantly affect the shelf life of the composition in terms of marketing. Glycerin is also shown to be necessary to sufficiently disperse the analgesic agent such that the composition does not need to be stirred or suspended before topical use. It teaches that metiisulfonylmethane and emu oil are included to help facilitate the absorption of the composition in the skin, and also because the pain relief characteristics in them and of themselves, potentiate the analgesic in order to increase the effectiveness of the composition. This patent fails to teach a composition that is effective in relieving pain when applied to various trigger points, distal to the actual perceived area of discomfort. In addition, the '772 patent requires the use of alcohol for the transdermal delivery, which causes degradation of the analgesic, and subsequently requires glycerin as a stabilizer to delay the degradation of alcohol. U.S. Patent No. 6,346,278 teaches a lipid extract of Perna canaliculus or Mytilus edulis as an active component, in a composition suitable for transdermal administration which includes an ointment or lotion base or vehicle, which may include a penetration enhancing agent in the skin to help the administration of the active component. Suitable bases or vehicles are oils such as olive or emu oil, administered alone or with a penetrant, such as cineole or limonene. U.S. Patent No. 6,444,234 discloses an alcohol containing pharmaceutical compositions for the transdermal administration of a medicament or other active agent by topical application of the composition to the skin of humans or other animals. The methodology for the formulation of these compositions that provide a very rapid absorption of drug, and transmigration in and through the skin and / or immune response, are based on a transdermal delivery system (TDS), where the drug is modified to form a true solution in a complex formed by particular solvents and modifiers of solvent and solute in combination with skin stabilizers. Analgesics such as ibuprofen and the like, MSM and emu oil, are presented as useful in combination with the transdermal delivery system. U.S. Patent No. 6,528,040 presents a formulation based on emu oil for use as an analgesic, anesthetic and antipruritic. The formulation contains from 0.01 to 13 percent by weight of alkyl esters; and from 20 to 70 percent by weight of emu oil, from 10 to 33 percent by weight of benzoin; from 0.2 to 2 percent by weight of allantoin; from 0.25 to 1.25 percent by weight of methylparaben and from 0.01 to 0.30 percent by weight of propylparaben. The formulation can be formulated as an atomizer or transdermal formula, and can be used for the treatment of chronic skin ulcers and burn wounds. U.S. Patent No. 5,855,597 presents a topical composition for pain relief in a person in need of such relief, consisting essentially of an effective amount of a combination of at least one corticosteroid analgesic, at least one analgesic of the arylpropionic acid type, and at least one local anesthetic of the p-aminobenzoic ester type; an amount sufficient to improve the effectiveness for the pain relief of the capsaicin combination, and an effective amount to increase the transmission thereof through the skin, of at least one phospholipid and at least one polyoxyethylenepolyoxypropylene copolymer. The American patent application number 2003/0031724 presents compositions that can be derived or processed in an effective way, from emu, Dromiceius novaehollandiae, and used as anti-inflammatory agents in patients. The application does not contemplate the use of MSM or an analgesic agent in a transdermal delivery environment. U.S. Patent Application No. 2001/0033838 discloses the use of emu oil and its various fractions as a carrier for antifungal, antibacterial and antiviral drugs and preparations. The use of MSM in combination with emu oil is replaced with an oil-based liposomal transdermal component. U.S. Patent No. 6,024,975 is directed to a high molecular weight drug that is administered transdermally by applying a polymer skin improver and an active drug to the skin of the patient. The drug can be encapsulated, or the drug solution can be partially encapsulated and partially free. The skin improver that is required is polyvinylpyrrolidone (PVP) and between 7 and 35% of the drug is mixed. An optional gelling agent can be added up to 20% by volume. The chemical system is administered preferably by means of a transdermal patch with multiple doses of drug, which includes a drug-impermeable support, sealed to form a series of compartments. Each compartment is a reservoir for a dose unit of an active drug designed to be administered transdermally. The support is adhesively secured to the skin of a patient. Individual devices are provided to lock the drug in a resealable manner in each of the reservoirs. The individual closure devices are removable, to release the dose unit in contact with the skin of the patient, and are activatable to control the absorption of the active ingredients of the drug. The description of the patent is largely directed to sets for transdermal medication, and more particularly to those sets consisting of multiple dose unit reservoirs, with each reservoir having closure means that can be individually torn and released., for the start and administration of the medication. However, it is suggested that the drug can also be administered in a cream. However, all formulations may require polyvinylpyrrolidone. U.S. Patent No. 6,444,240 is directed to insulin-containing compositions, formulated for topical application, and to a method for using the compositions for the cosmetic treatment of wrinkles.

BRIEF DESCRIPTION OF THE INVENTION The present invention describes a composition for a dermal delivery system containing an aqueous base vehicle, which includes American emu oil, isopropyl palmitate (PROTACHEM IPP), PEG-8 (a polyethylene glycol available under the trade name PROTACHEM 400 ), methylisulfonylmethane (MSM) and SEPIGEL 305 (a combination that includes polyacrylamide / iso-paraffin of 13 to 14 carbon atoms) and LAURETH 7. To this base vehicle, one or more active insulin ingredients are added, for example, HUMALOG In contrast to the use of injected insulin, the topical creams of the present invention have the advantage that they do not require the patient or caregiver to administer an injection; nor does the patient have to carry and / or transport the necessary paraphernalia to administer an injection. The dermal delivery system, as illustrated herein, is alcohol free, and therefore does not suffer from the problems of decreased storage life that alcohol use contained in prior art formulations brings with it. Since alcohol is not used, the presence of glycerin is not required either. Thus, a unique system for dermal-free delivery of alcohol is provided, which provides improved penetration through the dermal layers, thus providing an alternative to capsules and tablets, safer, faster acting, and easier to meet. According to this, it is an objective of this invention to provide a rapid cream-based dermal delivery system for the transdermal dosing of insulin compositions effective for the therapeutic treatment of diabetes. Another objective of the present invention is to provide a process for the manufacture of said dermal delivery system. Other objects and advantages of this invention will be apparent from the following description, taken in conjunction with the accompanying drawings, wherein certain embodiments of this invention are set forth by way of illustration and example.

DETAILED DESCRIPTION OF THE INVENTION In order to implement a dermal delivery system that provides improved penetration of the skin, it is necessary to understand the parameters that affect this phenomenon. Various factors that affect the penetration of the skin: 1) Solubility in oil (J. Pharm Sci "Linear relationships between lipophilic character and biological activity of drugs" 1972 Jan; 61 (1): 1-19) while more soluble in oil ( lipophilic) is the substance, the greater the penetration into the skin; 2) Molecular weight (the smaller the molecule, the penetration will be easier); 3) Creams, gels and liquids penetrate better than solids; 4) Penetration enhancers improve absorption topical lipophilic substances (Targeted drug delivery to the skin and deeper tissues: role of physiology, solute structure and disease, Clin Exp Pharmacol Physiol 1997 Nov; 24 (11): 874-9).

EXAMPLE 1 In accordance with the present invention, the ingredients for the base of the vehicle are first selected. American emu oil -3% isopropyl palmitate -3% PEG-8 (L-20) -4% SEPIGEL 305 ~ 3% * (* additional in increments of 1%, if needed to gel) Methysulfonylmethane -0.75% Water sterile (preferably de-ionized) to make up to 100% FORMULATION PROCEDURE To the base vehicle described above, the active ingredient insulin is added, according to the following procedure: 1. Weigh the active ingredients, incorporating one unit of HUMALOG insulin per 1 gram of cream; 2. Measure 3% American emu oil, in high speed mixing apparatus; 3. Add the active ingredients to emu oil. Mix until all the powder is incorporated in the oil. The mixture must be very dry; 4. Measure isopropyl palmitate and Peg-8 (L-20), add to the emu mixture; 5. Leave to mix during? A hour; 6. Add sterile water, mix for 20 minutes, scraping the sides of the mixing container occasionally; 7. Add SEPIEGEL 305 to 3%, let stand for 5 minutes; If the desired consistency has not been achieved, add SEPIGEL 305 in 1% increments until the desired consistency is achieved. In order to produce a composition for a transdermal insulin delivery system, the above procedure was followed, and subsequent tests were performed to establish the efficacy of the transdermal delivery system: APPLICATION OF TRANSDERMAL CREAM WITH INSULIN IN DOSES MEASURE . Measure 1 gram of mixture; 2. Apply to the inner side of the wrist and rub until the skin feels dry; 3. Take glucose levels every ten minutes and record the readings; 4. Glucose levels fall below 50 in 30 to 40 minutes; 5. I suggest 2 glucose tablets and 2 chocolate bars Hershey to stop the fall of the sugar level; 6. This study was repeated on 3 different occasions, thus demonstrating that insulin transdermally entered the circulatory system in therapeutically effective amounts, thereby effecting a change in the levels of sugar in the body. In accordance with this invention, it is understood that an insulin composition means any type of insulin useful for the therapeutic treatment of diabetes, used alone, or in any combination, in order to provide any desired effects. These compositions are illustrated by several species of insulin, such as a short-acting insulin mixture, long-acting insulin, insulins that provide a base-level concentration for a prolonged period and that can be supplemented with a second form. ulation to provide short-term activity control, and various combinations of them, but are not limited to them. All patents and publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are incorporated herein by reference in the same extent as if each publication was specifically and individually indicated to be incorporated by reference. It should be understood that while a certain form of the invention is illustrated, it is not limited to the specific form or arrangement of parts described and shown in the present application. It will be apparent to those skilled in the art that various changes can be made without departing from the scope of the invention, and that the invention should not be considered limited to that which is shown and described in the specification. A person skilled in the art will readily realize that the present invention is well adapted to achieve the objects and obtain the purposes and advantages mentioned, as well as those inherent therein. Any compounds, methods, procedures and techniques described herein are currently representative of the preferred embodiments, are intended to be exemplary and are not intended to be limiting in scope. Changes in these and other uses will occur to those skilled in the art, which will be included within the spirit of the invention, and are defined by the scope of the appended claims. Although this invention has been described in connection with preferred specific embodiments, it will be understood that the invention as claimed, should not be unduly limited to these specific embodiments. Undoubtedly, it is intended that the various modifications of the described modes to carry out the invention, which are obvious to those skilled in the art, are within the scope of the following claims.

Claims (4)

1. An alcohol-free insulin composition, effective for transdermal delivery, which consists essentially of: about 3% emu oil, about 3% isopropyl palmitate, about 4% PEG-8 (L-20), approximately 0.75% methylisulfonylmethane, SEPIGEL 305 in an amount effective to gel, a therapeutically effective amount of at least one species of insulin, and sufficient sterile water to make 100%.

2. A composition for the treatment of diabetes in a patient, which contains: about 3% emu oil, about 3% isopropyl palmitate, about 4% PEG-8 (L-20), about 0.75% methylisulfonylmethane, SEPIGEL 305 in an amount effective to gel, a therapeutically effective amount of at least one species of insulin, and sufficient sterile water to make 100%.

3. A process for making an alcohol-free insulin composition effective for the transdermal delivery, including: providing a therapeutically effective amount of at least one species of insulin; provide about 3% emu oil in a high speed mixer apparatus; adding said insulin to said emu oil and mixing until a homogenously mixed composition is formed; add about 3% isopropyl palmitate and about 4% PEG-8 (L-20) to said homogeneous mixture, and mix for about 30 minutes; add sterile water and mix for approximately 5 minutes, until homogeneous; add approximately 3% of SEPIGEL 305, and mix until homogeneous and a gel-like consistency is achieved; and add additional SEPIGEL 305 in increments of 1%, if necessary, until the desired gel consistency is achieved.

4. The product produced by the process of claim 3.