HUT69390A - Controlled, sustained release delivery system for smoking cessation - Google Patents

Abstract

A drug delivery system useful in treating an individual for a drug dependence is described. One embodiment of the system is useful for aiding individuals in the cessation of smoking or chewing nicotine containing products is described. The delivery system includes a physical constraint modulation system (PCMS<TM>) containing lobeline. The drug delivery system is capable of delivering lobeline to an individual in a controlled, sustained release manner and providing long-term therapeutic levels of lobeline to the individual. The delivery of lobeline in such a manner reduces or eliminates the individual's smoking or chewing habit. The PCMS may be a biodegradable polymer containing the lobeline capable of subcutaneous or intramuscular injection or implantation into the individual or may be part of a transdermal patch containing lobeline. Also described are methods of using the drug delivery systems in treating other drug dependencies and kits containing the drug delivery systems.

Description

According to the present invention, a subject is treated with at least one physical restriction modulated system for treating an individual's nicotine dependence, wherein the physical restriction modulated system releases an amount of lobelin that is capable of reducing the individual's nicotine requirement for at least one day.

The system, modulated by physical restraint, may be a biodegradable polymer administered subcutaneously, intramuscularly, or by implantation, or may be part of a transdermal patch.

PUBLISHING PAPER t / c939O

Representative:

DANUBIA Patent and Trademark Office Ltd. Budapest ! í \; / «, Ϊ A '-7 A ('I I: ; \ c '' 'C. 'THE U ' ^! Al; AA la Controlled pace. sustained release insurer rencl-

drug for smoking cessation

DYNAGEN Inc., Cambridge, MA, USA

inventors:

KITCHELL Judith, Newton,

MUNI Indu, A., MA, Reading,

BOYER Yvonne, Salem, MA, USA

Date of filing: 07/05/1992

Priority: 07/05/1991 (696,637) United States of America

States

International Application Number: PCT / US92 / 03860

International Publication Number: wo 92/19241

78354-6918 Gl / té

BACKGROUND OF THE INVENTION The present invention relates to a drug delivery system which provides sustained release of lobelin at a controlled rate for the treatment of nicotine dependence.

Recent studies have pointed to the association of smoking with heart and cancer. It is also known that smoking can have harmful effects on the fetus during pregnancy. In this way, there is a tendency to get people to stop smoking. However, smoking cessation is difficult because one of the components of tobacco, nicotine, is an additive (see Nicotine Addiction, Surgeon General, 1988). Currently, prescription-only smoking cessation aids are not always successful. Lobelin alkaloid is obtained from dried leaves and stems of Indian tobacco grass (Lobelia inflata). Chemically, lobelin is a substituted piperidine derivative. It has various physiological effects, some of which are similar to those of nicotine. The potency of lobelin for these effects is significantly lower than that of nicotine. Because of its pharmacological effects similar to nicotine, it has been considered as a substitute for nicotine to reduce nicotine addiction and to stop smoking. Although lobelin has been studied since at least 1930 as a smoking cessation aid, its effectiveness has been debated. In addition, significant undesirable side effects have been reported.

Currently, over-the-counter (Nicoban, Bantron, Cigarrest and Nic-Fit) formulations recommend lobelin-heme sulfate to help stop smoking. These preparations are for oral use and the recommended daily dose is up to 6 mg. Some of these formulations also contain an antacid agent to eliminate discomfort in the gastrointestinal tract, such as nicotine. Higher oral doses should not be used due to the concomitant side effects causing gastric upset. The efficacy of oral administration of lobelin 6 mg daily in promoting smoking cessation has not yet been demonstrated. Lobelin formulations available without a prescription for the treatment of tobacco addiction do not provide or maintain therapeutic levels of lobelin in blood or tissue. This may be due to low concentrations of lobelin in the formulation, poor absorption of the oral formulation, or metabolism, which makes it impossible to reach the critical therapeutic level of lobelin.

Although administration of daily doses of lobelin in excess of 10 mg has been reported, nausea and even vomiting have been reported. In addition, such oral doses require the self-administration of 18 tablets per day, which is not only unpleasant for the individual being treated, but also does not allow the physician to closely monitor the dosage.

Kalyuzhnyy [J. of Neural Psychiat 68 (1864-1870)] discloses intramuscular administration of lobelin hemisulfate. He gave two injections a day and injected up to 10 mg. Although the amount of Kalyuzhnyy sham used has been found to be therapeutically effective, the method is not practical because it requires two injections of lobelin daily.

Takagi et al. (Japanese Patent No. 1-197,435) disclose a tobacco replacement adhesive agent containing from 0.5 to 10% by weight of lobelin, which provides a higher blood concentration of lobelin for several hours, such as the same concentration of nicotine in the blood. using an adhesive agent. However, Takagi et al. Do not quantify the amount of lobelin released from the adhesive.

FIELD OF THE INVENTION The present invention relates to a drug release system for stopping smoking or chewing nicotine-containing products, which provides controlled release of lobelin in individuals. On the one hand, the system eliminates the need to administer lobelin twice daily or as multiple doses, while providing a therapeutically effective level of lobelin over a long period of time. The drug delivery system of the present invention has a physical restraint modulated system (hereinafter referred to as the FKMR instead of a physical restraint system) containing lobelin, which is designed and constructed to provide the subject with a sustained release of the therapeutic concentration of lobelin at a therapeutic concentration. The lobelin thus introduced into the individual reduces or eliminates the individual

smoking or chewing nicotine-containing products. FKMR may include a biodegradable polymer suitable for administration to individuals by subcutaneous or intramuscular injection; or as part of a transdermal patch applied to an individual's skin. When a biodegradable polymer is used in FKMR, the drug delivery system preferably consists of microparticles which are suspended in a pharmaceutically acceptable carrier just prior to subcutaneous or intramuscular injection. In the case where the FKMR is part of a transdermal patch, for example, a diffusion matrix containing lobelin or a multilayer patch containing the first layer of lobelin and the second layer of vehicle can be used. Lobelin is released from the first layer when it comes into contact with the vehicle. The transdermal patch containing the diffusion matrix is usually replaced after 7 days, and the multilayer patch is usually changed daily.

The present invention also relates to a method of treating nicotine addiction in individuals, such as treatment to stop smoking or chewing nicotine-containing products. In accordance with the present invention, the subject is administered to the subject at a controlled rate with sustained release, which provides the subject with therapeutic levels of lobelin over a long period of time. Preferably, the above release system is used. Lobelin is administered at intervals that can be easily coordinated with individual behavior modification programs.

The invention also relates to a kit for treating nicotine addiction. For example, these kits help stop smoking or chewing nicotine-containing products. A kit according to the invention comprises a sustained release system of the above type capable of delivering lobelin for long periods at therapeutic concentrations; and instructions for the user and / or health care provider to use the system to help stop smoking or nicotine-containing products to stop chewing. Preferred kits include a system for sustained release of the lobelin at therapeutic concentration for at least 3 weeks as a release system.

BACKGROUND OF THE INVENTION The present invention relates to a controlled release sustained release system for the passive delivery of a therapeutic concentration of lobelin to individuals over a long period of time. The present invention also relates to a delivery system for the administration of lobelin to individuals, which reduces or eliminates individuals' smoking or chewing habits.

The present invention also relates to a drug delivery system for delivering lobelin to individuals in such a manner that the active ingredient is delivered to the subject bypassing the gastrointestinal tract, thereby minimizing gastrointestinal side effects.

The present invention also relates to drug delivery.

- 7 r · • «* • 444 • 4« system for administering lobelin in a dose that is not too unpleasant for the individual and can be readily incorporated into a behavior modifying program to assist the individual to stop smoking .

The present invention also relates to a self-administering drug delivery system for delivering a therapeutically effective amount of lobelin.

The present invention also provides a therapeutic level of lobelin without the need for multiple daily doses.

The figures in the appendix are briefly described below.

1, 1B. and IC. Figures 1 to 5 show microparticles, microcapsules and elongated rods containing lobelin.

Figure 2 shows a transdermal patch containing a matrix with a diffusion layer.

Figure 3 depicts a multilayer transdermal patch.

Figure 4 shows a set of four packs and instructions for use of a transdermal patch containing a diffusion layer matrix.

Figure 5 shows a set of twenty-eight packages and instructions for use of a multilayer transdermal patch.

Figure 6 illustrates a syringe containing lobelin in its own right.

-δΙό, containing a biodegradable microparticulate polymer and a container containing a pharmaceutically acceptable carrier, and a kit comprising instructions for use.

Figure 7 shows the in vitro release of lobelin free base from PLGA microparticles (particle size 150-180 µm) at 30, 40 and 50% lobein content.

Figure 8 shows the in vitro release of lobelin free base from PLGA microparticles (particle size 38-106 µm) at 30% lobelin content.

Figure 9 shows in vivo release of lobelin free base, expressed as a percentage of lobelin remaining at the injection site, from formulations containing 30% and 40% of lobelin free base, respectively.

Figure 10 illustrates the in vivo effect of a dose of lobelin on the number of cigarettes smoked.

Figure 11 shows the in vivo effect of the dose of lobelin on the number of smoke outbreaks.

Figure 12 shows in vivo release of lobelin free base from PLGA microparticles containing 35% lobelin.

Figure 13 shows the effect of subcutaneous injection of microparticles containing lobelin in human volunteers on the number of cigarettes smoked.

The present invention relates to the treatment of nicotine dependence in a subject by administering to the subject a therapeutic level of lobelin at a controlled rate with sustained release over a period of at least one day. The procedure, combined with a smoking cessation program, is particularly effective. This program combines nicotine physical dependence with therapeutic approaches to reduce the individual's psychological addiction to smoking or nicotine-containing products. A preferred method of the present invention is a dosing schedule that is simply coordinated with a smoking cessation modification program. These programs are designed to teach individuals how to stop or reduce the use of nicotine-containing products by modifying their behavior. Typically, these programs include meetings with consultants at specific intervals, such as weekly or biweekly.

The term “easy-to-coordinate with a smoking cessation behavior modifying program” means periods that coincide with meetings with counselors at specific intervals, such as weekly or biweekly. For example, a release system may be designed to require weekly subcutaneous or intramuscular injection to maintain the therapeutic level of lobelin in the circulatory system. Weekly injections can easily be coordinated with a behavioral program advisor. The injection is preferably administered by medical staff or a consultant. The individual may schedule a weekly injection and any behavioral counseling necessary.

FIELD OF THE INVENTION The present invention relates to a drug delivery system to help individuals stop smoking or chewing nicotine-containing products. The delivery system includes a system modulated by physical restriction containing lobelin. The design and layout of the system allows an individual to gain therapeutic concentration of lobelin at a controlled rate over a period of at least one day. Typically, the delivery system is designed and constructed such that the physically restrained modulated system delivers lobelin subcutaneously, intramuscularly, or transdermally.

The drug delivery system provides individuals with a therapeutic level of lobelin over a long period of time. Lobelin in this way reduces or eliminates an individual's smoking or chewing habits.

The term individual refers in a broad sense to persons suffering from nicotine addiction. Thus, the term individuals refers to individuals who smoke or chew nicotine-containing products. Nicotine-containing products include any nicotine-containing product such as cigarettes, pipe tobacco and chewing tobacco.

FKMR contains substances or components, such as solids, liquids, gels or layers, that are capable of sustainably releasing lobelin. FKMRs useful in the process of the present invention include, for example, biodegradable polymers and transdermal patches.

Lobelin is chemically defined as 2- [6- (B-hydroxyphenylethyl) -1-methyl-2-piperidinyl] acetophenone, a compound of formula (I). It may be present as the free base or in the form of a water-soluble salt, e.g.

In formula I, X is an anion.

As used herein, the term lobelin also encompasses structural equivalents of the above compound having the same or similar functional characteristics. In particular, the structural equivalents are structurally similar to the above compound but optionally contain one or more substituents in the structural core. For example, substituents may be attached to a benzene ring provided that the suitability of the compound as a nicotine replacement is not adversely affected. Examples of such substituents include lower alkyl groups such as methyl, ethyl or propyl. Further, various lower alkyl groups such as ethyl or propyl may be attached to the piperidyl nitrogen instead of the methyl group.

The term sustained release controlled herein means that only a portion of the lobelin is released from the FKMR at a given time, while the remainder remains in the FKMR and is gradually released over a longer period of time. Longer time here means at least one day (24 hours), but can extend to 30 or even 90 days.

The long-term therapeutic level of lobelin is the level of lobelin that is sufficient to reduce or eliminate the chewing habits of an individual's smoking or nicotine-containing products for an extended period of time. For example, such a therapeutic level is a daily lobelin level of about 5 to about 30 mg, preferably averaged about 10 to about 20 mg, over a period of about one to at least thirty days. For these doses, the free base form of lobelin was used. Amounts of about 5 to about 30 mg of lobelin represent lobelin released from FKMR and not the level of lobelin in the circulatory system of an individual.

The FKMR in the drug delivery system may be present in a form suitable for subcutaneous or intramuscular injection, for example in combination with a biodegradable polymer. The in vivo degradation of the biodegradable polymer and the controlled release of lobelin at controlled rates provide a therapeutic level of lobelin over a long period of time. The polymer is selected so as not to cause a significant adverse reaction in the individual when administered in vivo. Examples of biodegradable polymers of the invention include lactic acid and glycolic acid, copolymers [poly (lactic / glycolic acid / PLGA)], lactic acid polymer (PLA), glycolic acid polymer (PGA), and polyesters such as polyorthoesters, polylactones, polyanhydrides and polyamino acids: Lactic acid and glycolic acid copolymers (PLGA) are preferably used.

Polymers made from glycolide and lactide dimers, such as PLGA, PLA and PGA, are known to be slowly hydrolysed and byproducts of their hydrolysis (lactic and glycolic acid) are normal metabolites. PLGA, PLA and PGA polymers are believed to be non-toxic, relatively non-inflammatory, non-tissue reactive. These polymers also have moderate strength, tensile stress, deformation and elasticity. Hereinafter, PLGA polymers are understood to mean PLA, PGA and PLGA polymers.

The specific lactide / glycolide ratio of PLGA polymers and the molecular weight of the polymer are taken into consideration when designing the drug delivery system. There are differences in the hydrophobic nature and crystal structure of lactic acid and glycolic acid. The use of a fast-hydrolyzing polymer for rapid, final clearance of lobelin (low molecular weight, low lactide content) is offset by the need for sustained release of relatively soluble lobelin, which is provided by a slow hydrolyzing polymer (high molecular weight, high lactide content). Based on these needs, the lactide / glycolide polymers are preferably used in a composition of about 50:50 to about 85:15, with a molecular weight of about 50,000 to about 150,000 daltons, and more preferably about 100,000 daltons.

An amount of lobelin is introduced into the polymer that allows sustained release of the lobelin from the polymer at the desired therapeutic level. Preferably from about 20 to about 65% by weight of the Lobelin, more preferably from about 30 to about 50% by weight, most preferably from about 30 to about 40% by weight, is introduced into a PLGA polymer having a lactide / glycolide ratio of about 85:15 and has a molecular weight of about 100,000 daltons. The composition of the biodegradable polymer and lobelin should be administered subcutaneously or intramuscularly. Such compositions include, for example, microparticulate, microcapsular, or elongated stick formulations of polymer and lobelin. 1A-1C. Figures 3 to 5 show micellar, microcapsule, and elongated rod shaped lobelin formulations. In this case, the lobelin is shown in Figure 1A. and IC. 1 to 4 are distributed in the biodegradable polymer 2. Another embodiment is illustrated in FIG. 1B. 1B, whereby lobelin 1 is encapsulated in the biodegradable polymer 2.

The size of the microparticles, microcapsules and elongated rods of the biodegradable polymer is chosen to provide a sustained release of the lobelin at a controlled rate by subcutaneous or intramuscular injection or implantation.

For microparticles, for example, the particle size is in the range of about 38 to about 250 microns, most preferably 38 to about 106 microns. Microcapsules have a size in the range of about 10 to about 250 microns. The elongated sticks have a diameter in the range of about 1 to 4 mm and a length in the range of about 0.5 to about 3 cm. The biodegradable polymer is preferably a microparticulate polymer. Preferably, the microparticles are suspended in a pharmaceutically acceptable carrier immediately prior to injection. The pharmaceutically acceptable carrier used is a suspension capable of forming a suspension with lobelin and delivering microparticles, which does not significantly adversely affect the nicotine substitution role of lobelin in vivo. Examples of pharmaceutically acceptable carriers for the administration of Lobelin include the following formulations:

Formulation 1: 0.38 g of carboxymethylcellulose, 3.75 g of mannitol and 0.08 g of Tween 80 in 20 ml of distilled water; more preferably

Formulation 2: 0.0127 g of carboxymethylcellulose, 0.056 g of mannitol and 0.027 g of Tween 80 in 20 ml of distilled water.

The microparticulate syringe can be used to aspirate the pharmaceutically acceptable carrier to form the suspension. Obviously, the suspension may be prepared by other methods. Alternatively, the suspension may be prepared separately from the syringe and then withdrawn into the syringe. The suspension is preferably injected into the subject at a time readily compatible with smoking cessation modification programs.

An important aspect of Lobelin containing microparticles is that the microparticles, when suspended in the vehicle, cannot be stored for a long period of time because a significant amount of lobelin from the microparticles would pass into the vehicle. Preferably, the suspension is used within about one hour after preparation.

If microparticles (or other forms that gradually decrease the amount of active ingredient released over time), special dosage regimens may be desirable, e.g. 20 mg daily, followed by descending release, and a daily dose of 14 mg lobelin on the eighth day. Obviously, a lower dose than the first is required to maintain the 15 mg level for the next seven days because of the first dose of lobelin η

of the remaining microparticles. Thus, for some FKMRs, different dosing schedules need to be prepared.

However, in the case of lobelin, there is no need to reduce the subsequent dose as such since it is believed that lobelin is a non-additive and is rapidly excreted from the circulatory system. This rapid clearance is thought to be due to binding to nicotinic receptors in the brain; that is, although lobelin may be rapidly secreted from the circulatory system, it may be present in the brain for a substantially longer period.

The FKMR may optionally be part of a transdermal patch. Transdermal patches have a number of advantageous properties, for example, they avoid the gastrointestinal tract, have a readily adjustable, sustained action, provide self-administration and immediately suspend administration if desired. By transdermal patch, we mean patches that can be attached to an individual's skin and have a portion or component for sustained release administration of lobelin at a controlled rate. Types of patches of the invention are, for example, matrix type and / or multilayer patches having a diffusion layer. These are described in detail below.

Many types of transdermal patches are well known to those of ordinary skill in the art and such patches have been previously described in detail. A general arrangement of a patch according to the invention is shown in FIG.

FIG. This patch comprises a diffusion matrix layer that contains a networked macroporous polymeric foam as the backbone of the viscoseelastic lobelin-polymer blend. The patch number 10 is a four-layered sheet structure that is designed to be glued to the skin. The outermost backing layer 12 serves as the primary structural component of the patch and also has a protective function to prevent the lobeline from exiting the patch through the outer layer. This layer is preferably made of a flexible elastomeric film or film having a thickness of 20-75 µm. Examples of such elastomers include polyether block amide copolymers, polyethylene methacrylate block copolymers, polyurethanes, silicone elastomers and the like. The matrix layer containing lobelin 14 also serves as a so-called reinforcing or enhancement layer (described below) and optionally as a pressure-sensitive adhesive for storing the lobelin. The matrix backbone is formed by a 16 mesh macroporous polymeric foam. Preferably, the network comprises substantially completely open pores (90% or greater). The pore size distribution of the mesh foam is typically about 10 to 40 pores per linear centimeter, while the density (in the unloaded state) is generally about 0.01 to 0.5 g / cm ³ . Polymers suitable for the preparation of such foam backbones include polyurethanes and polyethylenes. The pressure sensitive adhesive layer 18 covers the outer face layer 14 and the pressure sensitive adhesive layer 20 covers the pressure sensitive adhesive layer. The pressure-sensitive adhesive layer 14 consists of a pharmaceutically acceptable adhesive composition typically in the range of about 25 to 100 microns. The adhesive used is, for example, polydimethylsiloxane (Dow Corning 355 Pharmaceutical grade adhesive). The pores of the foam are completely or partially filled by a viscoelastic hydrophobic, lobelin-permeable polymer and a penetration enhancer. The polymer acts as a carrier for lobelin, while it controls the solubility of lobelin in the polymer and / or the penetration of the active ingredient into the skin by the so-called enhancer. The hydrophobic polymer renders the patch water resistant and prevents absorption of water in a liquid state, thereby adversely affecting its functionality and wearability. Examples of suitable polymers include polysiloxanes (silicone polymers), hydrophobic polyacrylates, polyurethanes, softened ethylene-vinyl acetate copolymers, and the like. As the reinforcing material described above, for example, Azone ™ M can be used. The mixture comprising lobelin also optionally contains an anti-pruritic agent.

Solutions for the above system are generally described in U.S. Patent No. 4,911,916, entitled "Diffusion Matrix for Transdermal Drug Delivery and Transdermal Drug Delivery Device Containing it", issued March 27, 1990.

These patches may be formulated to contain sufficient amounts of lobelin to release from about 5 to about 30 mg per day. Preferably, these patches are formulated to contain enough lobelin to release from about 5 to about 30 mg per day for 7 days, thereby allowing one patch to be worn for a week.

The optimal dosage range, i.e., the range within which lobelin exerts its maximum therapeutic effect and minimal side effects, is empirically determined. The patch or other delivery system is formulated to contain sufficient amount of lobelin to release a dose within the optimum dosage range over a desired period of time.

Another type of patch suitable for use according to the invention is illustrated in Figure 3 in its usual configuration. It also consists of four layers that define at least two separate compartments. One compartment contains lobelin, while the other contains a carrier which, when mixed with lobelin, allows the transdermal delivery of the lobelin. In patch 22, the backing layer 24 is secured to the speed control membrane 26 so as to form two compartments, namely the compartments containing lobelin 28 and vehicle 30. The adhesive layer 32 covers the release rate controlling membrane and the release control film 34 covers the adhesive layer.

A patch of about 75 microns of silanized polyester (or other suitable material treated with a release agent) was used as the release release film 34 to construct the patch. The adhesive layer 32 is poured onto the release liner. For example, the adhesive layer may be made of polyisobutylene. The adhesive layer is deposited on the rate controlling membrane 26 having a layer thickness of about 100 microns. Ethylene vinyl acetate may be used as the control membrane.

Subsequently, materials intended for the storage compartment 28 and the storage compartment 30 are placed on separate portions of the rate control membrane 26. The material for the compartment for the storage of lobelin 28 may be a free base of lobelin, while the compartment containing the vehicle may be an alcoholic or an aqueous / alcoholic solution.

In the final step, a suitable backing layer having a heat-sealable coating on one surface is placed over the surfaces to be formed for the compartments 28 and 30. The system is provided with a key lock 36 around the perimeter and between compartments 28 and 30 to form the compartments. It is desirable that the heat seal 28 between the two compartments be a less secure seal than the heat seal 36 around the perimeter so that the seal between the compartments can be selectively eliminated by pressure exerted by the user. Thus, any chamber may be pressurized to break the seal therebetween, thereby ensuring that the solution and the lobelin are mixed and the lobelin dissolves. The lobelin is then in a state where it is able to penetrate the rate-regulating membrane 26 and thus reach the skin of the wearer. As explained with respect to the patch shown in Figure 2, the compartments may also contain a penetration enhancer as described above to facilitate the uptake of the lobelin through the skin.

Preferred embodiments of the patch outlined above are described in detail in U.S. Patent 4,917,676. The patches contain sufficient amounts of lobelin to release about 5 to about 30 mg of lobelin per day, so such patches are used daily by individuals (so-called daily patches).

The present invention also provides a kit for assisting individuals to stop smoking. These kits contain an FKMR of the invention and instructions for use. For example, a kit for treating nicotine addiction may include at least one pack of a transdermal patch 30 containing lobelin and instructions for use 32, wherein the instructions provide the user and / or health care personnel with information on the use of the patch. The number of transdermal patches in the kit may depend on the type of transdermal patch and the duration of the do23 vomiting discontinuation program - for example, this may be a 3 or 4 week program for which the kit is designed. Typically, the duration of treatment is 4 to 8 weeks, typically 6 to 8 weeks.

A transdermal patch containing lobelin in a diffusion layered matrix is generally designed to deliver the drug over a prolonged period of time, for example 7 days. Accordingly, a four-week smoking cessation! Preferably, the kit for administration contains four packs of transdermal patch 30 as illustrated in Figure 4. Instructions for use # 32 provides the individual and / or health care personnel with instructions on changing the patches weekly, for example by using patch 1 on the first day and patch 2 on the eighth day.

A multi-compartment patch is typically designed for daily use. so a 3 or 4 week smoking cessation! The kit for the program may contain 21 or 28 transdermal patches 30, as shown in Figure 5. The enclosed instruction manual 32 provides information to individuals and / or medical personnel on the need to change the transdermal patch daily and also instructs the individual on how to contact the first compartment with the carrier in the second compartment. For example, it describes how an individual may be pressurized between two compartments »··

- 24 smooth seals need to be removed.

The kit may further comprise at least one storage unit of an injectable or implantable FKMR, in addition to the instruction manual 32, in the arrangement shown in Figure 6. For example, a kit may contain four to eight containers of the polymer / lobelin microparticulate system, a 4-8 week smoking cessation! program.

As explained above, it may be necessary in each case for each storage unit to contain a different amount from the microparticle / lobelin system, taking into account the remainder of each previous dose when the lobelin is continuously released from the microparticles. Alternatively, each container contains the same amount of microparticle / lobelin system, but with the guidance that a reduced volume of the resuspended microparticle / lobelin system should be injected for consecutive days of the treatment period. However, as noted above, it is not absolutely necessary to reduce the lobelin dose level during the treatment program as it is believed that lobelin is non-addictive and is rapidly cleared from the circulatory system.

The kit may optionally comprise at least one storage unit number 36 containing a pharmaceutically acceptable carrier. In addition, a syringe (Item 38) can be provided. The syringe may optionally be pre-filled with microparticles.

♦ · • * · 9 9 9 · · * * ·· * <· · * « _% ···« ί · <99 *

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention.

Example 1 Preparation of PLGA ml microspheres containing% lobelin

In the experiments described in the example, either the lobelin free base purchased from Sigma Chemical Co. or the base prepared from the lobelin sulfate purchased from Boehringer Ingelheim was used as the lobelin base. The compound was characterized by UV spectroscopy, high performance liquid chromatography (HPLC) and its melting point before use.

MEDISORB ™ 8515 DL lactide / glycolide biodegradable polymer was purchased from DuPont. The polymer had a lactide content of 85 ± 5% and a glycolide content of 15 ± 5%. Solvents (in the best quality available) were obtained from Fisher Scientific. The preparation was carried out as follows.

The polymer (3.5044 g) was dissolved in methylene chloride (23 mL) which corresponds to a 15 wt% solution. Lobelin (1.5006 g) is then added to the solution and the solution is stirred to promote complete dissolution. The resulting solution is layered on a clean glass plate element and spread with a Boston-Bradley adjustable knife. Subsequently, most of the solvent was removed under a stream of nitrogen and the resulting film was stripped from the glass and dried in vacuo. The density of the film obtained in the casting step is very low because of the high volume of unfilled solvent

- 26 * ···· 4 Λ • ·· · * »· · • · · · · · 44 volumes. This is reduced using heat and hydraulic pressure in the next compression step to reduce the permeation of the liquid into the microparticles. The film is made from rods with a Pasadéra Hydraulic Press.

The chopsticks are chopped into small particles using a commercially available chilled shredder. The small particles or powder are then placed on a USP sieve and the particles in the size range of about 38 to 106 µm, 106 to 150 mm and 150 to 180 mm are separated. The microparticles containing 30% lobelin were collected.

Example 2 Preparation of PLGA microparticles containing% lobelin

The procedure of Example 1 was followed except that 1.0000 g of lobelin were added to the crucible together with the polymer solution (1.501 g in 10 ml). The resulting microparticles containing 40% lobelin were collected.

Example 3 Preparation of PLGA microparticles containing% lobelin

Example 1 was repeated except that 2.0016 g of lobelin were added to the crucible together with the polymer solution (2.0016 g in 13 ml). The resulting microparticles containing 50% lobelin were collected.

··· £ approx

Example 4

Lobelin release from PLGA under in vitro conditions

The PLGA / lobelin microparticulate system used by

Prepared as in Examples 1, 2 and 3, it was exposed to a saline solution containing phosphate buffer by simulated immersion so that the concentration of the active ingredient in the buffer was not greater than 20%.

The microparticles were then placed in a sleeve which was placed in a test tube. Each day, the vagina was placed in a new test tube and the lobelin content of the saline containing the buffer was determined by UV analysis after extraction and evaporation with an organic solvent. Buffer lobelins were determined daily for the first two to three days and weekly thereafter. The results are shown in Figure 7; the figure shows the release of lobelin free base from 150-180 µm microparticles at 30%, 40% and 50% lobelin fill.

In either case, the total amount of lobelin is released within one week. The slowest dissolution was obtained with 30% lobelin filling, whereby, at 150-180 μτα particle size, only 60% of the lobelin was dissolved by the end of the first week.

Example 5

Lobelin release from PLGA under in vitro conditions

The analysis was carried out as in Example 4, except that the amount of lobelin remaining in the microparticles was ·· ····

- 28 gels were determined after soaking microparticles in saline containing phosphate buffer. The amount dissolved is obtained by subtracting the total amount remaining in the microparticles from the amount administered.

In the experiment, unlike the previous one, the microparticles of 38-106 ρτη produced in Example 1 were used. The microparticles were placed in an extraction sleeve and sealed with a glass wool plug. The pods were suspended in phosphate buffered saline containing 0.1% sodium azide (9 pods / 1.7 L). Samples were removed daily, air dried and vacuum dried. The dry pods were placed in a larger test tube and covered with sufficient dichloromethane to cover. To facilitate dissolution of the microparticles by rotating the test tubes, a known volume of 0.01 N sulfuric acid solution was added to each tube. After mixing, the acidic layer was separated and the whole was repeated two or three times. The lobelin content of the acidic fractions was determined by UV analysis. The value obtained is subtracted from the initial amount to obtain the amount of lobelin dissolved from the microparticles. The results are shown in Figure 7. Figure 8 shows the amount of lobelin free base dissolved from microparticles having a size of 30-106 gm containing 30% lobelin. Dissolution was essentially constant over the first 10 days, followed by a flattening curve for the last 4 days.

Example 6

Release of two formulations in rats Preparation of formulations

Two preparations were studied in the study. One formulation contained 30% lobeline free base filled PLGA microparticles and the other 40% lobelin free base filled PLGA microparticles. Within a half hour before injection, a suspension containing 20 mg / ml of the 30% preparation and 15 mg / ml of the 40% preparation was prepared with 0.94 g carboxymethylcellulose, 9.38 g D-mannitol, 0.2 g polysorbate 80 (Tween 80) in 50 ml water.

Study in rats

Female Sprague-Dawley rats weighing 250-300 g were used. Two animals were used as negative controls. 0.1 ml of vehicle was injected into the shoulder girdle of each animal from a syringe fitted with a 22 gauge needle. On day 7, both animals were sacrificed using carbon dioxide and the shoulder fat removed.

The other animals were formed into two groups: one group treated with 30% and the other with 40% lobelin-filled composition. Four animals from each group were selected as positive controls. These animals were also killed with carbon dioxide and the adipose tissue and facial part removed from the shoulder region. 0.1 ml of the formulation was added to vehicle as tissue vehicle.

Five additional subgroups were formed from each group, according to the suspensions in the animals for 4 hours, 1 day, 2 days, 5 days and 7 days prior to tissue sampling. Each subgroup consisted of four animals.

The formulations were ready for use as described above and in each case 0.1 ml aliquots were added. At the time of killing, fatty tissue and facial parts of the shoulder region were removed. In most, though not all, tissue sections containing microparticles are observed. However, it seems likely that some of the microparticles were behind the excision area and were not recovered.

Tissue extraction

Tissue specimen was placed in a short glass tube with 2-3 mL of dichloromethane. 100 μΐ of a 1 mg / ml solution of triprolidine in dichloromethane was added as an internal standard. The sample was homogenized with a Tissue Tearor ™ operating at 4500-8000 rpm and centrifuged in a Teflon-lined screw centrifuge tube for 7 minutes. Dichloromethane was carefully pipetted into a test tube, then 1 mL of 0.01 N sulfuric acid was added and shaken for 15-20 seconds. After phase separation, the upper (acidic) phase was carefully separated by pipette and the volume was measured. It was then transferred to another clean test tube or ampoule and filtered through a 0.45 μη nylon filter before use. The dichloromethane phase was extracted with acid until no lobelin was detected or the extraction was repeated up to five times.

Analysis

Acid samples were directly analyzed by HPLC. The amount of recovered lobelin was determined from a standard curve. This curve expresses the ratio of extracted lobelin concentration / internal standard concentration obtained from peak tissue control samples at various lobelin levels.

The assay was performed using the following HPLC system: Waters 5410 pump; Waters U6 type injector; Waters Lambda 481 LC spectrophotometer; Physics SP 4270 Integrator; Phenomenex Partisii Cg 5u column 100 x 4.6 mm to which a 30 x 4.6 mm column of the same charge is attached; a mobile phase; 60% phosphate buffer, pH 3: 40% (50:50 acetonitrile / methanol) system; flow rate 1.2 ml / min; AUFS value 1.0; detection was at 249 nm; sample volume; 4 μΐ.

The results for the 30 and 40% loaded microparticles were corrected for 75.4% efficiency of excised tissue extraction. However, the efficiency of recovering microparticles from animals was not considered.

The results are shown graphically in Figure 9. Depending on the different treatments, the percentage of dose found in the tissue sample is plotted. For the 30% charge, the release profile is slightly closer to the linear release than for the 40% charge.

Example 7

Examination of polyethylene sachets - study of in vivo release in rats

preparation

In the assay, a PLGA microparticulate formulation having 35% lobelin free base was used; the method of analysis is different from that described in Example 6. The formulation was enclosed in polyethylene bags of 20 gm pore size prior to implantation into rat shoulder girdle. The pore size of the bags is still adequate for the dissolution tests, but small enough to retain the microparticles (38 μπι with the smallest diameter).

Description of the experiment

Polyethylene bags (Biotek, Woburn, MA) were used. Twelve bags were sealed empty and cut to about 1 cm x 1 cm. Each of the remaining sachets were filled with about 4 mg of the above formulation and then sealed and cut to size. Female Sprague Dawley rats weighing approximately 250 g were quarantined. At time 0 (T = 0) of the experiment, the animals were anesthetized and only an incision greater than the width of the sachet was performed in the shoulder region. The pouch was submerged in normal saline solution with a tweezer and slipped under the skin with the tweezers. The incision was closed with one or two staples. On days 1, 2, 3, and 7, the pouch was removed from six control (empty pouches) and six formulation animals (at each time point). After the animals were anesthetized, the removal was performed by an "L" shaped incision around the pouch. Each patch was dipped in normal saline and then wiped with a paper towel. The bags were analyzed the following day after being stored in overnight polyethylene bags in a freezer. Immediately after removal of the bags, the animals were sacrificed.

HPLC analysis and sample preparation

Each sachet was cut and the contents of each sachet, together with the emptied and chopped sachet, were placed in a 10 ml volumetric flask containing approximately 5 ml of acetonitrile. The flask was sonicated for 10 minutes and allowed to warm to room temperature (about 30 minutes) and then made up to 10 ml with acetonitrile. Subsequently, exactly 0.1 ml of the stock solution thus obtained was weighed into a 10 ml volumetric flask and filled with the so-called working diluent (see below). 2.5 ml of this solution was transferred to another 10 ml volumetric flask and filled with the appropriate diluent.

HPLC analysis

The acidic samples were directly analyzed by HPLC. The amount of lobelin released from the sachets was determined from a standard curve. This curve expresses the ratio of lobelin concentration / internal standard concentration at various lobelin levels. HPLC determination was performed as described above with the following modifications.

The internal standard was prepared from triprolidine. 10.0 mg of accurately measured triprolidine was completely transferred to a 10 mL Type A volumetric flask and the flask was filled to the mark with the mobile phase. This yielded a standard stock solution of 1 mg / ml tripolidin, which was used to prepare the working dilution solution.

The working dilution solution was prepared from 1 ml of internal standard stock solution. Weigh 1 ml accurately with a Type A graduated pipette and place in a 100 ml volumetric flask and make up to the mark with the mobile phase (see below). Subsequently, exactly 5 ml of this solution was pipetted (Type A pipette) into another 100 ml volumetric flask and made up to the mark with the mobile phase. The working diluent thus obtained has a concentration of triprolidine of 500 ng / ml.

The standard solution was prepared from 10.0 mg of lobelin.

After accurate weighing and filling in a 10 ml Type A volumetric flask, the flask was filled to the mark with the mobile phase. This resulted in a 1.0 mg / ml stock solution of lobelin. Weigh exactly 1 ml of the lobelin stock solution into a 10 ml volumetric flask with a type A pipette and make up to the mark with the working diluent. 1 ml of the resulting solution was transferred to another 10 ml volumetric flask using a Type A graduated pipette and made up to the mark with working diluent. The standard lobelin solution thus obtained had a concentration of 0.01 mg / ml.

The mobile phase was prepared by adding 200 μΐ of triethylamine to 1 L of 62% 40 mM potassium acid solution (pH 3.00) and 38% acetonitrile. The solutions used in the preparation were degassed before use and filtered through a 0.2 μτα membrane filter.

Operating parameters: Phenomenex / Part isii 5C8 column 25.0 cm x 4.6 mm (inner diameter); Flow rate 1.0 ml / min; detection: at 249 nm with a sample volume of 35 μΐ.

The results are shown graphically in Figure 12. Depending on the duration of treatment, the average release of lobelin from the six pouches is shown as a percentage. In the figure, the times represent the average of six repetitions. At the end of the week, the percentage of lobelin released from the test sample sachet was approximately 95%. The results indicate that virtually all the amount of lobelin in the microparticles is released within seven days.

Example 8

Effect of Lobelin Sulphate on Human Subjects

Subjects enrolled in the study were long-time smokers or chronic smokers who had been smokers regularly for more than five years. Usually at least 20 cigarettes were smoked daily. All volunteers were healthy, non-obese adult males with no history of gastrointestinal, hepatic, neurological or haematological lesions. All volunteers were tested for health before being enrolled in the experiment.

Method

On days 1, 2, 3 and 4 of the drug administration, 0.4, 0.6, 0.8 or 1 ml of a 20 mg / ml solution of lobelin sulfate in the upper ventral forearm was administered by subcutaneous injection. form. The volunteers were then free to smoke as desired and the number of cigarettes smoked and smoke exhaled was recorded for 2 hours after the injection.

Results

Both the number of cigarettes smoked and the number of smoke exhalations decreased with the increase of the applied dose during the two hours after the injection. The results are illustrated in Figures 10 and 11. Figure 10 shows that during the two-hour period immediately after treatment with lobelin sulfate, the average number of cigarettes smoked declined substantially linearly with the dose of lobelin used. Similarly, during the two-hour period directly after treatment with lobelin sulphate, the average number of smoke outbreaks decreased significantly with increasing dose of lobelin, although the first effects were observed only at doses of at least 12 mg.

ι

Example 9

Study of the efficacy of a microparticulate formulation containing lobulin in humans

Subjects

A total of 12 volunteers (9 subjects and 3 placebo subjects) were selected based on the criteria described in Example 8; however, for two volunteers, the number of cigarettes smoked per day was 7 and 10, while the other smoked an average of approximately 20 cigarettes per day.

preparation

The PLGA microparticulate formulation containing the lobelin prepared in Example 1 was used. However, the concentration of lobelin in the formulation was adjusted to 35% by weight. Prior to injection, the preparation was resuspended in the following diluent: 50 ml of D-mannitol, 5 mg of carboxymethylcellulose sodium, 1 mg of polysorbate 80 and water were used in a volume sufficient for a final injection volume of 1 ml. A homogeneous suspension was thus obtained.

Method

On day 1 and / or day 2 of the drug test, an amount of about 0.6 to 0.8 of the suspension containing the above lobelin was administered by the procedure of Example 8, by subcutaneous injection. The volunteers were then free to smoke as desired and the number of cigarettes smoked was recorded for 8 days. The results are shown in Figure 13, with Day 1 being the first full day after injection.

Results

The number of cigarettes smoked decreased in the period following the injection compared to the period before the injection. The results are shown in Figure 13. The figure shows the percentage of cigarettes smoked over a 24 hour period as a percentage of the number of cigarettes smoked prior to treatment. This value was significantly reduced after the administration of the lobelin suspension.

Claims (56)

Claims 1. A method of treating an individual's nicotine dependence, comprising administering to the individual at least one physical restraint modulated system, wherein the physical restraint modulated system is a lobelin ♦ release, which reduces the individual's need for nicotine for at least one day. 2. The method of claim 1, further comprising providing the subject with behavior modification tips as part of a smoking cessation program. 3. The method of claim 1, wherein the treatment is continued for at least one week. 4. The method of claim 1, wherein said system modulated by physical restraint is a transdermal patch. 5. The method of claim 1, wherein the release system modulated by physical restraint is administered subcutaneously, intramuscularly, or by implantation. 6. The method of claim 5, wherein the physically constrained modulated system is a biodegradable polymer that liberates and biodegrades lobelin. The process according to claim 6, wherein the biodegradable polymer is selected from the group consisting of polylactic acid / glycolic acid copolymers, polylactic acid, polyglycolic acid, polyesters, polyorthoesters, polylactones, polyanhydrides and polyamino acids. The process according to claim 7, wherein the biodegradable polymer is a poly (lactic acid / glycolic acid) polymer. The process of claim 8, wherein the lactide / glycolide ratio in the polylactic acid / glycolic acid polymer is maintained at about 50:50 to about 85:15. 10. The process of claim 6, wherein said biodegradable polymer is in microparticulate form. 11. The method of claim 10, wherein the microparticles are from about 38 to about 250 µιη. The method of claim 6, wherein the biodegradable polymer is used in a pharmaceutically acceptable injection vehicle. 13. The method of claim 12 wherein the pharmaceutically acceptable injection vehicle is a carboxymethylcellulose solution. 14. The method of claim 1 wherein the system is a physically restricted modulation system that releases about 56 mg to about 114 mg of lobelin over a period of two days. 15. A drug release system for the treatment of nicotine dependence, characterized in that it consists of a system modulated by physical restraint, the construction and arrangement of which enable the individual to release the therapeutic concentration of lobelin at a controlled rate over a continuous period of at least one day. 16. The drug delivery system of claim 15, wherein the system is physically limited and comprises a transdermal patch. 17. The drug release system of claim 15, wherein the physically restricted modulated system comprises a biodegradable polymer that can be administered or implanted by subcutaneous or intramuscular injection. 18. The drug release system of claim 17, wherein the physically restricted modulated system delivers lobelin into the circulatory system. 19. The drug delivery system of claim 17, wherein the biodegradable polymer comprises polylactic acid / glycolic acid copolymers, polylactic acid, polyglycolic acid, polyesters, polyorthoesters, polylactones, polyanhydrides and polyamino acids. 20. The drug delivery system of claim 19, wherein the biodegradable polymer comprises a polylactic acid / glycolic acid polymer. The drug delivery system of claim 20, wherein the lactide / glycolide ratio in the polylactic acid / glycolic acid polymer is from about 50:50 to about 85:15. 22. The drug delivery system of claim 20, wherein the microparticles have a size in the range of about 38 to about 250 µπι. 23. The drug delivery system of claim 20, wherein the biodegradable polymer is in the form of microparticles suspended in a pharmaceutically acceptable injection vehicle. 24. The drug delivery system of claim 22, wherein the pharmaceutically acceptable injection vehicle is a carboxymethylcellulose solution. 25. The drug release system of claim 15, wherein the duration is at least 7 days. 26. The drug delivery system of claim 25, wherein the duration is at least 30 days. 27. The drug delivery system of claim 15, wherein the amount of lobelin in the range of about 56 to about 114 mg is released over 7 days. 28. The drug delivery system of claim 20, wherein the biodegradable polymer comprises from about 20 to about 65 weight percent of lobelin. 29. The drug delivery system of claim 28, wherein the biodegradable polymer comprises from about 30 to about 40% by weight of lobelin. 30. The drug delivery system of claim 16, wherein the transdermal patch comprises lobelin in a diffusion matrix layer. 31. The drug delivery system of claim 30, wherein the diffusion matrix layer further comprises a non-solvent-like absorption enhancer. 32. The drug delivery system of claim 30, wherein the diffusion matrix layer further comprises an anti-itch agent. 33. The drug delivery system of claim 30, wherein the lobelin is present as a free base. 34. The drug delivery system of claim 16, wherein the first compartment comprises a first compartment and a second compartment, wherein the first compartment comprises lobelin, the second compartment a carrier, and its construction and design allows the patch to be therapeutically significant. is not released until contact with the vehicle. 35. The drug delivery system of claim 34, wherein the carrier is an alcohol or an aqueous alcoholic solution. 36. The drug delivery system of claim 34, wherein the second compartment further comprises an absorption enhancer. 37. A kit for treating nicotine addiction, comprising: at least one system modulated by physical restraint, the construction and arrangement of which allows an individual to release a therapeutic concentration of lobelin at a controlled rate over a sustained period of at least one day; and an instruction manual that provides the user with information on using the release system to treat nicotine addiction. 38. The kit of claim 37 wherein the system is a transdermal patch modulated by physical restraint. 39. The kit of claim 38, wherein the kit comprises a sufficient number of patches to deliver the lobelin to the subject for at least one week. 40. The kit of claim 38, wherein the physical restriction modulated system releases about 56 to about 114 mg of lobelin over a period of seven days. 41. The kit of claim 38, wherein the patches are overnight patches. 42. The kit of claim 38, wherein the patches are seven-day patches. 43. The kit of claim 42, wherein the kit comprises a sufficient number of patches for a four-week smoking cessation program. 44. The kit of claim 38, wherein the transdermal patch has a first and a second compartment, wherein the first compartment comprises lobelin, the second compartment a vehicle, and its construction and design allows the transdermal patch to form a it is not released in a therapeutically significant amount until it is contacted with the vehicle. 45. The kit of claim 44, wherein the kit comprises a sufficient number of transdermal patches to provide a therapeutic level of lobelin over a long period of time in an individual. 46. The kit of claim 45, wherein the first compartment contains a sufficient amount of lobelin to release the therapeutic amount of lobelin for at least one day. 47. The kit of claim 45, wherein the first compartment contains a sufficient amount of lobelin to release about 56 to about 114 mg of lobelin for about 7 days. 48. The kit of claim 46, wherein the kit comprises at least 21 overnight transdermal patches for a three-week smoking cessation program. 49. The kit of claim 37, wherein the physical constrained modulated system comprises a biodegradable polymer for subcutaneous or intramuscular injection or implantation. 50. The kit of claim 49, wherein the biodegradable polymer is in the form of microparticles. 51. The kit of claim 49, wherein the biodegradable polymer comprises polylactic acid / glycolic acid copolymers, polylactic acid, polyglycolic acid, polyesters, polyorthoesters, polylactones, polyanhydrides and polyamino acids. 52. The kit of claim 51, wherein said biodegradable polymer is a poly (lactic acid / glycolic acid) polymer. 53. The kit of claim 52, wherein the polylactic acid / glycolic acid polymer has a lactide / glycolide ratio of about 50:50 to about 85:15. 54. The kit of claim 52, wherein the biodegradable polymer is a pharmaceutically acceptable injection vehicle. ΑΊ 55. The kit of claim 54, wherein the pharmaceutically acceptable injection vehicle is a carboxymethylcellulose solution. 56. The kit of claim 46, further comprising a diluent for re-suspending the system of physically restricted modulation of lobelin. The agent shall: DANUBIA gzaBaúatm ^ s Trademark Office Ltd.