JPH06507416A - Controlled sustained release delivery system for smoking cessation - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] A kit useful for the treatment of nicotine dependence.

38. Kit 39 of claim 37, wherein the physically forced modulation system is a transdermal patch. The kit contains a sufficient number of patches to transmit human heloberin for at least one week. 39. The kit of claim 38, comprising:

40 Physically forced modulation system for about 56 to about 114 mg over a 7-day period 39. The kit of claim 38, wherein the kit conveys lobeline.

41. The kit of claim 38, wherein the patch is a daily batch.

42. The kit of claim 38, wherein the patch is a 7-day patch.

43. A claim that the kit contains approximately a sufficient number of patches for a four-week smoking cessation program. Item 42 kit.

44, the transdermal patch has a first chamber and a second chamber, the first chamber containing lobeline. and the second chamber holds a transmitting substance, and the device is in contact with the transmitting substance. Constructed to prevent transfer of lobeline from the transdermal patch in a therapeutically sufficient amount until touch. 39. The kit of claim 38, wherein the kit is prepared by:

45. The kit is a transdermal patch that allows long-term therapeutic levels of lobeline to be delivered to humans. 45. The kit of claim 44, comprising a sufficient number of.

46. The first chamber is sufficient to deliver a therapeutic amount of lobeline for a period of at least one day. 46. The kit of claim 45, comprising an amount of lobeline.

47 The first chamber delivers about 56 to about 114 mg of lobeline over a period of about 7 days. 46. The kit of claim 45, comprising an amount of lobeline sufficient to reach the target.

48. The kit contains a transdermal package for at least 211 days useful in a three-week smoking cessation program. 47. The kit of claim 46, comprising:

49. Organisms in which a physically forced modulation system is injected subcutaneously or intramuscularly or is implanted. 38. The kit of claim 37, wherein the kit is a degradable polymer.

50. The kit of claim 49, wherein the biodegradable polymer is in the form of microparticles.

51. Biodegradable polymers include poly(lactic acid/glycolic acid) copolymer, polyacetic acid acid, polyglycolic acid, polyester, polyorthoester, polylactone, polyester 50. The kit of claim 49, wherein the kit is selected from the group consisting of linanhydrides and polyamino acids.

52, wherein the biodegradable polymer is a poly(lactic acid/glycolic acid) polymer; The drug delivery system according to claim 51.

53, the poly(lactic acid/glycolic acid) polymer is about 50:50 to about 85:1 53. The drug delivery system of claim 52, which is 5-lactide/glycolide.

54, the biodegradable polymer is supported in a pharmaceutically acceptable injection vehicle; 53. The method of claim 52, wherein the method is in the form of microparticles.

55, wherein the pharmaceutically acceptable injection vehicle is made of carboxymethylcellulose. 55. The method of claim 54, wherein the method is a solution.

56, and a diluent for resuspending the lobeline-containing physically forced modulation system. 50. The kit of claim 49, comprising:

Specification Applications related to controlled sustained release delivery system for smoking cessation This application is filed under related application number 07/696.6 filed on May 7, 1991. This is a continuation-in-part of No. 37 (Controlled sustained release delivery system for smoking cessation). Ru.

field of invention Embodiments of the invention provide a controlled and sustained lobeline treatment for the treatment of nicotine dependence. It is characterized by a drug delivery system that delivers

background Recent studies have linked smoking to both heart disease and cancer. Smoking can also cause pregnancy It may also have an adverse effect on the fetus during pregnancy. For this reason, humans try to stop smoking. I tend to want it. Nicotine, a component of tobacco, is an addictive drug (“nicotine”). It is difficult for people to stop smoking because it is difficult for people to stop smoking. .

Currently available over-the-counter products to help people quit smoking are not always successful.

Lobelin is the lobelia plant (Lcbelia inflata Lcbelia 1n) It is an alkaloid obtained from the dry leaves and young shoots of A. flatata. roberi Piperidine is a substituted piperidine compound that has several physiological effects, some of which It is similar to that made with nicotine. cause these physiological effects The potency of lobeline is significantly lower than that of nicotine. Lobeline medicine with nicotine Due to physical similarities, humans become less addicted to nicotine and stop smoking It has been considered a helpful nicotine substitute. at least 1930 The use of lobeline to help quit smoking has been studied since the 1900s; was under dispute. Moreover, serious undesirable side effects have been reported.

Products currently available and sold in stores include Nikoban ■, Bant Bantron, CigArrest” and Nic Nic-Fit is recommended by Roberin as an aid to smoking cessation. I'm proposing fete. These products are to be taken orally and the recommended daily use The amount is up to 5+eg. Antamide has been mixed into some products to increase nicotine. It overcomes gastrointestinal discomfort, the same side effect that occurs when higher oral dosage The dose will not work due to the gastrointestinal upset associated with this. help stop smoking The effectiveness of oral administration of lobeline at 6 mg/day has not been proven.

Currently Available Over-the-Counter Lobeline Preparations to Treat Smoking Cessation Yes Neither deviation appears to result in therapeutic blood or tissue levels of lobeline nor is unlikely to be maintained. This may be due to the low dose of Lobeline in the Lobeline formulation or the Poor absorption of oral preparations or metabolism that prevents lobeline from reaching clinically therapeutic levels Will.

The use of lobeline in oral formulations at an excess dose of 10 mg/day has been reported. However, such doses can cause nausea and even vomiting. Oral administration such as Another problem with dosage resins is that they require self-administration of as many as 18 tablets per day. .

This may not only be considered excessive for a connoisseur; I can't make adjustments.

Kalyuzhnyy (J, of Neural Psych hiat 68: 1864-1870 (1968)) is one syringe or one Note that lobeline hemi-sulfate is administered intramuscularly up to 0 mg twice daily. It is listed. The amount of lobeline administered by Karyuznyi was reported to be effective. However, since this requires twice-daily injections of Lobeline, the method of administration is is of no practical use.

Takagi et al. described a smoking substitute adhesive containing 0.5 to 10% by weight. ing. Takagi et al. demonstrated that lobeline blood concentrations were delivered using the same adhesive delivery system. reported that blood levels of nicotine remained higher for several hours compared to ing. Takagi et al. did not report the amount of mortarverine released from the adhesive.

Outline of the invention The present invention provides a delivery system for releasing regulated amounts of lobeline. may help you stop smoking or chewing nicotine-containing products. This provides an advantageous drug delivery system for helping humans. this transmission The system eliminates the need for twice-daily injections or multiple daily doses of Lobeline. and can provide lobeline at therapeutic levels for extended periods of time.

The drug delivery system is a physically forced modulation system (hereinafter PCM5) containing lobeline. ). This is a controlled and sustained release method of lobeline treatment for individuals. It is intended and arranged to be communicated on a level. method like this You can transmit lobeline by smoking or chewing nicotine-containing products. suppress or eliminate a person's desire for

PCM5 contains biodegradable polymers suitable for subcutaneous or intramuscular injection in humans or may be part of a transdermal patch applied to human skin. Utilize biodegradable polymers In PCM5, the delivery system is preferably in the form of particulates, which can be injected subcutaneously. and suspended in a pharmaceutically acceptable vehicle immediately prior to injection or intramuscular injection.

PCMs that utilize transdermal patches are, for example, diffuse layer matrices containing lobeline. lix may be used, or the first chamber may contain lobeline and be transferred to the second chamber. It may be a multi-chambered patch containing the substance. Lobelin is the first chamber when it comes into contact with a transmitter. It is released from Transdermal patches with a diffusion layer are typically replaced every seven days; Multilocular transdermal patches are then typically changed daily.

The present invention also provides methods for treating humans for nicotine dependence, i.e., using nicotine-containing products. It also relates to how to stop sucking or chewing items. The method is drug delivery to humans in a controlled, sustained release that provides long-term therapeutic levels of drug to humans. This includes administering the drug. The method preferably uses the above-mentioned delivery system. It will be done. Lobelin can be administered to humans for an easily completed period in a behavior modification assistance program. can be given.

The invention also relates to kits useful for treating nicotine dependence. For example, this key It is important to stop smoking or chewing nicotine-containing products. It is useful to help humans. The kit can be used to vape nicotine-containing products or Users considering using the system to help stop chewing and/or along with a guide to provide information to health care professionals. The type of sustained release system described here that is capable of delivering long-term therapeutic levels of Including tem. Preferred kits contain therapeutic levels of lobeline for at least three weeks. Includes a delivery system capable of providing controlled sustained release.

The purpose of the present invention is to provide regulated therapeutic levels to proactively provide long-term therapeutic levels to humans. The object of the present invention is to provide a sustained release delivery system.

Another object of the invention is to reduce the habit of smoking or chewing tobacco in humans. Transmission capable of transmitting human heloberin in a manner that increases or eliminates The goal is to provide a system.

Yet another object of the invention is to avoid passing the drug through the gastrointestinal (Gl) tract and thus A drug delivery system that can deliver lobeline to humans with minimal Gl side effects The aim is to provide

Yet another object of the present invention is to behavior change assistance programs designed to help people give up smoking. Provides a drug delivery system for delivering lobeline in simply bulk doses Is Rukoto.

Yet another object of the invention is a self-administerable method for delivering lobeline in therapeutically effective amounts. The objective of the present invention is to provide a drug delivery system that is capable of providing effective drug delivery.

Furthermore, another object of the present invention is that the treatment of lobeline does not require multiple daily administrations. The aim is to provide a high level of medical care.

Brief description of the drawing Figures IA, IB and IC show lobeline-containing microparticles, microcapsules and and represents an elongated rod.

FIG. 2 depicts a transdermal patch with a diffusion layer matrix.

Figure 3 depicts a multilocular transdermal patch.

Figure 4 depicts a kit containing four packaged transdermal patches along with instructions.

Figure 5 depicts a kit containing 28 packaged multilocular transdermal patches along with instructions. vinegar.

Figure 6 shows a pharmaceutically acceptable syringe containing microparticles of lobeline-containing biodegradable polymer. Represents a kit containing a retrieval vehicle and instructions.

Figure 7 shows that lobeline-free base material was prepared from PLGA microparticles (150-180μ) for 30 %.

Represents in vitro release at 40% and 50% lobeline loading.

Figure 8 shows the lobeline from PLGA microparticles (38-106μ) with 30% lobeline loading. Represents in vitro release without base.

Figure 9 depicts the in vivo release of lobeline-free bases, with 30% lobeline-free bases. and from formulations containing 40% lobeline-free base. It is expressed as a percentage of lobeline.

Figure 10 represents the in vivo effect of lobeline dose on number of cigarettes smoked.

Figure 11 depicts the in vivo effect of lobeline dosage on number of puffs. .

Figure 12 shows the distribution of lobeline-free base from PLGA microparticles at 35% lobeline loading. Represents in vivo release.

Figure 13 shows the number of cigarettes smoked by participants following subcutaneous injection of PCM5. Figure 2 represents the in vivo effects of lobeline-containing PCM5 formulations.

detailed description The present invention relates to a method for treating humans with nicotine dependence. This method including administering therapeutic levels of lobeline over a period of one day.

This method is particularly effective in combination with a smoking cessation program. A program like this Therapies to treat physical dependence in humans smoked nicotine-containing products behavior modification cows that allow humans to reduce their mental indulgence in chewing or biting. combined with nusering.

The preferred method of the invention is easily completed using a smoking cessation behavior change aid program. These programs, which include dosing resins to teaching people how to give up or reduce their use of nicotine-containing products It is designed as follows. Typically, these programs are scheduled on a regular schedule. This may mean meeting regularly with your caran seller, e.g. every week or every two weeks. include.

The term “period of time easily completed in a smoking cessation behavior change assistance program” refers to For example, - regularly scheduled weekly or bi-weekly meetings with the caran seller; It is intended to include matching time periods. For example, the delivery system - weekly subcutaneous or intramuscular injection to maintain therapeutic levels of lobeline in the human circulatory system. Can be planned as required. - Weekly injections with behavior change aid Easily coordinate weekly appointments with Calan Seller from Gram. Preferably, note The shots are administered by a medical professional or carancer. In humans, injections and Make a one-week appointment to get both the necessary behavioral change assistance and counseling. There will be.

The invention also prevents humans from smoking or chewing nicotine-containing products. drug delivery systems that are advantageous in assisting in the treatment of cancer. The transmission system is Robeline including a Physically Forced Modulation System (PCMS). This system has at least Therapeutic levels of human heloberin are delivered in a controlled, sustained-release manner over the course of a day. is constructed and arranged to transmit the information. Typically, the transmission system The physically forced modulation system delivers lobeline to the circulatory system subcutaneously, intramuscularly, or transcutaneously. constructed and arranged to do so.

Drug delivery system used to provide long-term therapeutic levels of human heloberin It will be done. Delivering lobeline in this way may reduce smoking or chewing habits in humans. disappear or disappear.

The term human refers to humans who are suffering from nicotine dependence (i.e. humans). relates to humans who smoke or chew nicotine-containing products. Contains nicotine The product is any product that contains nicotine, such as cigarettes, vibrator cigarettes, or and chewing tobacco.

The term PCM5 includes substances or ingredients, e.g. in a sustained release manner. It is a solid, liquid, gel or layer capable of releasing lobeline. The present invention Examples of PCM5 that can be used in biodegradable polymers and as part of transdermal batches are be.

The term lobeline refers to 2-[6-(B-hydroxyphenethyl)-1- It contains methyl-2-piperidylco-acedobuenone. Robelyn is playing It may be in the form of a free base or as a water-soluble salt, such as a hydrochloride or sulfate or a It may also be in the form of water-soluble salts, such as palmoate.

(In the formula, X represents an anion.) The term lobeline also refers to structural compounds of the above compounds that occupy the same or similar functional characteristics. It also includes individual items. Structural equivalents are compounds that are structurally similar to the above compounds. The core structure may have one or more substituents. For example, replace This group adversely affects the compound's ability to act as a substitute for nicotine. Unless otherwise specified, it may be located anywhere on the benzene ring. As an example of a substituent are lower alkyl groups such as methyl, ethyl, and propyl groups. another Examples include lower alkyl groups in which the methyl group of the piperidyl nitrogen atom is different, such as It may also be substituted with ethyl or propyl groups.

The term "controlled sustained release" means that a portion of lobeline is released into the PCM5 at a given time. during which the remaining lobeline was retained in PCM5 and for an extended period of time. The method involves the delivery of lobeline in a manner that releases it gradually across the body.

The extended time is for at least one day (24 hours), but about 30 days. Alternatively, it may be for a long period of time, such as up to 90 days.

Long-term therapeutic levels of the term lobeline are defined as Significantly reduce a person's habit of sucking or chewing cotin-containing products or Contains levels of lobeline sufficient to eliminate it. This therapeutic level Examples include about 5 to about 30 mg per day, preferably over a period of about 1 to about 30 days. from about 10 to less (both average about 12 mg) per day. Based on the free base form of lobeline. This dose of about 5 to about 30 mg of lobeline is The amount of lobeline released from PCM5, and the amount of lobeline detected in the human circulatory system. It's not about the amount of.

The drug delivery system PCM5 may be in a form suitable for subcutaneous or intramuscular injection, such as in combination with biodegradable polymers. What is the term biodegradable polymer? Dissolved in vivo in a controlled sustained release manner to provide long-term therapeutic levels of Contains a polymer capable of degrading and transmitting lobelin. Polymers in vivo The substances used in the present invention are selected so as not to cause significant adverse effects on humans when administered. Examples of biodegradable polymers that can be used include, for example, poly(lactic acid/glycol) acid) copolymer (PLGA), polylactic acid (PLA), polyglycolic acid (P GA), polyesters such as polyorthoesters, polylactones, polyanhydrides Contains polyamino acids. A preferred biodegradable polymer is PLGA.

Polymers made from glycolide and lactide dimers are implanted into tissues It is known to be slowly hydrolyzed, and is a by-product of cholera hydrolysis ( Both lactic acid and glycolic acid) are normal metabolites. PLGASPLA and and PGA are believed to be non-toxic, relatively non-inflammatory, and non-inflammatory. - Tissue reactive. Polymers also have moderate strength and tensile strength, compressibility and and flexibility. Hereinafter, the term PLGA includes PLA, PGA and PLGA. used as such.

The specific ratio of lactide/glycolide of the PLGA polymer and the molecular weight of the polymer are: These are factors to consider when planning a drug delivery system. lactic acid and glycol Differences in acid hydrophobicity and crystallinity, and rapid final clearing of lobeline Rapidly hydrolyzing polymers (low molecular weight, low lactide content) for slow hydrolyzing Relatively soluble resulting from water-splitting polymers (high molecular weight, high lactide content) Balanced with sex for sustained release of sex lobeline. Based on these needs, Preferred polymers for lobeline delivery are from about 50:50 lactide/glycolide to about 8 The range is 5:15 lactide/glycolide. Preferred polymers also have molecular weight In the range of about 50.000 to about 150.000 Daltons, preferably about 100.00 It has 0 daltons.

Lobeline is present in an amount that provides sustained release of Lobeline from the polymer at the desired therapeutic level. It is blended into polymers. Lactide/glycolide content approx. 85:15 and min Preferred incorporation of lobeline into PLGA polymer with molecular weight of about 100,000 Daltons The amount is about 20 to about 65% by weight, based on the weight of the polymer, more preferably about 30-50% by weight, most preferably about 30-40% by weight.

The formulation of lobeline with a biodegradable polymer indicates that it is capable of subcutaneous or intramuscular deposition. It should be ensured that the These include injectable formulations such as polymer/lobelin compositions. Contains fine particles, microcapsules or elongated rods of matter.

Figures LA-IC represent microparticles, microcapsules, and elongated rods, respectively.

Lobeline is incorporated into the biodegradable polymer 2 as shown in Figures IA and IC. There are 1. Alternatively, Lobelin 1 is a biodegradable polymer as shown in Figure 2. It may be enclosed within.

Biodegradable polymer microparticles, microcapsules and elongated rods can be used subcutaneously. or intramuscularly injected or implanted while providing controlled sustained release It is large enough to release phosphorus. An example of the size of fine particles is approximately 3 It ranges from 8 to about 250 microns, most preferably from about 38 to about 106 microns. microca Example pcell sizes range from about 10 to about 250 microns. The size of the extended rod Examples of sizes range from about 1 to 4 meters in diameter and from about 0.5 to about 3 CIl in length. .

A preferred form of biodegradable polymer is microcapsules. microcapsule is preferably suspended in a pharmaceutically acceptable vehicle immediately prior to injection. drug approval The acceptable vehicle is one that forms a suspension with the particulates and allows transport of the particulates. and the ability of lobeline to replace nicotine when administered in vivo. selected so as not to have a significant negative impact on power.

Examples of pharmaceutically acceptable vehicles useful for lobeline delivery include, for example: Contains a solution made by sea urchin: Compounding agent No. 1-0.38g carboxymethyl cell Loin, 3, 75g Mannitol, 0.08g Tween 80 Distilled water 20a +l; Compounding agent No. 2 (preferred) -0,0127g carboxymethyl sesame Lulose, O, 056g Mannitol, 0, 027g Tween 80 Distilled water In 20m1. Using a microparticle-containing syringe, add a pharmaceutically acceptable vehicle to create a suspension. You can also suck out Kuru. Of course, other methods of making suspensions may also be used. stomach. A suspension is created outside the syringe and then drawn into the syringe. Then the suspension , using behavior change assistance programs such as smoking cessation programs, preferably briefly. It can be injected into humans only for a period of time to be completed.

For lobeline-containing microparticles, the microparticles have a sufficient amount of lobelin to remove the lobeline from the vehicle. cannot be suspended in the vehicle for an extended period of time because it will be released into That should be understood. Preferably, the suspension is approximately 1 Injected within hours.

microparticles (or another form in which the amount of drug released will gradually decrease over time) specific means of administration may be desirable. For example, at least 1 If 5 mg/day is the desired level of sustained release, the microparticle dosage should be It will be made to deliver 20 mg/day per month and up to 14 mg per 8 days per month. straight As will be appreciated, the second dose is a continuation of the residual particulates of the first dose. to achieve a level of 15a+g/day for the next 7 days for lobeline release It may be necessary to lower the first dose. In other words, a specific PCM5 legend delivery system may be required for different dosing regimens.

However, this tapering of the next dose concentration is not recommended for lobeline. is not necessary, it is non-addictive and is immediately cleared from the circulatory system. is believed. This rapid elimination is directed to nicotine receptors located in the brain. This seems to be due to the binding of lobeline. That is, lobeline is removed directly from the circulatory system. Although immediately removed, it will remain in the brain for a substantially longer period of time.

PCM5 is also part of a transdermal batch. Transdermal patches do not involve the gastrointestinal tract , easy to control and long-lasting action, self-administration and immediate discontinuation. has advantages. The term transdermal patch refers to a patch that can be applied to human skin and patch having a portion or component that transmits lobeline in a sustained release manner. . Examples of the types of patches that can be used in the present invention include diffusion layer matrices and/or has a multilocular patch. These are described in detail below.

There are many transdermal patches that are well known to those skilled in the art and well described in the prior art. There is a chi. A schematic of one patch useful in the present invention is shown in FIG. The patch in Figure 2 is The framework holds the viscoelastic lobeline-polymer mixture and is made of reticulated porous polymer. Includes a diffusive matrix layer using foam. Although Patch IO adheres to the skin, A suitable 4-layer laminated composite material. The outermost layer lined with layer 12 is the device serves as the main structural element of the Acts as a protective cover to prevent Backing layer 12 preferably has a thickness of about 10 Made from ~75μ thick elastic elastomer sheet or film. like this Examples of elastomers are polyether block amide copolymers, polyethylene Methacrylate block copolymer, polyurethane, silicone elastomer, etc. It is.

The lobeline-containing matrix layer 14 includes lobeline reservoirs, reinforcements and optionally Acts as a pressure sensitive adhesive. The framework of the matrix is a reticulated porous polymeric foam 1 It is 6. Preferably, the framework is almost completely open (90% or more). It is.

The porosity of reticulated foams is typically about 10 to 40 pores per linear cm. , the density (unfilled) is generally about 0. It is in the range of O1 to 0.57 cm3. this Such foams are polyurethane and polyethylene.

A pressure sensitive adhesive layer 18 covers the exposed surface of the matrix layer 14 and a release layer 20 covers the exposed surface of the matrix layer 14. Coat with pressure sensitive agent. The pressure sensitive adhesive layer 14 is a medical adhesive typically having a thickness of about 25 to 100 μm. It is a drug composition. An example of such an adhesive is polydimethylsiloxane (Dow Co. 355 medical grade adhesive).

The pores of the foam are made entirely or partially of a viscoelastic hydrophobic lobeline permeable polymer and Filled with tougheners. Polymer acts as a carrier for lobeline However, the enhancer may affect the solubility of lobeline in the polymer and/or the absorption of the drug into the skin. It acts to regulate. Hydrophobic polymers make the device water resistant and from being absorbed into the device, thereby increasing its functionality and abrasion resistance.

Examples of such polymers include polysiloxane (silicone polymer), Water-based polyacrylate, polyurethane, plasticized ethylene-vinyl acetate copolymer etc. An example of a useful toughening agent is ＾zoneTM. Robelyn The mixture optionally includes an anti-pruritic agent.

A device of the above nature is disclosed in U.S. Patent No. 4.911.9 filed on March 27, 1990. No. 16 (named “Diffusion matrices for transdermal drug administration and transdermal drugs containing the same”) The entire description is included here for reference. Ru. Such a patch will release about 5 to about 30 II 1 g of Lobeline for 7 days. It will be formulated to contain a sufficient amount of lobeline. Preferably this These patches should be worn for about seven days, so that one patch can be worn for a week. Formed to retain enough lobeline to release from 5 to about 30 mg/day .

Optimal dosage range, i.e. Lobeline exhibits maximum therapeutic efficacy and minimum adverse side effects Dosage ranges are determined empirically. Patch or pond transmission system Lobelin has enough lobeline to release the dose within the optimal dosing range for the desired period of time. Shaped and formulated to contain.

A schematic diagram of another patch useful in the present invention is shown in FIG. The patch in Figure 3 contains at least two It is a four-layer composite material that defines two separate chambers. One chamber contains Robeline, the other The chamber is a transmitter that lobeline can transmit transdermally when mixed with lobeline. including.

The patch 22 has two chambers, a lobeline-containing chamber 28 and a transmitter-containing chamber 30. It has a backing material 24 sealed to the speed regulating membrane 26 to create a speed control membrane 26. The adhesive layer 32 is , the rate controlling membrane, and the release sheet 34 covers the adhesive layer.

To form the device, a 75μ thick silanized polyester (or release agent) (other suitable materials treated with) are used as the release sheet 34. The adhesive layer 32 It is cast onto a release sheet, which may be, for example, polyisobutylene.

The adhesive layer is then laminated to the rate control membrane 26, which is approximately 100 microns thick. ethylene-acetic acid Vinyl may also be used as a control membrane.

Next, the materials that will become the contents of the lobeline containing chamber 28 and the transmitter chamber 30 are speed controlled. Placed in separate areas on the segmental membrane (the material for the lobelin-containing chamber 28 is alcoholic or or an aqueous/alcoholic solution.

Finally, a suitable backing material 24 having a heat-sealable coating on one surface is applied to the chamber. Place it on the two areas that should be 28 and 30 and along the perimeter of the device. and heat seal 36 between the two areas forming the two chambers 28 and 30. two The heat seal 38 between the two chambers is less reliable than the surrounding heat seal 36. Therefore, the seals between the chambers can be selectively ruptured under pressure applied by the user. It will be.

In this way, pressure is applied to one of the chambers to break the seal between the chambers; This will mix the solution and lobeline and dissolve the lobeline. Then Robeline used It passes through a rate regulating membrane 26 for transmission to the person's skin. Figure 2] Like Kutsuchi, the chamber contains enhancers that affect the absorption of lobeline through the skin. It's okay to stay.

A preferred form of the patch described below is disclosed in U.S. Pat. No. 4.91, filed April 17, 1990. 7.676 (titled “User Activated Transdermal Therapy System”). , the full disclosure of which is incorporated herein by reference. Such a patch is about Lobelin It should contain enough lobeline to release 5-3 kg/day; This patch is suitable for personal daily batching.

The present invention also relates to kits useful for assisting humans in quitting smoking. The kit is a book Contains a PCM5 transmission system according to the invention as well as instructions for use. parable For example, a kit for treating nicotine dependence may include at least one drug containing lobeline. The user and/or contains guidance documents providing information for health care professionals. Transdermal treatment provided in the kit The number of patches depends on the type of transdermal patch and the smoking cessation program for which the kit is planned; For example, following a 3-week or 4-week smoking cessation program. In general, treatment Courses are 4 to 8 weeks long, with 6 to 8 week programs being typical.

Transdermal patches containing lobeline in the diffusion layer matrix are generally used for long-term, e.g. Days are planned. That is, the kit for the 4-week smoking cessation program is It includes four packaged transdermal batches 30 as shown in FIG. Manual 32 is and/or health care workers and provide weekly patches. and For example, Day 1 - Batch No. 1, Day 8 - Patch No. 2, etc.

Multilocular transdermal patches are generally designed for daily use. 3 weeks or 4 The kit for implementing the weekly smoking cessation program is as shown in Figure 5. Each includes 21 or 28 multilocular transdermal patches 30. Handbook 32 is for humans and/or health care provider with information to change the transdermal patch daily. Also, how do we bring the transmitter in the second chamber into contact with the first lobelin in humans? I will teach you what to say. For example, a person must break pressure-sensitive seals between two chambers. No.

The kit also includes an injectable or implantable PCM5 delivery system as shown in Figure 6. It includes at least one container 34 of stems and instructions for use. parable For example, the kit contains polymer/lobelin microparticles for use in smoking cessation for 4-6 weeks. Contains containers for 4 to 8 weeks. As discussed above, each container contains each initial dose microparticles/lobeline to explain the continuous release of lobeline from the microparticles remaining from the It is necessary to include different amounts of Alternatively, each container is with instructions to inject a reduced amount of microparticle/lobelin resuspension per day. may contain the same amount of microparticles/lobelin.

However, as mentioned above, lobeline is non-addictive and rapidly cleared from the circulatory system. therefore, it may be necessary to reduce the dose level of lobeline during the treatment program. There's no need.

The kit further includes at least one container of a pharmaceutically acceptable vehicle. It's okay to stay. A syringe 38 is also provided in the kit. The syringe is pre-filled with microparticles. It's okay.

The present invention will be explained in more detail with reference to the following examples, but the present invention is not limited thereto. It's not a thing.

Example 1 - Preparation of PLGA microparticles containing 30% lobeline from Boehringer Ingelheim or from Boehringer Ingelheim. It was made from lobeline sulfate. Compounds were analyzed by UV spectroscopy, HP Characterized by LC and melting point. MEDISORB T I″8515 D L lactide/glycolide biodegradable polymer contains 85±5% glycol It is licolic acid. The solvent (highest grade available) was Fischer Sci. Obtained from NTIFIC. Polymer (3,5004g), 15% by weight and dissolved in methylene chloride (23a+1). Pouring Lobelin (1,5006g) Added to the reamer solution and stirred the solution to complete the mixture. Pour the solution onto a glass plate. Then, cast onto a horizontal piece and cast it onto a horizontal piece. ley), applied with a conditioning blade. After evaporating most of the solvent under a nitrogen stream, remove the The lum was peeled off from the glass and placed in a vacuum desiccator.

Films formed during the casting process are difficult to remove because the solvent removal process leaves a very large porosity. and had a very low density. The porosity is reduced by a compression process using heat and hydraulic pressure. reduced by reducing the passage of liquid into the particles. The film was heated to about 70°C in Pasadena. dena) extruded into rods using fluid pressure.

The extruded rods are crushed into small particles using a commercially available crusher equipped with a cooled crushing chamber. Shattered. Following milling, the powder or small particles are passed through a USP sieve, approximately 38- Microparticles in the range of 106μ, 106-150μ, and 150-180μ were collected. 30 Microparticles containing lobeline were collected.

Example 2 - Preparation of PLGA microparticles containing 40% lobeline Polymer solution (1,501 g, in 10 m1) and 1.0000 g of Niloherin were placed in the jar (other than the actual Example 1 was repeated. Gold particles containing 40% lobeline were formed and collected.

Example 3 - Preparation of PLGA microparticles containing 50% lobeline Polymer solution (2,001 6g (in 13ml) and 2.0016g of lobelin in a jar. Example 1 was repeated. Gold particles containing 50% lobeline were formed and collected.

Example 4 - In vitro release of lobeline from PLGA Prepared in Examples 1.2 and 3 The manufactured PLGA/Lobeline microparticles were made with drug content in the buffer solution that never exceeded 20%. exposed to phosphate buffered saline under simulated sink conditions. Cylindrical particles This was then placed in a test tube. - Transfer the cylinder to a new tube every day; Lobeline content in PBS solution was extracted and concentrated in organic solvent followed by UV It was determined by analysis. The first two analyzes of the buffer for lobeline content Daily for ~3 days and then on a weekly schedule thereafter. The results are shown in Figure 7. . Figure 7 shows PLGA microparticles (15 0-180μ) represents the release of lobeline free base from T.

None of the systems released complete lobeline content within one week.

The 30% loading showed the slowest release. At 30% filling, 150-180 For μ microparticles, only 60% of lobeline was released at the end of the second week. Ta.

Example 5 - In vitro release of lobeline from PLGA Analytical method for this example The method is to measure the amount of lobeline remaining in the microparticles after leaching the microparticles in the PSS solution. This is different from the fifth embodiment described above. To obtain the released amount of the entire amount remaining in the fine particles subtracted from the amount originally loaded into the microparticles.

Using microparticles with a size of 3g-106μ made as described in Example 1 And the particles themselves are the tools. Place the microparticles into the extraction cylinder and use the glass wool stopper. coated with. Suspend the cylinder in a phosphate buffered saline solution containing 1% sodium azide. Cloudy (9 cylinders/1.7i). Remove samples daily, air dry, then vacuum dry did. Transfer each dry cylinder to a large test tube and add enough CH2Cl2 to remove the cylinder. covered. Vortex was applied to aid particle dissolution. of the measured amount into the container. 0.01 NHz SO4 was added. After mixing, remove the acidic layer and repeat the process 2-3 times. did. The acidic fraction was analyzed by UV for lobeline content. discovered The total amount of lobeline released from the microparticles was subtracted from the initial value to obtain the amount of lobeline released from the microparticles.

The results are shown in FIG. Figure 8 shows PLGA microparticles (38-1 06μ) represents the release of lobeline free base. The release was over the first 10 days. It remained almost constant and decreased over the last four days.

Example 6 - Release study of two formulations in rats Two formulations were tested. 1 One formulation contained PLGA microparticles with 30% lobeline free base loading; The compound contains PLGA microparticles with 40% lobeline free base loading. Inject 3 0 minutes before 30% formulation 20mg/a+1 or 40% formulation 15fl1g/m A suspension was made in a diluent containing 94 g carboxymethyl in 50 ml of water. Cellulose), 9.38g D-Mayutol 12g Polysorbate 80 (Tu Een 80)).

animal testing Female Spraque-Davley Rat (250 -300g) was used.

Several animals were used as negative controls. Add a 0.1 ml aliquot of vehicle to , into the scapular region of each animal from a syringe fitted with a 22 gauge needle. 7th day Several animals were sacrificed with CO2 and adipose tissue from the scapula region was removed.

The remaining animals were divided into two groups: those receiving the 30% formulation and those receiving the 40% formulation. What you receive. From each group, 4 animals were used as positive control group. these animals The adipose tissue and fascia of the scapula were removed. Before the time of analysis, vehicle A 1 ml aliquot of the formulation was added to the tissue sample.

From each group, another subgroup of five animals was selected and suspended prior to obtaining tissue samples. Represents different periods of time during which the cloudy liquid remains: 4 hours; 1 day; 2 days: 5 days: and 7 days. this There were four animals in each of these subgroups.

The formulations were prepared for the use described above, in each case O, 1 ml aliquots. was gotten. At the time of stratification, the adipose tissue and fascia in the scapular region of each animal were Extracted. In most cases, but not all, particulate-containing tissues parts will not be observed. However, some of the particles may cross the excised area. It appears that this material was therefore not recovered.

tissue extraction Place the tissue sample in a short glass test tube with 2-3 ml of CH2Cl□. . 10 hμl of a 1 mg/a+1 solution of triprolidine in CH, C1° (internal standard ) was added. 4500-8000rp ■Tissue Tearor T1 ’ was used to homogenize the sample. Place the sample in a Teflon liner screw cap. Transfer to a centrifuge tube using a cap and centrifuge for 7 minutes. Cll2CI□ Carefully pipette off and transfer to test tube. To this solution O, OIN HzS04 1.1 was added and the mixture was vortexed for 15-20 seconds. After layer separation has occurred, The upper (acidic) layer was carefully removed with a pipette and the volume of this acidic solution was measured.

The acidic solution is then transferred to a new, clear test tube or vial and adjusted to zero before injection. ．． Filtered through a 45μ nylon filter. Extraction of CHzCb using acid , and repeat until no more lobeline is detected, or up to 5 times. Repeated until.

analysis Acidic samples were analyzed directly by HPLC. The amount of lobeline recovered varies. Lobeline extracted from tissue control samples spiked with various lobeline levels. based on standard curve.

The HPLC system formulated was as follows; ) 510 pump; Waters U6. Syringe, Waters Lambda Max ( Waters Lambda Max) 481 LC spectrophotometer ;SpectraPhysics S P 42 70 inch greater; Phenomenex Particill (Phen.

wenex Partisil) (, 5u 100 x 4.6mm column, 3 0 x 4.61 mm guard column, with the same packaging.

The movable digit was as follows: 60% phosphate buffer, pH 3; :50C[13CN/MeOH). Flow rate is 1.2ml/min, AUF31.0 +Detection 249mn; 4μl sample injection volume.

The results for 30% and 40% loaded microparticles were compared to 75.4% of the resected tissue. Adjustments were made for extract efficiency. There is no evidence regarding the efficiency of collection of particulates from animals. No adjustments were made.

The results (shown in Figure 9) are plotted for tissue samples for different types of treatment periods. Graphed as a percentage of the dose seen in the pull. 30% filling is 40% filling There was a somewhat more linear release curve than the filler.

Example 7 - Polyethylene "pouch" for in vivo release studies in rats evaluation compound The analytical method for this example was to use PLGA microparticles with a 35% lobeline free base loading rate. Example 6 differs from Example 6 above in that one formulation containing children is tested. compound was sealed in a polyethylene bag with 20μ holes and then transferred to the shoulder area of the rat. I planted it. These bags are porous enough to be used for dissolution studies, but It has pores small enough to hold particulates (minimum particulate size is 38μ).

Method using polyethylene pouches (Biochiku, Woburn, MA). Ta. Heat seal 12 pouches without filling, approx. 1cs+ x approx. 1c It was cut into a size of m. Fill the remaining pouches with approximately 4i+g of the above formulation each. and sealed and treated the surrounding area in the same way. 250g female splatter each Kudau lei rats were obtained and isolated. At 0:00, each rat was anesthetized and a pouch was placed on the shoulder area. An incision was made slightly wider than the width of the pouch. Hold the pouch with forceps and immerse it in standard salt solution. Forceps were then used to slide the hebouch under the skin. Cut with 1 or 2 stable needles I closed my mouth.

On days 1, 2, 3, and 7, the pouches were administered to six control animals (empty pouches) and and from six animals (at each time point) that received the formulation. This take The method of removal is to anesthetize the animal and make an L-shaped incision around the pouch. Met. The pouch was exposed by lifting the skin. Standard salt for each pouch Rinse with solution and pat dry with paper towel. polyethylene pouch The samples were stored in a plastic bag in the refrigerator overnight and analyzed the next day. Pouch all animals After making the broth, the animals were immediately slaughtered.

Sample preparation for HPLC analysis Cut open each pouch, empty its contents, and remove the chopped pouch with acetonate. Toryl was added to a 10ml flask containing approximately 5ml. flask for 10 minutes Sonicate and cool to room temperature for approximately 30 minutes) and remove all contents in flask. Add acetonitrile to the volume to 10 ml (i.e., up to the entire volume) and use the “Stock Solution”. After that, add 0.IQll of stock solution to exactly 10ml volumetric flask. and filled the volume with hydraulic fluid (described below). Then 2.5+ of this solution One aliquot was transferred to another 10 ml volumetric flask and the volume was filled with working fluid. .

HPLC analysis Acidic samples were immediately analyzed by HPLC. Amount of lobeline released from each pouch is based on a standard curve of lobeline concentration/internal standard concentration at various lobeline levels. Ta. HPLC analysis was performed as described above with the following modifications.

Accurately weigh the internal standard preparation nitriprolidine (10.0 mg) and make 10ω1 volume. Quantitatively transfer to a volumetric flask (type A), fill the volume with a movable girder, and add the triprolidine concentration. An internal standard stock solution with 1,0 mg/ml was obtained. Using this storage solution Use diluent made.

Diluent used: Internal standard stock solution 1111 to 1001 using a type A volumetric pipette 111 volumetric flask and filled to volume with a movable spar (described below). after that, Transfer the latter solution accurately to a second 100 ml volumetric flask (using a type A volumetric pipette). , fill the entire volume with a movable girder and make the diluent used. The diluent used is triprolidine. The concentration was 500 ng/ml.

Standard preparation: Accurately weigh Lobelin control standard solution (10.0 mg) and prepare 1QmlA. Quantitatively transfer to a volumetric flask and fill the volume with a movable girder until the lobeline concentration is 1. Q A lobeline stock solution with mg/ml was obtained. Using a type A volumetric pipette, Accurately transfer 1 ml of the phosphorus stock solution to a 1 ml volumetric flask and make up the volume with the diluent used. A filled standard lobeline solution was made. Standard lobeline solution has a lobeline concentration of 0.01m g/ml.

Degas the solution in all parts of the movable girder and filter it through a 0.2μ membrane filter. was used. The movable girder is 200μm triethylamine 62% 40+oli phosphorus Addition to mixture II containing the acid salt (pH 3°00) and 38% acetonitrile. Made by.

Operating conditions, column: Phenomene/P artisil) 5C8 (25.0 cIIl x 4.6 m in diameter). flow rate 1.0 IIll/min; detection was at 249 nm. A 35 μl injection volume is used.

The results (shown in Figure 12) are shown in Figure 12 for six cases plotted as a function of treatment duration. It is expressed graphically as the average percentage of lobeline released. illustrated Time points represent the average of 6 replicates. - At the end of the test sample, The percent lobeline released from the cage was approximately 95%. The result is fine particles This shows that almost all of the lobeline contained in the analyte is released within 7 days.

Example 8 - Materials and Methods - Efficiency Study Subjects of Lobeline Sulfate in Humans person Subjects consist of long-term or chronic smokers who have been in the habit of smoking for more than 5 years.

They habitually smoke more than 20 cigarettes per day. All participants are healthy and fat. Adults with no known gastrointestinal, hepatic, neurological, or blood abnormalities It was sex. Prior to enrolling in the study, each participant was examined for behavioral health.

Method 1. Drug administration test. 2. On days 3 and 4, 2 Q mg/ml Robelin 0.4, 0.6, 0.8 or 1 part of the Ruphate solution on the ventral side of the forearm. Injected subcutaneously into the 1/3 area. Collaborators are then free to smoke and smoke as they wish. The number of cigarettes smoked and the number of puffs were reported in the 2 hours after the shot.

result Both the number of cigarettes smoked and the number of puffs during the 2 hours after lobeline injection. also decreased as the dose increased. The results are shown in Figures 10 and 11. From Figure 10, To be clear, cigarettes smoked in the 2 hours immediately after treatment with lobeline sulfate The average number decreased approximately linearly as a function of lobeline dose. Similarly, Robeline The average number of puffs during the 2 hours immediately after treatment with sulfate was small (both 12 m Although the initial effects were not observed until doses of It decreased significantly as it increased.

Example 9 - Materials and Methods - Efficiency of lobeline-containing microparticles in humans Study subjects A total of 12 participants (9 subjects and 3 placebo subjects) were employed as described above in Example 8. They were selected according to their characteristics. Two people who smoke 7 and 10 cigarettes per day Other than the strongmen, the remaining participants smoked an average of nearly 20 cigarettes per day.

compound The formulation containing lobeline-containing PLGA microparticles was prepared according to the method described in Example 12. It was manufactured. However, the concentration of lobeline is 35% by weight. adjusted to provide particles. Before injection, the formulation was diluted with a diluent (D-mannitol). (50+++g), sodium carboxymethylcellulose (5mg), polysulfate Resuspend in Rubate 80 (1 mg) and water for injection (11) to create a homogeneous suspension. I made a liquid.

Method On day 1 and/or 2 of the drug administration test, approximately 0° Amounts of 1 to 0.8111 were injected subcutaneously as described in Example 8. The collaborators are They were then free to smoke as they wished and report the number of cigarettes they had smoked over an 8-day period. child These results are shown in Figure 13, where day 1 represents the first full day following the first injection. represent.

result The number of cigarettes smoked in the period following the injection was compared to the number of cigarettes consumed before the injection. It has become less than that. The results are shown in FIG. As is clear from Figure 13, before treatment The number of cigarettes smoked in a 24-hour period compared to the number of cigarettes smoked in a Reported as % of Bako. This % decreases substantially following injection of lobeline suspension did.

equivalent Those skilled in the art will be able to determine, using no more than routine experimentation, the specific embodiments of the invention described herein. You will be able to identify many equivalents.

These and all other equivalents are intended to be included within the scope of the following claims.

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Claims (56)

[Claims] 1. administering at least one physically coercive modulation system to a nicotine-dependent human; , the physically forced modulation system induces human response to nicotine for a period of at least one day. nicotine dependence, which consists of releasing an amount of lobeline effective in reducing the desire for How to treat people with this disease. 2. Additionally, behavior change counseling can be provided as part of a smoking cessation program. 2. The method of claim 1, comprising: 3. 2. The method of claim 1, wherein said time period is for at least one week. 4. 2. The method of claim 1, wherein the physically forced modulation system is a transdermal batch. 5. The physically forced modulation transmission system is administered subcutaneously, intramuscularly or by implantation. 2. The method of claim 1. 6. the physically forced modulation system is a biodegradable polymer; 6. The method of claim 5, wherein the lobeline-releasing polymer is biodegradable. 7. The biodegradable polymer may include poly(lactic acid/glycolic acid) copolymer, poly(lactic acid/glycolic acid) copolymer, Acetic acid, polyglycolic acid, polyester, polyorthoester, polylactone, 8. The method of claim 7, wherein the polyanhydride is selected from the group consisting of polyanhydrides and polyamino acids. 8. The claim that the biodegradable polymer is a poly(lactic acid/glycolic acid) polymer. Method of Section 7. 9. The poly(lactic acid/glycolic acid) polymer is about 50:50 to about 85:15 9. The method of claim 8, which is cutide/glycolide. 10. 7. The method of claim 6, wherein the biodegradable polymer is in particulate form. 11. 11. The method of claim 10, wherein the microparticles are about 38 to about 250 microns in size. 12. the biodegradable polymer is carried in a pharmaceutically acceptable injectable vehicle; 7. The method of claim 6. 13. Claim 1 wherein said injection vehicle is a solution of carboxymethyl cellulose. Method 2. 14. The physically-forced modulation system has a range of about 56 m to about 114 m over a period of 7 days. 2. The method of claim 1, wherein g of lobeline is released. 15. Human Heloberin with controlled sustained release over a period of at least 1 day A physically forced modulation system designed and arranged to emit therapeutic levels of A drug delivery system for the treatment of nicotine dependence, comprising: 16. 16. The drug delivery system of claim 15, wherein the physically forced modulation system is a transdermal patch. Mu. 17. The physically forced modulation system can be injected subcutaneously or intramuscularly or implanted. 16. The method of claim 15, wherein the polymer is a biodegradable polymer. 18. 18. The drug of claim 17, wherein the physically forced modulation system delivers lobeline to the circulatory system. agent delivery system. 19. Biodegradable polymers include poly(lactic acid/glycolic acid) copolymer, polyvinegar acid, polyglycolic acid, polyester, polyorthoester, polylactone, polyester 18. The method of claim 17, wherein the method is selected from the group consisting of linanhydrides and polyamino acids. 20. The biodegradable polymer may be a poly(lactic acid/glycolic acid) polymer. The drug delivery system according to claim 19. 21. The poly(lactic acid/glycolic acid) polymer is about 50:50 to about 85:15. 21. The drug delivery system of claim 20, which is lactide/glycolide. 22. 21. The method of claim 20, wherein the microparticles are about 38 to about 250 microns in size. 23. The biodegradable polymer is suspended in a pharmaceutically acceptable injection vehicle. 7. The method of claim 6, wherein the method is in the form of microparticles. 24. The pharmaceutically acceptable injection vehicle is made of carboxymethyl cellulose. 23. The method of claim 22, wherein the method is a solution. 25. 16. The method of claim 15, wherein the time interval is for at least 7 days. 26. 26. The method of claim 25, wherein the time interval is for at least 30 days. 27. The drug delivery system delivers about 56 to about 114 mg of lobeline for a 7 day period. 16. The drug delivery system of claim 15, wherein the drug delivery system releases: 28. 20. The biodegradable polymer comprises lobeline and about 20 to about 65% by weight. the method of. 29. 28. The biodegradable polymer comprises lobeline or about 30 to about 40% by weight. the method of. 30. 17. The drug delivery method of claim 16, wherein the transdermal patch comprises lobeline in the diffusion matrix layer. system. 31. 31. The method of claim 30, wherein the diffusion matrix layer further comprises a non-solvent adsorption enhancer. . 32. 31. The method of claim 30, wherein the diffusion matrix layer further comprises an anti-pruritic agent. 33. 31. The method of claim 30, wherein lobeline is in its free base form. 34. A transdermal patch having a first chamber and a second chamber, the first chamber being a lobe. The second chamber holds the transmitter, and the second chamber holds the transmitter, and the second chamber retains the transmitter. is designed not to be released from the patch in therapeutically sufficient amounts until contact with the 17. The drug delivery system of claim 16, wherein the drug delivery system is arranged. 35. 35. The drug of claim 34, wherein the transmitter is alcohol or a hydroalcoholic solution. transmission system. 36. 35. The method of claim 34, wherein the second chamber further includes an adsorption enhancer. 37. The following: Therapeutic levels of human lobelin in controlled sustained release for a period of at least one day at least one physically forced modulation system designed and arranged to emit M; Providing information to users regarding the use of delivery systems to treat nicotine dependence a guide to A kit useful for the treatment of nicotine dependence. 38. 38. The kit of claim 37, wherein the physically forced modulation system is a transdermal patch. 39. The kit includes a patch for transmitting lobeline to humans for at least one week. 39. The kit of claim 38, comprising a sufficient number. 40. The physically forced modulation system provides about 56 to about 114 mg over a 7-day period. 39. The kit of claim 38, which conveys lobeline. 41. 39. The kit of claim 38, wherein the patch is a daily patch. 42. 39. The kit of claim 38, wherein the batch is a 7 day patch. 43. Request that the kit contains enough batches for a four-week smoking cessation program Item 42 kit. 44. The transdermal batch has a first chamber and a second chamber, the first chamber containing lobeline. and the second chamber holds a transmitting substance, and the device is in contact with the transmitting substance. Constructed to prevent transfer of lobeline from the transdermal batch in therapeutically sufficient amounts until contact 39. The kit of claim 38, wherein the kit is prepared by: 45. The kit is a transdermal patch that allows long-term therapeutic levels of lobeline to be delivered to humans. 45. The kit of claim 44, comprising a sufficient number of. 46. The first chamber is sufficient to deliver a therapeutic dose of lobeline for a period of at least one day. 46. The kit of claim 45, comprising an amount of lobeline. 47. The first chamber delivers about 56 to about 114 mg of lobeline over a period of about 7 days. 46. The kit of claim 45, comprising an amount of lobeline sufficient to reach the target. 48. The kit provides a transdermal package for at least 211 days useful in a three-week smoking cessation program. 47. The kit of claim 46, comprising: 49. Organisms in which physically forced modulation systems can be injected or implanted subcutaneously or intramuscularly 38. The kit of claim 37, wherein the kit is a degradable polymer. 50. 50. The kit of claim 49, wherein the biodegradable polymer is in particulate form. 51. Biodegradable polymers include poly(lactic acid/glycolic acid) copolymer, polyvinegar acid, polyglycolic acid, polyester, polyorthoester, polylactone, polyester 50. The kit of claim 49, wherein the kit is selected from the group consisting of linanhydrides and polyamino acids. 52. The biodegradable polymer may be a poly(lactic acid/glycolic acid) polymer. The drug delivery system according to claim 51. 53. The poly(lactic acid/glycolic acid) polymer is about 50:50 to about 85:15. 53. The drug delivery system of claim 52, which is lactide/glycolide. 54. the biodegradable polymer is carried in a pharmaceutically acceptable injectable vehicle; 53. The method of claim 52, wherein the method is in the form of microparticles. 55. The pharmaceutically acceptable injection vehicle is made of carboxymethyl cellulose. 55. The method of claim 54, wherein the method is a solution. 56. Further diluent to resuspend the lobeline-containing physically forced modulation system. 50. The kit of claim 49, comprising: