JPH05501539A - compressed powder drug - 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] compressed powder drug weight 1. Uomeikama Bonno The present invention provides compressed powder matrices for drugs used in transmucosal release of drugs. The present invention relates to a composition and a method for producing the same. More specifically, the present invention provides precise amounts of drugs. Compositions for non-invasively administering agents through the mucosal tissues of the mouth, pharynx and esophagus; The present invention relates to methods and apparatus for making such compositions.

2. Le Tsui's back weight In recent years, the field of pharmacology, which concerns the administration of drugs to treat various conditions, has greatly developed. It has been reached. However, despite very impressive developments in the field, Drugs continue to be administered using much the same techniques that have been used for years. Ru. The majority of formulations continue to be administered orally or by injection.

However, it is known in the art that none of these routes of administration can be used in all cases. Furthermore, both routes of administration were found to have some drawbacks. Often.

Oral administration is probably the most commonly practiced method of administering drugs. The drug is It is usually formulated into a tablet, capsule, or liquid base and then swallowed. oral administration administration is often preferred due to its convenience; furthermore, oral administration is generally , is risk-free, painless and easy to perform for most patients.

However, oral administration of drugs has some drawbacks. One drawback is that pediatric patients and geriatric patients often have difficulty swallowing gunpowder; This means that patients are often unwilling to take liquid medications. Furthermore, many For some drugs, the act of swallowing them increases stomach capacity and can cause nausea and vomiting. increases the chance of vomiting, i.e. this is a particularly dangerous condition for pre-anesthetized patients. It is.

Another factor related to oral administration is the rate of absorption of the drug into the bloodstream after swallowing. However, it differs depending on the hater. Absorption of drugs occurs from the stomach to the small and large intestines. It relies on drug movement and secretion by these organs. anxiety and strikes drug response dramatically reduces their movement and secretion, preventing or reducing the final effectiveness of the drug. may reduce the effect of the drug and delay the onset of the drug's effect.

Most importantly, there is usually a gap between the time of oral administration and the time when the therapeutic effect of the drug begins. This means that there is a substantial delay in As mentioned above, drugs enter the bloodstream To enter, it must pass through the gastrointestinal system, which typically takes 45 minutes. Or it takes more time. As mentioned earlier, anxiety and stress There are many things that can increase this.

For multiple applications, e.g. i1 before surgery! Pre-medication or pain or serious When immediate relief of medical symptoms or fast-acting effects of drugs are required, This delay is unacceptable, at a time when rapid patient turnover is essential to cost savings. In today's outpatient facilities and operating rooms, excessive delays in drug action are easily tolerated. I can't stand it.

A further disadvantage of oral administration is that many drugs, especially those of the central nervous system ('CN5J) or or drugs with cardiovascular effects are metabolized almost immediately. Stomach level Veins from the small and large intestines pass directly through the liver. Therefore, blood flow Drugs that enter the body first pass through the liver before being distributed to the systemic blood circulation. .

Over 60% of most drugs (compared to essentially 100?≦ for some camphor drugs), this It is removed from the patient's bloodstream during the "first pass" through the liver. As a result, economic Word of mouth! 1 is used for a large number of drugs, especially for pre-surgical preparatory administration or induction of anesthesia. For most central nervous system and cardiovascular drugs used in critical care settings is impractical.

In addition, the liver removes excess drugs from the bloodstream, adding further stress to the liver. . This is the cardiovascular or renal vascular area! or if it has been carried out for a long period of time , is particularly important. The liver can become overburdened by drug metabolism; The agent must be excreted in the patient's urine. As a result, liver [ii or renal S damage] increases the risk of

Another few points found when administering drugs orally are that dosage determination is be prepared or determined for use with “normal” patients. Ru. Most drugs have different effects on different patients. These effects are , patient habits, subtle genetic differences between patients, blood volume, age and many other known factors. and depends on unknown factors. Oral administration of o-pills is prohibited in some places. Rather than giving you the ability to adjust the precise dosage needed to achieve the desired effect, The dosage is calculated to produce normal effects in normal patients. As a result Therefore, individual patients may be underdosing or overdosing.

Patients who are underdosed due to low sensitivity to the drug may have a reaction recommended by their doctor. Patients with overdosage, which cannot cause May cause dangerous deterioration of lung function. This is caused by prolonged hypopnea (surgery later requiring mechanical ventilation), which may cause cardiac dysfunction and cardiac arrest. Ru.

To avoid certain disadvantages of oral administration, injections are often used to administer drugs. (usually intravenously or intramuscularly), the drug enters the patient's bloodstream. This results in rapid entry into the Additionally, this type of release allows the patient's liver to Multiple drug removals are avoided. Instead, the drug is , it will be rapidly distributed to various parts within the patient's body.

Most patients, especially children and the elderly, have an aversion to injections. ! Pj, For some people, this aversion is so pronounced that using injections becomes a serious problem. There is something that happens. Intense psychological stress worsens the patient's debilitated condition The patient may be seriously ill or debilitated or injured. injection may be inappropriate if

Furthermore, the metabolic sensitivities of various drugs (particularly those related to central nervous system activity) have been investigated. Individual variations are more severe when using the injection route, to prevent overdosing. is administered to the patient at a lower than normal dose, followed by additional injections as needed. It is customary to replenish the dose. In this titration, repeated injections are used. This in turn greatly increases the patient's stress. Additionally, patient response The dosage varies widely depending on the characteristics of the particular patient, so it is important to administer the correct dose and cannot produce any effect.

One common way to prepare a patient for surgery is to administer sedatives or anxiolytics. The administration of drugs orally. Rapid initiation of sedation or anxiolysis must be Six-day surgery, which was not a critical factor, is now even more so. Increased use of outpatient facilities for use and cost savings in modern medical practice Against slightly overdosing in anesthesia due to changes in practice such as pressure for In order to avoid increasing medical costs for patients due to secondary delays in recovery, Rapid onset of and use of absolutely ideal doses are required. central nervous system Oral administration of drugs related to activity (sedation and sedation without excessive sedation) It is a fixed number that causes a rapid onset of anxiety relief.

Some researchers administer drugs through the buccal mucosa of the cheek pouches or by sublingual administration. Name of the inventor of the invention that suggests that there is something that is or is possible. ゛, METHODS ANDCOMPOSITI, filed on May 1, 1985 ONS FORNONINVASIVE ADMINISTRATION OP 5EDATIVES.

Co-pending application entitled ANALGESIC3, AND ANESTHETIC3 Thing 06. See '729.301. Such as mouth, pharynx and There is clear utility in administering therapeutic agents through the mucosal tissues of the esophagus and esophagus. By this route When administering a drug, the drug is not exposed to the digestive fluids of the stomach and intestines; When passing through the body for the first time, it mainly bypasses the liver, thereby distinguishing drugs. The metabolism and/or deactivation of

Typically, drugs administered by any of the methods described above have an unpleasant taste.

As a result, it allows for buccal or sublingual administration via the oral mucosal tissues In addition, certain pleasant-tasting agent masses, such as "Yangde" matrix, may also be added. It is necessary to mix drugs.

Manufacturing drug-containing candy products by existing methods involves melting the therapeutic agent into the candy. Add to the side mass 0 Next, mix the resulting mixture thoroughly and add (8 melted canday mass) Next, pour the mixture while it is still molten to ensure proper distribution of the drug in the mixture. and solidify into a semi-solid mass. Alternatively, pour the hot candy side mass into the mold. The size and shape may be determined as desired.

For effective application of the drug, the final candy product must ensure consistent retention of the drug. must contain the drug uniformly distributed throughout, or - For therapeutic applications, varying amounts within known and controlled ranges may be used to administer the drug. Point B is where it is desirable to vary the hand speed, while keeping the solid drug constant. or Note, ti< is found when attempting to blend in a controlled manner. drug Many of these are insoluble or partially present in one or more components of the hard candy mass. It is only soluble. Therefore, the resulting product lacks uniform distribution of the drug. is often found.

Furthermore, if the temperature of the Yuyande side mass is increased to achieve a more uniform distribution (normal Significant drug decomposition has been found to occur at temperatures above approximately 230"C. Although the degree of degradation varies, high temperatures generally impair drug handling and unsuitable for cleaning and processing. Therefore, the manufacturing method of candy products itself The body may break down and/or deactivate therapeutic agents.

Additionally, many drug-containing camp-lozenges currently available are placed in the mouth. It breaks easily when mixed. As a result, no constant release of drug into the mucous membrane 411m occurs, Rather, the crushed lozenge is largely chewed and swallowed, and the drug is 6 Therefore, Camp-Trouble enters the bloodstream via the gastrointestinal tract as described above. However, there are extremely important limitations to its use in drug administration via the oral mucosal tissue. That is understood. As a result, lozenges can be used as powerful fast-acting drugs, e.g. Used to administer drugs that affect the intravenous, cardiovascular, or renal vascular systems. There wasn't.

There was a prospect of administering certain persimmon drugs through the oral mucus tissue, but the desired form was not found. The development of well-acceptable methods for manufacturing and administering drugs in There was no catch. Acceptable candy made for use in most pharmaceuticals developing the product without heating it to the point where it is expected to decompose. It was impossible.

p) (gk during the day) may adversely affect the administration of certain drugs by the mucosal route of administration. It must also be noted that, in this technical field, adhesive II! through the organization drug administration is best achieved when the drug is in its non-ionized form. was found. The change in pH is the percentage of drug that is in the non-ionized state at a particular time. drastically affect the rate. As a result, the pH condition during the day is 5. Having the drug present in an ionized form that is highly unsuitable for movement through tissues limits the effectiveness of certain drugs administered bucally or sublingually in that 8 Considering the above, it is possible to obtain accurate efficacy for each patient by using appropriate methods and compositions. Given the correct dosage for the effect, it can deliver a powerful, fast-acting drug. This is considered an important advance in the field. Lack of overdosing, underdosing points and "escapes the immediate metabolism found in first-pass effects 1, and furthermore, Such methods and compositions do not require injection by 1. The thing is, It is considered a relevant advance in the art.

When drugs (including insoluble drugs) are placed in soluble matrices, the mixture undergoes decomposition. It is an object of the present invention to provide methods and compositions for compounding without heating to the point of , is considered to be another important advance in the field. insoluble drug We present such a method that provides the ability to uniformly incorporate agents into soluble 71 helices. This is considered to be one of the most relevant advances in the art.

When a drug is released through mucous membranes, it exists primarily in non-ionized form. We believe that providing a way to adjust the pH to It will be done.

Such compositions and methods are disclosed and claimed herein.

day t and self The present invention provides a pharmaceutical composition for use in transmucosally administering a powerful, fast-acting drug. The present invention relates to a composition and a manufacturing method for manufacturing. Furthermore, the present invention provides sufficient drug A dose-to-effect method is used to precisely produce the desired effect. -effect manner). Compositions and Methods The present invention further provides for incorporating therapeutic agents into bases for flavored confections. compress the solid confectionery mixture onto the appliance or holder. or fixation. In use, the present invention , provides for the administration of drugs through the mucosal tissues of the pharynx and esophagus, thereby injecting The problems of both oral administration and oral administration are avoided.

Using the present invention, drugs can be delivered almost as far as by injection and by oral administration. can be introduced into the patient's bloodstream much faster than using a given route, and at the same time The negative aspects of both can be avoided.

According to the present invention, by incorporating the drug into a soluble drug substance, These benefits are obtained. Soluble candy in the form of compressed powder lollipops --Using drug mixtures to achieve the exact desired effect in a dose-effect manner or The drug can be administered until the Next, place the lollipop in the patient's mouth. can be removed from Furthermore, the method of the present invention allows for the formation of drug-containing troches. A compressed powder composition is provided that overcomes a number of limitations. Geometric dilution according to the invention The combination of dry powder components according to After the initial thorough mixing, add one or more of the following components to the flaps of the previous component. Add the least heavy ingredients and mix thoroughly with the existing mixture. This method can be used to Repeat until all ingredients, including the drug, are thoroughly mixed.

After mixing, the mixture is compressed under high pressure to form a one-piece candy product. . The special confectionery ingredients are mixed to form the mixture into a unitary solid mass. this Ingredients include, for example, compressible refined powdered sugar and maltodextrin. be.

This method overcomes many of the problems of the prior art. Adding a drug to a 71-liquid product requires effort to dissolve the drug. I can do it. In addition, the amount typically required to produce the molten candy matrix is However, high temperatures that cause drug decomposition are avoided using the present invention. did Therefore, a drug with a melting point of less than about 130°C to 140°C or decomposition below the melting point of the drug Even those drugs that you may experience are combined in soluble mud 1 lunx. be able to.

Another advantage of the present invention is that seasoning gaps are overcome. flavor Addition flexibility allows for the ability to incorporate any specific flavor into the matrix. given that solubility of the ingredients is not required. Therefore, seasoning flavorings, Drugs and other ingredients (which may be insoluble in liquid form) - if they are dry powders It is also easily mixed when present as a

Buffers and pond type pH and pKa modifiers also provide maximum drug efficiency can be added at the same time. The non-ionized form of the drug is more easily penetrated through mucous membranes. It is understood that it is easily transported. Therefore, the pH (and the corresponding pxa ) can be adjusted to maximize the percentage of non-ionized drug available The effectiveness of the drug is maximized when

A variety of lollipop shapes are further possible using the present invention, e.g. may be interspersed between the layers of candy.9 According to the present invention, the use of a solid powder , any desired type of mold can be used for compression molding of lollipops. be able to.

Furthermore, when the candy matrix is compressed, the bars are assembled into the matrix. It may be desirable to incorporate Or, once the candy is formed, The sticks may be adhered to the candy matrix with a confectionery adhesive.

Once the stain has achieved the desired effect, remove the stick from the patient's mouth. To make it possible to easily take out frozen candy. This is done through the mucous membranes of the mouth. This is a substantial improvement over existing methods of administering drugs.

The present invention further provides for controlling the rate of dissolution of the composition once it has been administered to a patient. Provides the following benefits: This can be done in two ways. First, dissolution rate chemically by including hydrophobic substances (e.g. calcium stearate) Dissolution can be slowed down by changing to or accelerated by lactose. Wear. Additionally, dissolution can be controlled by the degree to which the mixture is mechanically compressed. I can do it.

oral mucosal tissues from such compressed powder matrices that are within the scope of the present invention. The drugs administered through these tissues quickly enter the patient's bloodstream through the veins that are located in these tissues. Enter the crab. Drugs with observable or monitorable effects (e.g. central nervous system appropriately monitor the patient's response to drugs that affect the cardiovascular or renal vascular system). By looking at the zero order, which indicates when the drug has caused the appropriate reaction, You may remove the lollipop or its consumption rate to maintain the desired effect. You may change it to hold.

The risk of overdosing to a patient that continues to exist is eliminated by using the present invention. It is understood that qualitatively it is minimized. for the drug to be absorbed by the body The speed can be changed by changing the rate at which the lollipop melts. I can do it. This can be done by changing the intensity with which the patient licks the lollipop. Therefore, it can be achieved. In addition, it means that the lollipop is formed during molding. Dissolution of the compressed powder matrix by changing its degree of compaction This can be achieved by adding certain drugs that reduce sex.

With the present invention, drug doses are given over a period of time rather than all at once. and the rate of administration may be adjusted if it is deemed necessary. can. Once a satisfactory drug response has been achieved, the patient can suck the lollipop. This can easily be stopped or the doctor can remove the lollipop from the patient's mouth. data can be easily retrieved.

Concave plate O Rin star story Figure 1 shows a mold for molding a candy-drug matrix with an associated ram. FIG.

FIG. 2 shows one implementation of a lollipop within the scope of the present invention! A perspective view of IE1 be.

FIG. 3 is an exploded diagram of the lollipop embodiment shown in FIG. 2. FIG.

FIG. 4 is a perspective view of another embodiment of the lollipop of the present invention.

Figure 5 illustrates one method of joining sticks to a candy matrix. FIG. 2 is a cutaway diagram of another embodiment of the lollipop of the present invention.

A day full of beautiful details 1. Eunron The present invention relates to a composition that promotes transmucosal release of a drug and a method for producing the same.

Briefly, the present invention provides for the introduction of lollipops or similar types containing therapeutic agents. Regarding products. The drug is released into the mouth when the patient licks a sugar candy containing the drug. , released to the patient through the mucosal tissues of the pharynx and esophagus.

This special release method allows the drug to be released orally or by injection. One of the major advantages of the present invention is that it overcomes some of the limitations found in It is the ability to introduce drugs to patients in a ``dose-effect'' manner. medicine is accurate is given to the patient until the desired effect is achieved, which is a predetermined amount of the drug. This is different from the prior art method, which introduces the following information to person i. Once the desired effect Once the lollipop is available, the patient or health care professional should remove the lollipop from the patient's mouth. Remove to area.

The present invention discloses a method of manufacturing a lollipop containing one or more therapeutic agents. According to the present invention, it is possible to reduce the amount of U For example, in the present invention, as opposed to liquid components at high temperatures, Indicating that mixing solid powders at room temperature is necessary to produce a molten candy side mass Decomposition of the drug, which often occurs at high temperatures, is thereby avoided. this is, Drugs whose touch point is in the range of 130°C to 140°C and below, or the melting of drugs Facilitates the use of those agents that may experience degradation below the point.

Additionally, solid powders are mixed together so that they are in a heated/8 liquid or suspension. Components that may be chemically incompatible in some cases can be mixed. known methods When forming drug-containing confections by It is said that the components of the pond may be insoluble when placed in the same liquid environment. found in points. Furthermore, the chemical incompatibility between components U is defined in the present invention as be excluded.

Once the desired ingredients are thoroughly mixed, they are compressed under high pressure into a solid agent layer. do. Typically a pressure in the range of about 2,000 Newtons to about 5,000 Newtons Contraction force is preferred. As a result, the compressed powder matrix is more compact than by chemical means. Rather, they are joined by physical means. By changing the degree of compression force, you can The rate at which the data dissolves in the patient's mouth can be varied. shape the mixture The greater the compression force, the slower the compressed powder matrix will dissolve in the mouth.

The dissolution rate of a lollipop can also be controlled chemically1, e.g. The rate can be reduced by adding hydrophobic substances such as calcium stearate. Wear. Alternatively, dissolution can be increased by adding hydrophilic substances such as lactose. I can do it.

According to the present invention, the compressed 1a powder 7 Trinks can be bonded to a holder such as a stain. to form a lollipop. Bonding the compressed powder matrix to the holder This makes it easier to administer the correct dose. Once a specific effect is triggered Once released, remove the lollipop using the holder described above. Can be done. Additionally, compressed solid side masses containing drugs with complex and unpleasant flavor characteristics may Numerous ingredients are added to the product to overcome its unpleasant flavor characteristics. and therefore a mechanical support system such as a holder is required.

Bonding the confectionery to the holder is done by attaching the stick to the holder when the lollipop is formed. May be produced by compaction into a powder matrix or once Once the matrix is formed, glue the sticks with some kind of confectionery glue or pond. It may be adhered to the candy matrix by a suitable adhesive or as described below. Immediately before use, place the drug and candy discs into a suitable shape, as mentioned in The lollipop may be assembled by sliding it onto the holder.

Compression or bonding of drug-containing confections onto holders facilitates transmucosal absorption of various therapeutic agents. It is understood that this can be facilitated. Connection to the holder is attached to the patient It also facilitates demonstrable transfer of drugs to and from A holder can invest at any particular point in time. Provides a convenient reference point related to the amount of drug administered, thereby It is easy to determine the amount of candy dissolved in the patient's mouth.

Local anesthetic, antiplaque agent, local antipruritic, local antisecretory and local antifungal Localization of the effects of agents such as drugs can also be achieved according to the present invention . central nervous system agents (e.g. sedation, anxiolysis, analgesia, amnesia and anesthesia), Cardiovascular agents (e.g., antihypertensives and antianginals), vasoactive agents and Rapid systemic effects with many other therapeutic agents can also be achieved using the present invention. can do.

Mounting the drug dose onto the holder also temporarily holds the drug for testing. Make it easy to remove or reduce its effect if necessary. oral Unlike the administration of those drugs by or even sublingually, the present invention The composition can be easily removed to assess the induced effects at any particular time point. can be done. When using gunpowder or lozenges, intermediate It is usually not practical, if not impossible, to remove it from the patient's mouth at this stage. There isn't.

The compressed powder matrix bonded to the holder can also prevent confections from being swallowed. Wear. One major problem with existing lozenges is their friable nature. Ru. Once the lozenge is crushed, controlled transmucosal release is not possible.

Additionally, there is some possibility that the patient may choke on pieces of the lozenge.

The present invention provides the ability to deliver palatable medications. For many drugs, many Due to the extreme bitterness or other unpleasant taste of drugs, it has traditionally been difficult to provide palatable drugs. With the present invention, favorable taste characteristics can be achieved with a variety of flavors. , by adding sweeteners, etc. to produce the ideal product formulation. Can be done. Since the ingredients are mixed as solids, there are no insoluble preparations in the molten candy agent layer. Problems associated with mixing flavoring ingredients are avoided.

Additionally, the present invention provides for the use of free acid forms of certain drugs and their The agent is buffered on both ends of the pH and the resulting bad taste is avoided. It is important to note that it has been found that it is possible to .

2. Establishment legislation Desirable Agents for Forming Lollipops - For Producing Confectionery Mixtures , it is usually necessary to mix several common components. These ingredients The types of ingredients used to make typical confections, the desired agents and M. There are other chemically active components such as Wr-law, etc. The types of ingredients included are generally as follows: It is classified into the following types.

(1) Flavorings for seasoning, (2) sweetener, (3) flavor enhancer, (4) mold release agent, <5) 1 buffering agent and (6) One or more therapeutic drugs.

As previously mentioned, these ingredients must be combined to facilitate the mixing and compaction process. It is preferable that each of these be given as a powder, as these ingredients happen to be insoluble. Facilitates mixing of ingredients even if they are chemically or chemically incompatible. Ru. Any initial materials or inactive ingredients must be on the GRAS list (“Generally Recognized as Safe”). It must be one of the following:

A wide range of flavors produce good taste and desirable agents within the scope of this invention Available for: These are needed to mask the unpleasant taste of the drug.

Flavoring agents can be mixed, if desired, to create a specific flavor combination that is compatible with a particular drug. Some confectionery seasonings that have been used in connection with the present invention Flavoring agents include artificial vanilla, vanilla cream, honeysuckle, cherry, and Dutch halibut. Tsuka, Gray 1, Coconut, Chocolate, Menthol, Licorice, Lemon and butterscotch.

Each of these seasoning flavors is available in concentrated powder form. Confectionery technology field Other seasoning flavors known in the art are also acceptable due to their ease of mixing with the ingredients of the present invention.

All of the numerous seasoning flavors have the specific desirability required for any particular application. 6 can be mixed in any desired ratio to produce taste characteristics, e.g. Flavor combinations can be varied to suit the flavor characteristics of any particular drug. You may change it.

Artificial colors can also be added to the composition to produce the desired color of the final product. . The seasoning flavors described above, like the other main ingredients, are generally white powders. . Therefore, if a colored final product is desired, further coloring is necessary.

Coloring is a code that indicates the type and concentration of drug contained in a particular lollipop. It can be important as a mode. “Generally recognized as safe” (rGRAS J) and therefore of the type commonly used in the confectionery industry. Both can be used to color products.

In order to provide a palatable drug, it is necessary to add sweeteners to the composition.

Currently preferred sweeteners include aspartame and Nutrasweet. (NutraSweet)] and compressible refined powder sugar. fI! ! sweetness of Other substances, such as fructose, are also acceptable for use within the scope of the present invention. Furthermore, entering Sweeteners or combinations of sweeteners that produce medicinal and palatable confections It is desirable to be compatible with other ingredients such as

Maltodextrin can also be added to give a palatable composition. .

Typically, maltokistrin is used to reduce unpleasant flavors in the composition (e.g., the bitter taste of most drugs). It is used to erase Furthermore, maltodextrin is added to the final lollipop. It is a highly compressible powder that facilitates the molding of day products.

For certain applications, flavors may be added to the composition to obtain a palatable product. – It may be desirable to add enhancers. Flavor enhancer is a lollipop 1 Flavor enhancement within the scope of the present invention to provide a more pleasant sensation in the mouth of a patient while consuming Strong drugs include ribotides (nucleotides) and monosodium glutamate ( There are substances such as 'msg').

Some chemicals require the addition of a lubricant to release the lollipop from the mold. Sometimes it is desirable to do so. This type of material can also provide a certain amount of waterproofing. Wear. As previously mentioned, the rate at which a lollipop dissolves in a patient's mouth is chemically It can also be physically controlled by the degree of compression of the composition. These moisture As a lubricant or mold release agent, compritol 888, Stereo Substances such as calcium phosphate and sodium stearate may be mentioned. Wear. These substances can increase dissolution or they are necessary Dissolution can also be inhibited by

As discussed in further detail below, it may be desirable to buffer the composition. . I! The mechanism allows the drug in the mouth to pass through the mucous membranes of the mouth, throat, and esophagus. 6 compositions that provide the ability to provide a favorable pH environment for The active ingredient or drug is Affects pH changes in the salivary environment of the mouth to facilitate existing in ionized form It can make a difference.

In addition, properly adjusting the pH may prevent excessively acidic (e.g. sour) or Where a basic (e.g. bitter) agent is used to produce a product with better flavor. can be of help. As a result, citric acid/sodium citrate etc. The reaction system has been found to be desirable for inclusion in soluble compacted powder matrices. It was done.

A wide variety of other substances such as fillers and bulking agents, such as lactose, may also be desirable. Something 1. be understood. Other fillers and extenders of the type known in the art. Agents can also be used.

Added to the confectionery matrix described above is a suitable therapeutic agent or It's a drug. As discussed in more detail below, various agents have been shown to treat this type of matrix. It is easily incorporated into the box. These include the central nervous system, cardiovascular system or blood vessels. Contains substances that affect the vascular system.

A typical lollipop within the scope of this invention contains 2000 mg (2 g) each To produce 20 shapes, the following ingredients may be included:

Ingredients Citric acid 1% 0.2 Ribotide 2% 0.4 Compritol 888 2% 0.4 Aspartame 2% 04 Vanilla minute pieces 5% 1.0 Vanilla cream microshards 5% 1.0 Wild chili microshards 3% 0.6 Minute fragments of Seiyohatu 3% 0.623% 4.6g Common active substances The molded drug is then placed in the desired container, whether it is an adult, a minor, a child, or a newborn. Mask or optimize flavor perception so that it is ultimately tolerated by the patient group be able to.

Each component is mixed in dry form with the other components to produce the composition of the invention.

Currently, it is preferable to use geometric dilution methods when mixing various components. be. Using this method, first the two lowest weight components (as proportions of the final product) are ) are thoroughly mixed with each other.

Once those two ingredients are thoroughly mixed, start the next smallest or first ingredient. Add ingredients equal in weight to the existing mixture and mix thoroughly. This process is Repeat until all ingredients are added and thoroughly mixed with all other ingredients. It will be done.

A exponentially increasing dilution means complete and thorough mixing of all components.

The use of the methods described above may result in incomplete mixing and loss of components throughout the mixture. There is almost no even distribution. Existing methods are incomplete due to insolubility of the product However, this was recognized as an advance in the technology. It will be.

Once complete mixing is achieved, the mixture remains constant; the ratio is adjusted to deliver the drug amount. Compressed with relatively strong pressure. About 2,000 newtons to about s, ooo newts Compressive force between the pills is currently preferred, but it is possible to compress the ingredients into a uniformly accumulated pill layer. Any pressure sufficient to do so was used.

In the use of the present invention, similar methods have been implemented for producing drug-laden dragees. No, no heating is required to turn the mixture into a molten mass. As a result, sufficient mixing and Thermal decomposition of the drug ingredients is avoided while a balanced product is provided.

The dragee mass is attached to a rod-like holder or other similar type of holder. It will be done. The holder is attached to the dragee using dragee adhesive. Alternatively, the hol The powder may be compressed into a lollipop (lollipop shape) using the compression forces described above. stomach.

Each figure shows several methods for manufacturing dragee pill layers as well as attaching the holder. Illustrate the method. FIG. 1 discloses a shaped block 10. FIG. Of the 10 shaped blocks The section includes a recess 12 formed in any desired shape, so that the above-mentioned components are It can be sufficiently compressed to produce cut-shaped preparations. Shape block 10 is 1 Divided into 4 and 16 halves. Each half of the block 10 of the shape is fully compressed If done, it can be removed to remove the dragee.

Ram 18 is also illustrated in FIG. Ram 18 fits into recess 12 and the base of the depression 12 is formed for compressing the dragee. Ram 18 has a hole through its interior to accommodate rod 20. That is, the rod 20 is compressed Can be placed throughout the dragee prior to. Then the ram 18 is tightened around the rod 20. Compress the dragee. Following compression of the dragee, the rod is tied securely in place.

FIG. 2 discloses another embodiment of the dragee of the present invention. Sugar agent illustrated in Figure 2 has alternating layers of dragee portions 22 and drug portions 24. each alternating segment The disc is shaped like a disc and the width of the disc can be varied depending on specific needs. disk 22 and 24 easily slides over bar 26 and stops on fastener 28. In other words, the sugar agent Sembly's method is designed to provide varying drug doses in response to changing circumstances. can be adapted. In fact, patients themselves can assemble the appropriate sugar drug; In addition, the content of the drug can be changed at any time to meet the specific needs of the patient. can.

FIG. 3 illustrates a method for assembling embodiments of the invention as illustrated in FIG. Show. In FIG. 3, drug disk 24 and dragee disk 22 are shown along rod 26. exist apart. As can be seen from FIG. slides over the top and stops on the catch 28. The number of disks and the composition of these disks are Can be easily modified to suit specific patient needs.

Rod 26 may be of various shapes. For example, for rod 26, the cross-sectional shape is an egg. It is desired that it be shaped or triangular. This means that disks 24 and 26 are rotating rods. This will prevent the wheel from rotating. Furthermore, the hook for attaching the rod 26 is made of metal. , an additional sleeve (not disclosed) was installed over the exposed part of the rod, and disk 2 4 and 26 may be fixed.

FIG. 4 illustrates further embodiments of construction within the scope of the present invention. In Figure 4 In this case, the drug and dragee are laterally divided along a cylindrical mass of dragee. That is, medicine The pie-shaped portions of agent 32 and dragee 34 are compressed together along rod 30. An example is shown in Figure 4. As shown, drug portions 32 and dragee portions 34 alternate on the dragee exterior surface. do. Alternatively, appropriate levels of drug can be achieved by changing the space in that segment. The dosage may also be provided.

FIG. 5 illustrates an alternative method for the connection between dragee 36 and rod 38. An example is shown in Figure 5. The rod 38 shown is constituted by a number of protrusions 40. The protrusion 40 is a sugar agent widen towards the exposed part of the handle to prevent it from slipping off the handle. I'm looking forward to it. That is, when the dragee 36 is compressed around the rod 38, the pill layer becomes tight. and join it to the rod.

Thus, the present invention offers considerable flexibility in the composition of dragees containing appropriate drugs. It can be understood that the The amount of drug contained in all sugar preparations varies over a wide range. be able to. Additionally, the various methods of attaching dragees to the rod allow for a wide range of flexibility. used to provide.

pH and pKa control Most drugs are weak acids or bases, and can be either non-ionized or ionized. It is well known that they exist in solution in different forms. Drug not ionized It was found that the moieties are usually lipid soluble and can easily cross cell membranes. Opposition However, the ionized moiety is lipid-insoluble and often cannot cross the lipid membrane of the cell. do not have. Additionally, ionized drugs often have small particles due to positive or negative charges. cannot pass through the hole in the cystic membrane. As a result, the ionized form of the drug affects the central nervous system and heart. It is usually not possible to produce drug effects on the visceral and renal vasculature.

Whether a drug exists in an ionized state depends on its pKa and its pKa. It is highly dependent on the pH of the corresponding solution. The present invention controls the pH of the solution and It offers a unique possibility to control the pKa of drugs.

Ingredients of lollipops or other dosage forms contain elevated concentrations of non-ionized drug. It is made to signal that the pH of the saliva in the mouth has changed sufficiently. be able to. As the percentage of non-ionized drug increases, the corresponding This increases drug adsorption across the mucosa. Therefore, it affects the pH environment of saliva. By determining the actual extent and rate of drug adsorption, and thus the drug The onset of the effect can be greatly improved. pH buffer system ( For example, ionized by adding citric acid/sodium citrate). The delivery of non-lipid-soluble (lipid-soluble) forms of the drug can be greatly facilitated.

To reach maximum drug delivery, the pKa should be in the range of about 5 to about 8. is often desired. pKa is a dissociation constant, which means that a given acid or base Normal pH is defined as 50% ionized and 50% non-ionized. determined. pKa can be calculated from pH if the concentrations of charged and uncharged components are known. If you can calculate and know which components have changed and which components have not changed, you can use the well-known Hendeson - Can be calculated using the Hasselbalch formula. Hendason/S-1 Cell The Palhi formula is as follows: pKa　-pH+　loglA-/HAI In the formula, A-/HA is not ionized. is the ratio of the ionized drug form ("A-") to the free drug form ("HA"). .

pKa at different pHs, i.e. effective effect on non-ionized drugs is extremely dramatic. For example, methohexita, a drug that acts on the central nervous system. Its pKa is 7.9. If saliva I)H is normally 7.5, its value is as follows. Near below, applied to Hendesson-Hasselpalch formula, 9-7 ．． 5+log (X) (log of ratio of ionization to non-ionization) where X is the ratio of ionized to non-ionized drug form. solve this equation As a result, 60% of the effective methohexital under normal conditions in the mouth is non-ingestive. It is suggested that it exists in an on state. As mentioned above, non- The ionized drug form is the primary form that passes through cellular lipid membranes.

When the pH of saliva is lowered to about 6.7 by buffering, the pKa changes dramatically.

This results in a corresponding dramatic change in the amount of effective drug. In this condition 94% of the effective drug exists in non-ionic form.

By comparing the pKa obtained under the two sets of pH conditions described above, dramatic changes can be seen. I can understand what is happening. Due to the change from pH 7.5 to pH 6.7, fat The concentration of drug in nonionic form that can pass through the plasma membrane is improved to greater than 50%.

This result results in a dramatic improvement in drug delivery across cell membranes in the mouth. and a corresponding increase in the effectiveness of orally administered drugs.

Changes in pH such as those discussed above require a special buffer system within the dragee component. This can be achieved by incorporating One of the currently preferred buffer systems is citric acid/ There is a sodium citrate type. However, other commonly used buffers (phosphorus (such as acids) may also be used. By using such buffers, oral drugs Dramatically better results are achieved where absorption is completely viable and optimal. It will be done.

Another advantage of changing the PTI is that it may improve the taste of the medicine. is recognized. Drugs with very high pH are typically very bitter. As the pH decreases It becomes less bitter, then salty, and finally sour. add flavor As a result, the taste of medicines in the low pH range can be sufficiently improved. As a result, drug delivery In addition to improving the pH, buffering the pH can also improve the taste of the composition. Become.

4. Effective therapeutic drugs In order for the present invention to work effectively, it is usually necessary to have lipophilic or or other chemical modifications of the candy matrix. It is necessary to be able to render the therapeutic agent loaded therein into a lipophilic form. That is, p Drugs with a Ka between about 6 and about 8 are currently preferred.

It is recognized that the present invention may be used with drugs having different melting points.

Although even low melting point drugs may be used in the present invention, such drugs may be susceptible to deterioration. Due to such problems, known methods cannot be attached to candy matrices. was difficult. For example, one of the currently preferred drugs for use in connection with the present invention One, methohexital has a melting point of about 96°C. Methohex by conventional techniques In order to attach the sitar to the candy matrix, the drug must be dissolved. This can put the active drug at risk for many alterations.

The present invention has application to a variety of drugs that act on the central nervous system. For example, the present invention Thyrophenones (e.g. droperidol and haloperidol); benzodiases pins (e.g., valium, midazolam, triazolam, ofsadilam, and razebam), gABA stimulants (e.g. etomidate): palpyrate (e.g. For example, pentatol, methohexitol, thiamazole, bendoparbital, and hexabarbicur); di-isopropylphenol drugs (e.g., Zypri); van); and ease of oral administration of other central nervous system drugs such as levodopa. used for. Other drugs may also be used alone or in combination within the scope of the present invention. It is recognized that it may be used for However, drugs are usually lipophilic and efficacious. It is important to have the same characteristics as above, and the other general characteristics mentioned above.

Table 1 lists some CNS-acting compounds suitable for attachment to the lollipops of the present invention. 1 depicts a drug as well as some characteristics of the drug.

Drugs that act on the cardiovascular system and renal vasculature can be added to the compressed powder lollipops of the present invention. It can also be attached to a pool. Some examples of such agents are shown in Table 2.

In addition to the foregoing, the compressed powder matrix of the present invention can be attached to There are many other drugs. Examples of such agents are shown in Table 3.

Benzkinamite 25-100 mg Meclizine 25-Zoo mm Gram metoclopramide 5-20 Milligram prochlorperazine 5-2 5 Milligram Trimethobenzamide Zoo-2500 Milligram Clotrima Sol 10-20 milligrams Nice Cutin 100,000-500. Go o Unit carbidopa with levodopa 10-50 levodopa 100 -750 milligrams Sucralfate 1-2 grams Albutyrol 0.8-1.6 milligrams Aminophylline 100-500 Milligram beclomethasone 20-50 Microgram daphyllin 10 0-400 milligram epinephrine 200-500 microgram fulni Giride 25-50 Microgram Isoetaline 170-680 Microphone Microgram Isoproterenol Hydrochloride 60-260 Microcrum Metaproterenol Nord 0.65-10 milligrams Oxytriphylline 50-400 milligrams Gram terbutaline 2.5-10 Milligram theophylline 50-400 Milligram terbutaline 2-4 milligrams Methysergide 2-4 milligrams Propranolol 80-160 Milligram Suloctidyl 200-300 Milligram ergonovine 0.2-0.6 Milligram oxytocin 5-20 Unit Desmopressin Acetate 10-50 Microgram Reprene 7-14 My Crogram Pap Pressin 2.5-60 Unit Insulin 5-20 Uni Cut Within the scope of the present invention, the medicament may be in the form of a lollipop or candy. The amount of drug used for application depends on more conventional injection and oral administration techniques. The amount used is usually different from the amount used. Lipophilic nature, potency, and end use of drugs Depending on the application, the total concentration of drug in a typical lower pot will vary from the amount typically used for a single injection. It may contain up to 50 times the amount of drug to be used. For practical purposes, Table 1 ．． 2 and 3 represent the currently predicted range of drug amounts that could typically be used. show.

A variety of agents may be used within the scope of the present invention. According to the present invention, Cancellation of drugs that are otherwise insoluble, have an unpleasant taste, or have other undesirable characteristics attached to the matrix. This ability is achieved through compression formation of candy preparations. Granted.

As mentioned above, methohexital is currently preferred for use in Lollibop of the present invention. It is one of the most commonly used drugs. The study tested six volunteers with methohexital. This was done by administering Lolibop. Loliporap is 500 milligrams each. Contains methohexital of rum. Each patient begins to absorb Loliposop I felt the sedative effect of the drug within a few minutes. These tests were performed using the Lollibop of the present invention is effective in oral administration of mettoveki/tal in terms of drug dose and effect. and showed.

By using methohexital loribosob mentioned above, mild or severe It was possible to produce a strong sedative effect or induce anesthesia. The sedative effect is By removing loribosop when the desired degree of sedation is reached, the desired sedative effect is achieved. can be gradually increased up to a level.

Additionally, the use of methohexital through the oral mucosa produces the greatest sedative effect. This result shows that the amount of drug required for treatment is significantly reduced. The amount of drug is , 25-30 mg/kg when methohexital is administered rectally. from 6 to 8 mg/kg with loliposov.

In summary, a variety of agents may be utilized within the scope of the present invention. is recognized. At the same time, several advantages are obtained. Deterioration of the drug can be avoided and At the same time effective delivery of drugs is facilitated. Drugs can be administered depending on the amount of drug and effect. This allows for precise control of the medicinal effects produced.

smelly The following examples illustrate embodiments according to the invention. These examples are for illustrative purposes only. The following examples are representative of the various embodiments of the invention that may be made in accordance with the invention. It will be understood that it is not intended to be comprehensive or exhaustive.

Example 1 In this example, methohexital was placed in a compressed dosage form.

Methohexital is a known anxiolytic, sedative and useful for anesthetizing patients. It is an effective lipophilic drug. Due to its strong potency and lipophilicity, the present invention It is an excellent drug for administration through mucous membranes.

An effective mixture was prepared by mixing the following ingredients: Color Note Cavity Gram Citric acid 1% 0,2 Ribotide 2% 0.4 Compritol 888 2% 0.4 Aspartame 2% 0.4 Vanilla Micro Cap 5% 1.0 Vanilla Cream Micro Cap 5% 1.0 Weilt Thieri Microcap 3% 0.6 Peppermint Mic Rockcap 3% 0.6 Compressible sugar 20% 4.0 Methohexital sodium 25% 5.0 Maltodextrin 32% 6. 4 100% 20 in a mixer so that all ingredients are evenly distributed in the mixture. mixed. and each 2 gram aliquot has a final volume of 2 square centimeters. commercially available Wakunos coated compressed paper with sufficient force to It was compressed by hydraulic power around the luder. By this method, 0.5 grams each Ten pharmaceutical forms containing methohexital that act through the mucous membranes of the mouth have been prepared and implemented. Example 2 In this example, triazolam was provided in the form of a compressed formulation. triazola drugs are known and effective anxiolytics, sedatives, and useful for anesthetizing patients. It is a lipophilic drug. Due to its strong efficacy and lipophilicity, the present invention can penetrate mucous membranes. This makes it an excellent drug for controlled administration.

An effective mixture was prepared by combining the following ingredients: λmu Triazolam 0.05% 0.01 Citric acid 1% 0.2 Ribotide 2% 0.4 Compritol 888 2% 0.4 Aspartame 2% 0.4 Vanilla Micro Cap 5% 1.0 Vanilla Cream Micro Cap 5% 1.0 Weilt Thieri Microcap 3% 0.6 Peppermint Mic Rockcap 3% 0.6 Compressible sugar 25.65% 5.13 Maltodextrin 50.3% 10.26100% 20.0 in a mixer so that all ingredients are evenly distributed in the mixture. mixed. and each 2 gram aliquot has a final volume of 2 square centimeters. Commercially available cotton-sos coated compressed paper with sufficient force to Hydraulically compressed around the holder. By this method, each Ten pharmaceutical forms were prepared containing triazolam of Lam that act through the mucous membranes of the mouth. Ta.

Example 3 In this example, oxazepam was provided in the form of a compressed dosage form. Oxazepa drugs are known and effective anxiolytics, sedatives, and useful for anesthetizing patients. It is a lipophilic drug. Due to its strong efficacy and lipophilicity, it is effective against mucous membranes due to Invention 1. It is an excellent drug for continuous administration.

An effective mixture was prepared by combining the following ingredients: Shengbon % Gram Citric acid 1% 0.2 Oxazepam 1.5% 0.3 Ribotide 2% 0.4 Compritol 888 2% 0.4 Aspartame 2% 0.4 Vanilla Micro Cap 5% 1.0 Vanilla Cream Micro Cap 5% 1.0 Weilt Thieri Microcap 3% 0.6 Peppermint Mic Rockcap 3% 0.6 Compressible sugar 25.17% 5.03 Maltodextrin 50.33% 10.07100% 20 in a mixer so that all ingredients are evenly distributed in the mixture. It is mixed. and each 2 gram aliquot has a final volume of 2 square centimeters. commercially available wax-coated compressed paper with sufficient force to Hydraulically compressed around the holder. By this method, 30 milligrams each Ten dosage forms containing lamb's oxazepam that work through the mucous membranes of the mouth have been prepared.

Example 4 In this example, lorazebam was provided in the form of a compressed formulation. Lorazebum is Known and efficacious parents useful for anxiolytics, sedatives and anesthetizing patients It is a fatty drug. Due to its strong efficacy and lipophilicity, the present invention provides a It makes an excellent drug for administration.

An effective mixture was prepared by combining the following ingredients: parent % g Lorazebum 0.2% 0.04 Citric acid 1% 0.2 Ribotide 2% 0.4 Humpritol 888 2% 0.4 Aspartame 2% 0.4 Vanilla Micro Cap 5% 1.0 Vanilla Cream Micro Cap 5% 1.0 Weilt Thieri Microcap 3% 0.6 Peppermint Mic Rockcap 3% 0.6 Compressible sugar 25.6% 5.12 Maltodextrin 51.2% 10.24100% 20 in a mixer so that all ingredients are evenly distributed in the mixture. mixed. and each 2 gram aliquot has a final volume of 2 square centimeters. Use a commercially available wax-coated compressed paper block with sufficient force to It was compressed by hydraulic power around the luder. By this method, 4.0 milligrams each Ten dosage forms containing ram's lorazepam that work through the mucous membranes of the mouth have been prepared.

Example 5 In this example, etomidate was applied in the form of a compressed dosage form. etomiday is a known and effective anxiolytic, sedative, and useful for anesthetizing patients. It is a lipophilic drug. Due to its strong efficacy and lipophilicity, the present invention can penetrate mucous membranes. This makes it an excellent drug for controlled administration.

An effective mixture was prepared by combining the following ingredients: citric acid 1% 0.2 Ribotide 2% 0.4 Compritol 888 2% 0.4 Aspartame 2% 0.4 Vanilla Microcap 5% 1.0 Vanilla Cream Microcap 5% 1.0 Weilt Thieri Microcap 3% 0.6 Peppermint Mic Rockcap 3% 0.6 Compressible sugar 25.3% 5.06 Maltodextrin 50.7% 10.14100% 20 in a mixer so that all ingredients are evenly distributed in the mixture. mixed. and each 2 gram aliquot has a final volume of 2 square centimeters. Use a commercially available wax-coated compressed paper block with sufficient force to It was compressed by hydraulic power around the luder. By this method, 20 milligrams each Ten dosage forms containing the mucosal etomidate that are effective through the mucous membranes of the mouth have been prepared.

Example In the example, thiamylal was provided in the form of a compressed formulation. thiamilar is a known and effective anxiolytic, sedative, and useful for anesthetizing patients. It is a lipophilic drug. Due to its strong efficacy and lipophilic properties, the present invention This makes it an excellent drug for specific administration.

The effective mixture was prepared by combining the following ingredients: % grams per person Citric acid 1% 0.2 Ribotide 2% 0.4 Compritol 888 2% 0.4 Aspartame 2% 0.4 Vanilla Micro Cap 5% 1.0 Vanilla Cream Micro Cap 5% 1.0 Weilt Thieri Microcap 3% 0.6 Peppermint Mic Lokiap 3% 0.6 Thiamyral Sodium 25% 5.0 Maltodextrin String 32% 6.4 Compressible sugar 20% 4.0 100% 20 in a mixer so that all ingredients are evenly distributed in the mixture. mixed. and each 2 gram aliquot has a final volume of 2 square centimeters. Use a commercially available wax-coated compressed paper block with sufficient force to It was compressed by hydraulic power around the luder. By this method, 0.5 grams each Ten dosage forms containing thiamylal were prepared that were effective through the mucous membranes of the mouth.

Example 7 The same method described in Example 1 can be used to substitute levadopa for methohexital. It is used by letting Levadopa is essential for the treatment of Parkinson's disease used as.

Example 8 In this example, insolpidodinylate was installed in the form of a compressed dosage form.

20 milligrams each of isosorbide dinylate (total calculated weight 20 grams) To produce a 20m dosage form of 2000 milligrams (2 grams) containing The following ingredients were mixed: Ingredients % Grams Insorbide dinitrate 1% 0.2 Citric acid 1% 0.2 Ribotide 2% O14 Compritol 888 2% 0.4 Aspartame 2% 0.4 Vanilla Microcap 5% 1.0 Vanilla Cream Microcap 5% 1.0 Weilt Thieri Microcap 3% 0.6 Peppermint Mic Rockcap 3% 0.6 Compressible sugar 25.3% 5.06 Maltodextrin 50.7% 10.14100% 20 in a mixer so that all ingredients are evenly distributed in the mixture. mixed. and each 2 gram aliquot has a final volume of 2 square centimeters. Use a commercially available wax-coated compressed paper block with sufficient force to It was compressed by hydraulic power around the luder. By this method, each lO milligram A pharmaceutical formulation containing insorbide dinitrate, which acts through the mucous membranes of the mouth, has been investigated. Manufactured.

Example 9 In this example, captopril was used instead of isosorbide dinylate. The same method as described in Example 8 is used except that.

Example IO In this example, nifedipine was used instead of insorbidinylate. The same method as described in Example 8 is used except that.

Example 11 In this example, clonidine was used instead of isosorbide dinylate. Otherwise, the same method as described in Example 8 is used.

Example 12 In this example, esmolol was used instead of insorbidinylate. The same method as described in Example 8 is used except that.

Example 13 In this example, nitroglycerin was chosen for attachment to the compressed dosage form. Ru. Nitroglycerin is used in hypertension, especially during surgery related to cardiovascular treatment. to control angina and blood pressure, and to control hypertension during surgical procedures. It is a useful, known, and efficacious lipophilic drug.

Due to its strong potency and lipophilicity, it is an excellent choice for administration through mucous membranes according to the invention. Becomes a drug. The effective mixture is 16 milligrams of nitroglycerin; 400 milligrams Lamb citric acid; 400 milligrams Calcium stearate: 17.1 grams compressible sugar; 17. grams of maltodextrin; 600 milligrams of pepper Mint Microcaps: 1.2 grams of cherry microcaps and 2 grams Prepared by mixing vanilla microcaps of rum. and 2 grams each Aliquots are commercially prepared with sufficient force so that the final volume is 2 cm2. hydraulically compressed around a wax-coated compressed paper holder.

2, each containing 0.8 milligrams of nitroglycerin, by the method described above. 0 lollipops are prepared.

Example 14 2, each containing 10 milligrams of nianidipine (total calculated weight 20 grams) The following ingredients were mixed to produce ten 000 milligram (2 gram) dosage forms. Combined: Combritol 888 5% 1.0 Vanilla Micro Cap 5% 1.0 Vanilla Cream Micro Cap 5% 1.0 Nifedipine 19.0% 3.8 Compressible sugar 21.7% 4.34 Maltodextrin 43.3% 8.66100% 20 grams The optimal Appropriate changes in the flavoring ingredients may be made to form the preparation in an acceptable manner. , made with this composition to mask or finalize the perception of flavor. .

Example 15 In this example, ergotamine is chosen for mounting in a compressed dosage form.

Ergotamine is a known and effective drug that is useful in relieving pain associated with migraines. It is a lipophilic drug. Due to its strong efficacy and lipophilicity, the present invention can penetrate mucous membranes. This makes it an excellent drug for controlled administration.

The effective formulation is 40 milligrams of ergocumin; 5.22 grams of compressible sugar; 10.44 grams of maltodextrin: 400 milligrams of asparagus game: 200 mg natural mint: 600 mg cherry: 1°0 Grams of artificial vanilla; 1. θ grams of artificial vanilla cream; 300 milligrams prepared by mixing Ribotide, and 800 milligrams of Humpritol 888. Ru. and each aliquot of 2000 milligrams FL has a final volume of 2 square cells. Commercially available Waknos coated compression with sufficient force to It is compressed hydraulically around the paper holder. 4 milligrams each by the method described above. Ten lollipops containing lamb's ergotamine are prepared.

Example 16 Within the scope of the present invention, used in the treatment of pain associated with candidiasis of 0. The drug-containing Lollibop is as per Example 1 except that the ingredients are mixed in the following amounts: It is manufactured by method 5.

Ingredients % Grams Clotrimazole 1.0% 0.2 Natural mint 1.0% 0.2 Wilt Thieri - 3.0% 0.6 Combritol 888 4.0% 0.8 Artificial vanilla S, O% 1.0 Artificial vanilla cream 5.0% 1.0 Compressible sugar 25.83% 5.17 Maltodextrin 51.67% 10.33 2 each by the method described above Ten lolipogs containing 0 milligrams of clotrimazole are prepared.

Example 17 Medications within the scope of the invention used in the treatment of pain associated with symptoms of esophagitis The lollipop containing the agent was prepared according to Example 15 except that the ingredients were mixed in the following amounts: Manufactured by the method.

Ward residence % grams Natural mint 1.0% 0.2 Wild Thieri - 30% 0,6 Combritol 888 4.0% 0.8 Artificial vanilla 5.0% 1.0 Artificial vanilla cream 5.0% 1.0 Compressible sugar 9.5% 1,9 Maltodextrin 19.0% 3.8 aluminum sulfate sinusaccharide 50.0% 10.0 By the method described above, each containing 1 gram of aluminum sulfate sucrose 10 lollipops are prepared.

Kenryu side 18 Medicaments within the scope of the invention used in the treatment of pain associated with respiratory distress Loliponop containing was prepared as in Example 15 except that the ingredients were mixed in the following amounts: manufactured by the method.

Ingredients % Grams Natural mint 1.0% 0.2 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Wild Jewelry 3.0% 0.6 Humbritol 888 4.0% 0.8 Artificial vanilla 5.0% 1.0 Artificial vanilla cream 5.0% 1.0 Oxytribuirin 10.0% 2. 0 compressible sugar 22.83% 4.57 Maltodextrin 45.67% 9.13 20% each by the method described above Ten lollipops containing 0 milligrams of oxytriphylline are prepared.

Example 19 This drug is used to treat patients who experience nausea or have a tendency to vomit. The drug-containing lollipops within the scope of the stated purpose shall be prepared by mixing the ingredients in the following amounts: Produced by the method of Example 15 with the exception of the following.

Ingredients % Grams Natural mint 1.0% 0.2 Aspartame 2.0% 0.4 Meclizine 2.5% 0.5 Wilt Thieri - 3.0% 0.6 Combritol 888 4.0% 0.8 Artificial vanilla 5.0% 1.0 Artificial vanilla cream 5.0% 1.0 Compressible sugar 25.33% 5.07 Maltodextrin 50.67% 10.13 By the above method, 50.67% each Ten Lolibops containing 0 milligrams of meclizine are prepared.

Example 20 Medicaments within the scope of the present invention used in the treatment of symptoms associated with polysomia The prepared lollipops were prepared using the method of Example 15, except that the ingredients were mixed in the following amounts: Manufactured by.

Per unit % Gram Desmogrecin 0.001% O-0002 Natural Mint 1.0% 0 ,2 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Wilt Thieri - 3.0% 0.6 Combritol 888 4.0% 0.8 Artificial vanilla 5.0% 1.0 Artificial vanilla cream 5.0% 1.0 Compressible sugar 26°17% 5.234 Maltodextrin 52.33% 10.47 2 each by the above method Ten lollipops containing 0 micrograms of desmopressin are prepared.

Example 21 Medications within the scope of the invention used in the treatment of symptoms of Parkinson's disease Manufactured by.

Ingredients % Grams Natural mint 1.0% 0.2 Carbidopa 1.25% 0.25 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Wilt Thieri - 3.0% 0.6 Combritol 888 4.0% 0.8 Artificial vanilla 5.0% 1.0 Artificial vanilla cream 5.0% 1.0 Levodopa 12.5% 2.5 Compressible sugar 21.58% 4,32 Maltodextrin 43.17% 8.63 25% each by the above method 10 pieces containing milligrams of carbidopa and 250 milligrams of levodopa of lolliposop is prepared.

Example 22 Object of the invention used to induce labor or reduce postpartum hemorrhage drug-containing lollipops, except that the ingredients are mixed in the following amounts: It is manufactured by the method of Example 15.

Ingredients % Grams Oxytocin 0.001% 0.0002 Natural Mint 1.0% 02 Ribotide 1.5% 0.3 Aspartame 20% 0.4 Wilt Thieri - 3.0% 0.6 Combritol 888 4.0% 0.8 Artificial vanilla 5.0% 1.0 Artificial vanilla cream 5.0% 1.0 Compressible sugar 26.17% 5.234 Maltodextrin 52.33% 10.466 each by the above method Ten lollipops containing 20 micrograms of oxythone are prepared.

Example 23 Lolibo containing a drug within the scope of the invention for use in the treatment of diabetic symptoms The cup was made by the method of Example 15 except that the ingredients were mixed in the following amounts: Surin 0.05% 0.01 Natural mint 1.0% 0.2 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Wilt Thieri - 3.0% 0.6 Combritol 888 4.0% 0.8 Artificial vanilla 5.0% 1.0 Artificial vanilla cream 5.0% 1.0 Compressible sugar 26.15% 5.23 Maltodextrin 52.3% 10.46 30% each by the above method Ten lollipops containing units of insulin are prepared.

FIG, I FIG, 3 FIG.4 Submission of translation of written amendment (Patent Law Article 184-7, first page February 1992 / Rigoe

Claims (1)

[Claims] 1. Drug-containing matrices for use in transmucosal release of drugs to patients A method for producing a (a) Certain forms that can be absorbed through the mucosal tissues of the mouth, pharynx and esophagus Obtain the amount of drug: (b) capable of producing a compressible glycoma matrix and dissolving in the patient's mouth; (c) obtaining the drug and the carbohydrate material; A drug in which the drug is substantially dispersed throughout the matrix. producing a drug-containing matrix, the drug-containing matrix forming a drug-containing matrix in the patient's mouth; Dissolution of the drug releases the drug for absorption through mucosal tissues. and (d) compressing the drug-containing matrix in a mold to When the body's drug mass dissolves in the patient's mouth, the drug is absorbed through mucosal tissues. Forming a unitary drug mass to be released simultaneously; The above method comprising the steps. 2. administering a drug to a patient according to claim 1, wherein a buffering agent is added to the drug-containing matrix; A method for producing a drug-containing matrix for use in transmucosally releasing a drug. 3. Buffers are used to facilitate transmucosal absorption of drugs when the integrated drug reservoir is dissolved. In order to A drug for use in transmucosally releasing a drug to a patient according to claim 2. A method for producing an agent-containing matrix. 4. For patients according to claim 3, wherein the buffering agent is citric acid/sodium citrate. Method for producing a drug-containing matrix for use in transmucosal release of drugs . 5. the drug is sufficient so that the drug can be absorbed through mucosal tissues lipophilic, used for transmucosal release of a drug to a patient according to claim 1; A method for producing a drug-containing matrix for use in drug-containing matrices. 6. In order to form a drug-containing lollipop, the hologram is used as part of an integral drug mass. administering the drug transmucosally to a patient according to claim 1, further comprising the step of incorporating a drug. A method of manufacturing a drug-containing matrix for use in release applications. 7. The holder is surrounded by a drug-containing matrix during the compression step (d). 7. A patient according to claim 6, wherein the lix is incorporated into a single dosage mass by compressing it. Manufacture of drug-containing matrices for use in transmucosal release of drugs against Method. 8. The holder is fixed to the monolithic mass after the compression step (d). 7. The patient according to claim 6, wherein the drug is incorporated as part of an integral drug mass by Method for producing a drug-containing matrix for use in transmucosal release of drugs . 9. The soluble carbohydrate material in the drug-containing matrix comprises compressible sugars. Containing a drug for use in transmucosally releasing a drug to the patient described in claim 1 Method of manufacturing the matrix. 10. The drug-containing matrix releases the integral drug mass from the mold after the compression step (d). 10. Administering a medicament to a patient according to claim 9, comprising a lubricant so as to be moldable. A method for producing a drug-containing matrix for use in transmucosal release. 11. the drug-containing matrix includes at least one flavor enhancer; A drug-containing drug for use in transmucosally releasing a drug to a patient according to claim 1. A method for producing a matrix. 12. The drug-containing matrix helps eliminate any unpleasant flavors of the drug. Administering the drug to the patient according to claim 1 through the viscous membrane containing maltodextrin as described above. A method for producing a drug-containing matrix for use in membrane release. 13. A substantially water-insoluble component is added to the drug-containing matrix to allow Dissolution of the integral drug mass of the substantially water-insoluble components in the drug-containing matrix transmucosal release of the drug to a patient according to claim 1, wherein A method for producing a drug-containing matrix for use in 14. The sugar mixture is applied with a force in the range of about 2000 Newtons to about 5000 Newtons. Used for transmucosal release of a drug to a patient according to claim 1. A method for producing a drug-containing matrix for. 15. administering a drug to the patient according to claim 1, wherein the drug is methohexital; A method for producing a drug-containing matrix for use in mucosal release. 16. If the drug is triazolane, oxazepam, lorazepam, etomidate and administering a drug to a patient according to claim 1 selected from the group consisting of thiamylal; A method for producing a drug-containing matrix for use in transmucosal release. 17. Administering a drug to the patient according to claim 1, wherein the drug is nitroglycerin. A method for producing a drug-containing matrix for use in mucosal release. 18. In a dose-to-effect manner, Drug-containing lollipop for use in transmucosal delivery of drugs to patients - a manufacturing method, comprising: la) lipophilic forms that can be absorbed through the mucosal tissues of the mouth, pharynx and esophagus; obtain a certain amount of medication; (b) capable of producing a compressible glycoma matrix and dissolving in the patient's mouth; (c) most drugs are the pK of the drug so that it remains in a non-ionized state to facilitate mucosal absorption (d) obtain a buffering agent capable of modifying a; (d) the agent, the soluble carbohydrate material; the agent and the buffer so that the agent is substantially dispersed throughout the matrix. producing a drug-containing matrix such that the drug-containing matrix is To be absorbed through mucosal tissues by dissolving the matrix in the mouth (e) pressuring the drug-containing matrix in a mold; When the drug is compressed and dissolved in the patient's mouth, the drug passes through the mucosal tissue. Forming a monolithic drug mass that can be released for absorption by be administered in a manner; and (f) as part of an integral drug mass to form drug-containing lollipops; Incorporate holder; The above method comprising the steps. 19. The holder is covered with a drug-containing macer around the holder during the compression step (e). 19. The trix according to claim 18, wherein the trix is incorporated into an integral mass by compression. Drug-containing lollipop for use in transmucosal delivery of drugs to patients - manufacturing method. 20. After the compression step (e), the holder is fixed to an integral drug mass. 19. The patient of claim 18, wherein the patient is incorporated as part of an integral drug mass by of drug-containing lollipops for use in transmucosal release of drugs against Production method. 21. The drug-containing matrix helps eliminate any unpleasant flavors of the drug. 19. Administering a drug to a patient according to claim 18 containing maltodextrin as described above. A method for producing a drug-containing matrix for use in mucosal release. 22. 19. The patient of claim 18, wherein the buffer comprises citric acid/sodium citrate. Manufacture of drug-containing matrices for use in transmucosal release of drugs against Method. 23. 19. To the patient of claim 18, wherein the drug-containing matrix comprises compressible sugar. A method for producing a drug-containing matrix for use in transmucosally releasing a drug. 24. 19. To the patient according to claim 18, wherein the drug-containing matrix comprises a fragrance ingredient. A method for producing a drug-containing matrix for use in transmucosally releasing a drug. 25. The sugar mixture is applied with a force in the range of about 2000 Newtons to about 5000 Newtons. used for transmucosal release of a drug to a patient according to claim 18, A method for producing a drug-containing matrix for use in drug-containing matrices. 26. administering a drug to a patient according to claim 18, wherein the drug is methohexital. A method for producing a drug-containing matrix for use in transmucosal release. 27. If the drug is triazolane, oxazepam, lorazepam, etomidate and 19. A drug for a patient according to claim 18 selected from the group consisting of thiamylal. A method for producing a drug-containing matrix for use in transmucosal release of a drug. 28. The drugs include isosorbide dinitrate, captopril, nifedipine, and clonidine. and esimolol. A drug-containing tomato for use in transmucosally releasing a drug to the patient described in 8. How to make Lix. 29. administering a drug to a patient according to claim 18, wherein the drug is nitroglycerin. A method for producing a drug-containing matrix for use in transmucosal release. 30. administering a drug to a patient according to claim 18, wherein the drug is a potent fast-acting drug; A method for producing a drug-containing matrix for use in transmucosal release. 31. 31. The patient according to claim 30, wherein the medicament has an effect on the central nervous system of the patient. Preparation of drug-containing matrices for use in transmucosal delivery of drugs to people Construction method. 32. 31. The patient of claim 30, wherein the medicament has an effect on the patient's cardiovascular system. Preparation of drug-containing matrices for use in transmucosal delivery of drugs to people Construction method. 33. 31. The patient of claim 30, wherein the medicament has an effect on the renal vasculature of the patient. Preparation of drug-containing matrices for use in transmucosal delivery of drugs to people Construction method. 34. The material in the drug-containing matrix forms a monolithic drug mass after the compression step (d). 21. The patient-friendly product of claim 20, comprising a lubricant to enable release from the mold. Method for producing a drug-containing matrix for use in transmucosal release of drugs . 35. Claim that the lubricant is comptritol 888 Containing a drug for use in the case of transmucosal release of the drug to the patient described in item 34 Method of manufacturing the matrix. 36. The release agent is a substantially water-insoluble component, and the dissolution of the monolithic drug mass in the patient's mouth is by its substantially water-insoluble components in the drug-containing matrix. for use in transmucosally releasing a drug to a patient according to claim 34. A method for producing a drug-containing matrix for use in medicine. 37. A drug-containing composition for use in transmucosally releasing a drug to a patient. There it is, An effective amount of the drug that can be absorbed through the mucosal tissues of the mouth, pharynx, and esophagus. Drugs that can; Soluble compresses that are compressed into a monolithic mass that can dissolve in the patient's mouth a synthetic carbohydrate material in which the drug is substantially uniformly dispersed throughout the monolithic drug mass; , the drug is distributed in the mouth, pharynx and throat by dissolving the drug mass in the patient's mouth. said material adapted to be released for absorption through the mucosal tissue of the esophagus; A buffering agent that is further dispersed substantially uniformly throughout the monolithic drug mass, and which so that the drug remains in a non-ionized state to facilitate transmucosal absorption of the drug with a drug-containing rod: and a drug-containing rod as described above, which can modify the pKa of the drug. A holder means fixed to an integral drug mass like a candy, Facilitating the insertion and removal of a monolith containing the drug into and out of the patient's mouth said composition comprising: said holder means shaped as such. 38. 38. A patient according to claim 37, wherein the buffering agent is citric acid/sodium citrate. A drug-containing composition for use in transmucosal release of a drug. 39. the soluble carbohydrate material in the drug-containing matrix comprises a compressible sugar; A drug for use in transmucosally releasing a drug to a patient according to claim 37. Containing composition. 40. A monolithic drug-containing mass is used to aid in the production of drug-containing lollipops. 3. The lubricant according to claim 3, comprising a lubricant substantially uniformly distributed throughout the unitary mass so that Drug-containing composition for use in transmucosally releasing a drug to the patient described in 9. thing. 41. A monolithic drug mass containing a drug is free from any unpleasant airflow of the drug in the monolithic drug mass. A matrix substantially uniformly distributed throughout the unitary mass to help eliminate taste. transmucosal delivery of a drug to a patient according to claim 39, further comprising rutodextrin. A drug-containing composition for use when dispensing. 42. The monolithic mass of the drug-containing matrix is substantially uniform throughout the monolithic mass. 42. Further comprising dispersed at least one flavor enhancer. A drug-containing composition for use in transmucosally releasing a drug to a patient. 43. The monolith containing the drug slows dissolution of the monolith in the patient's mouth. A substantially water-insoluble component is dispersed substantially uniformly throughout the unitary mass to Used for transmucosal release of a drug to a patient according to claim 37, further comprising: A drug-containing composition for.