Prodrug composition and therapeutic method

Abstract

The present invention provides a therapeutic method using a pharmaceutical composition containing a prodrug. [Solution] A method for treating a medical condition in a human subject, comprising administering a composition comprising a prodrug and a permeation enhancer from a matrix; the permeation enhancer facilitates the permeation of the prodrug through mucosal tissue to achieve an effective plasma concentration of the pharmaceutically active form of the prodrug in the human subject in less than one hour.

Description

[Technical Field]

[0001] (Claiming priority) This application claims priority to U.S. Provisional Application No. 62 / 929,737, filed on November 1, 2019, and The entire text is incorporated herein by reference.

[0002] (Technical field) The present invention relates to pharmaceutical compositions and therapeutic methods. [Background technology]

[0003] (background) The active ingredient of a drug or pharmaceutical is administered to the patient in a planned manner using one or more prodrugs. It is delivered by. The active ingredient is also at least one in the composition as part of the drug delivery system. It can also be delivered to the patient in combination with other active ingredients or drugs. In certain cases, pro The drug itself may have biological activity, and in addition, one or more active drugs may be present. It may also have the ability to convert or transform into it. [Overview of the Initiative]

[0004] (overview) Prodrug design is a crucial part of drug discovery, and involves improving solubility, enhancing stability, and modifying the design. It surpasses its parent drug in terms of improved bioavailability, reduced side effects, and higher selectivity. It can offer many advantages. In the selection and design of prodrugs, the drug delivery site and tissue Potential influences include type, enzymatic transformation, steric hindrance, and other molecular considerations. There is.

[0005] For transdermal or transmucosal delivery of drugs or pharmaceuticals, prodrugs, drugs, active ingredients, or pharmaceuticals are used. To partially or completely destroy at least one biological membrane effectively and efficiently, either alone or in combination. It may be necessary to pass through the format or traverse it by another method.

[0006] Broadly speaking, the treatment method for human diseases involves the use of a matrix, prodrugs, and permeation enzymes. The process involves administering a composition containing a enhancer, wherein the permeation enhancer is a prodrug that penetrates mucosa. It facilitates penetration through tissues and enables the pharmaceutically active development of prodrugs in human subjects in less than one hour. Effective plasma concentrations of sex-specific morphogenetic compounds can be achieved.

[0007] In one embodiment, the method for treating this condition further involves the use of the prodrug to provide the pharmaceutically active ingredient. It may include administering the drug.

[0008] In one embodiment, the matrix is ​​1000:1 to 1:1000 for the permeable enhancer. It has a weight ratio relative to the rag. In one embodiment, the production of the permeation enhancer The weight ratio to the g is 100:1 to 1:100. In one embodiment, the enhancer's prod The weight ratio to the rag is 50:1 to 1:50. In one embodiment, the permeation enhancer The weight ratio to the prodrug is 50:1 to 1:1. In one embodiment, the permeation enhancer The weight ratio of the prodrug is 50:1 to 10:1. In one embodiment, the permeation The weight ratio of the enhancer to the prodrug is 10:1 to 1:10.

[0009] In one embodiment, the prodrug contains 0.01 to 90% by weight of the matrix. In one embodiment, the prodrug contains 0.1 to 50% by weight of the matrix. The permeation enhancer then contains 1 to 50% by weight of the matrix. In one embodiment, The permeation enhancer contains 5 to 25% by weight of the matrix.

[0010] In one embodiment, the pharmaceutically active form of the prodrug has a Tmax of less than 240 minutes. In one embodiment, the prodrug has a Tmax of less than 120 minutes. In one embodiment, The aforementioned prodrug has a Tmax of less than 60 minutes.

[0011] In one embodiment, the prodrug has a Cmax of 0.1 pg / ml to 50,000 pg / ml. In some embodiments, the prodrug has a particle size not exceeding 200 microns. In one embodiment, the prodrug and the permeation enhancer simultaneously penetrate the mucosal tissue. do.

[0012] In one embodiment, the prodrug is an ester of the pharmaceutically active form of the prodrug. be. In one embodiment, the prodrug is an alkylate of the pharmaceutically active form of the prodrug. Includes Steal. In one embodiment, the prodrug is the butyl ester of the pharmaceutically active form of the prodrug. Includes Teru.

[0013] In one embodiment, the prodrug is an isopropyl form of the pharmaceutically active form of the prodrug. Contains ester. In one embodiment, the prodrug is the ethyl ester of the pharmaceutically active form of the prodrug. Includes Teru. In one embodiment, the prodrug comprises an ester of epinephrine.

[0014] In one embodiment, the prodrug is converted to the active form of the prodrug compound. In one embodiment, at least half of the administered prodrug was converted in less than 240 minutes. It can be done. In one embodiment, at least half of the administered prodrug is converted in less than 120 minutes. It will be done.

[0015] In one embodiment, at least half of the administered prodrug is converted in less than 60 minutes. It can be done. In one embodiment, at least half of the administered prodrug is converted in less than 30 minutes. It can be done. In one embodiment, at least half of the administered prodrug is converted in less than 15 minutes. It can be done.

[0016] In one embodiment, at least half of the administered prodrug is converted in less than 10 minutes. It can be done. In one embodiment, at least half of the administered prodrug is converted in less than one minute. It can be done. In one embodiment, the prodrug is converted into an active compound with a concentration of 20 pg / ml to approximately 40 ng / ml. The concentration develops within 120 minutes.

[0017] In one embodiment, the matrix is ​​a chewable or gelatin-based dosage form, Capsules, inhalation forms, lyophilized solid dose units, mist, powder, spray, liquid, gum It is applied as a gel, cream, film, or tablet. In one embodiment, the matrix is ​​a pharmaceutical film with an oral cavity residence time of less than 90 minutes. . In one embodiment, the matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 60 minutes. . In one embodiment, the matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 15 minutes. .

[0018] In one embodiment, administration of the prodrug stimulates one or more adrenergic receptors. In one embodiment, administration of the prodrug stimulates the α1 adrenergic receptor, which is associated with epinephrine. It does not need to be activated with respect to n. In one embodiment, the administration of the prodrug is 1 or The above adrenaline receptors are activated in a 10:1 ratio with respect to epinephrine.

[0019] In one embodiment, the administration of the prodrug minimizes the side effect of epigastric pain. The administration of lodrugs can reduce or minimize the side effect of epigastric pain. In one embodiment, The administration of this prodrug eliminates the side effect of epigastric pain.

[0020] In one embodiment, the medical condition falls within the range of anaphylaxis. In one embodiment, the aforementioned medical condition is an allergic reaction. In one embodiment, the aforementioned medical condition is an abnormality of the lungs.

[0021] In one embodiment, the permeation enhancer contains a phenylpropanoid. In this case, the phenylpropanoid is eugenol or eugenol acetate.

[0022] In one embodiment, the phenylpropanoid is cinnamic acid, cinnamic acid ester, cinnamon It is an aldehyde or hydrocinnamic acid. In one embodiment, the phenylpropanoid is It is cavicol. In one embodiment, the phenylpropanoid is safrole.

[0023] In one embodiment, the permeation enhancer contains an essential oil extract of the clove plant. In one embodiment, the permeation enhancer is a compound. In one embodiment, the permeation The over-enhancer is a biosynthetic product. In one embodiment, the permeation enhancer is a natural product. be.

[0024] In one embodiment, the permeation enhancer is eugenol, for example, 15-95% eugenol. Includes a terpenoid. In one embodiment, the permeation enhancer is a terpenoid, terpene or ses. Contains kiterpenes. In one embodiment, the permeation enhancer contains benzyl alcohol. In one embodiment, the permeation enhancer includes farnesol. The permeation enhancer contains a self-emulsifying excipient. In one embodiment, the permeation enhancer The enhancer contains linoleic acid. In one embodiment, the permeation enhancer is, for example, cation Contains surfactants such as ionic surfactants.

[0025] In one embodiment, the matrix includes a mucosal-adhering, water-soluble polymer. In one embodiment, the composition containing the prodrug includes one or more prodrugs, Each of these prodrugs is a derivative of a pharmaceutically active ingredient. In some of these embodiments, the prodrug is One example of a drug is dipivefrin.

[0026] In one embodiment, the first prodrug is the first ester of epinephrine, and the The second prodrug is the second ester of epinephrine, and the first ester of epinephrine The tel and the secondary ester of epinephrine are different.

[0027] In one embodiment, the prodrug is a compound of formula (I); [ka] (In the formula, each R 1a , R 1b , R 2 and R3 is independently H, C1-C16 acyl, alkylaminocarbonyl l, alkyloxycarbonyl, phenacyl, sulfate or phosphate, or, R if, or, R 1a , R 1b , R 2 and R 3 are not H, then R 1a and R 1b together are , R 1a and R 2 together are, R 1a and R 3 together are, R 1b and R 2 together are, R 1b and R 3 together are, or R 2 and R 3 together have a cyclic structure with a dicarbonyl, disulfate or diphosphate moiety) or a pharmaceutically acceptable salt thereof.

[0028] In certain embodiments, R 2 and R 3 are H, and each R 1a and R 1b is independently ethanol, n-p ropanoyl, isopropanoyl, n-butanoyl, isobutanoyl, sec-butanoyl, tert -butanoyl, n-pentanoyl, isopentanoyl, sec-pentanoyl, tert-pentanoyl l, or neopentanoyl. In some embodiments, R 1a and R 1b both are ethanol, n-propanoyl, isopropanoyl, n-butanoyl, isobutanoyl, sec- butanoyl, tert-butanoyl, n-pentanoyl, isopentanoyl, sec-pentanoyl , tert-pentanoyl, or neopentanoyl. In some embodiments, R 1a and R 1b One of them is ethanol, n-propanoyl, isopropanoyl, n-butanoyl, iso Butanoyl, sec-butanoyl, tert-butanoyl, n-pentanoyl, isopentanoyl, s ec-pentanoyl, tert-pentanoyl, or neopentanoyl may also be used.

[0029] Broadly speaking, the treatment method for the disease involves administering prodrugs from the matrix. This can be achieved, and the prodrug can be activated at a rate of 20 pg / ml to approximately 40 ng / ml of the active compound in less than 240 minutes. It will be converted.

[0030] Even if the aforementioned prodrug is converted to an active compound at a concentration of 200 pg / ml to approximately 1200 pg / ml in less than 120 minutes, Good. In one embodiment, the prodrug is converted to an active compound at a concentration of 200 pg / ml to approximately 1200 pg / ml. The conversion takes less than 0 minutes. The prodrug is also converted to an active compound at a concentration of 200 pg / ml to approximately 600 pg / ml. The conversion may take less than 0 minutes. In one embodiment, the prodrug is 200 pg / ml to about 600 pg / ml. It is converted to the active compound at g / ml in less than 45 minutes. In one embodiment, the prodrug is 200 It is converted to an active compound with a concentration of approximately 600 pg / ml in less than 30 minutes.

[0031] In one embodiment, the prodrug is converted to an activated compound of 200 pg / ml to approximately 600 pg / ml. It produces a sustained concentration of a substance. In one embodiment, less than 100% of the prodrug is converted. In another embodiment, 100% of the prodrug will be converted.

[0032] Broadly speaking, the treatment method for the disease includes administering a prodrug, and the prodrug is The conversion results in an active compound with an activity concentration of 20 pg / ml to approximately 40 ng / ml within less than 240 minutes, and In some cases, 100% of the prodrug is converted. In some cases, the treatment method for the condition is methyl The process involves administering a prodrug from a compound, the prodrug being converted into an active compound. An activity concentration of 20 pg / ml to approximately 40 ng / ml occurs within 240 minutes, in which case the prodrug 1 Less than 00% is converted. The prodrug can be administered from the matrix.

[0033] In one embodiment, the prodrug is a therapeutic level of epinephrine exceeding 100 pg / ml. The drug can be produced for at least 1 hour. In one embodiment, the prodrug is 1 A therapeutic level of epinephrine exceeding 00 pg / ml can be produced for at least 2 hours. In one embodiment, the prodrug is a therapeutic drug containing more than 100 pg of epinephrine. The bell is produced for at least 3 hours. In one embodiment, the prodrug is 100 pg / ml This produces therapeutic levels of epinephrine exceeding the recommended dose for at least four hours.

[0034] In one embodiment, the permeation enhancer may be a plant extract. In one embodiment, The over-enhancer may contain phenylpropanoids. In one embodiment, the pharmaceutical The composition may contain fungal extracts. In one embodiment, the pharmaceutical composition may be saturated or non-saturated. It may contain saturated alcohols. In one embodiment, the alcohol is benzyl alcohol Aromatic or aliphatic alcohols such as kohl may also be used. In some cases, flavonoids, plant Substance extracts, phenylpropanoids, eugenol, or fungal extracts are used as solubilizers. Yes, it is possible. In one embodiment, the phenylpropanoid is eugenol, eugenol acetate, Cinnamic acid, cinnamic acid ester, cinnamaldehyde, or hydrocinnamic acid may also be used. In one embodiment, phenylpropanoid may be chavicol. In another embodiment, phenylpropanoid Lopanoid may be safrole. In one embodiment, the plant extract is the essential oil of the clove plant. Extracts, such as essential oils extracted from the flower buds, leaves, or stems of the clove plant, may also be used.

[0035] In one embodiment, the prodrug may be administered from a polymer matrix. The polymer matrix may contain polymers, and these polymers may include water-soluble polymers. The polymer may be polyethylene oxide. The polymer may be a cellulose-based polymer. However, that is also acceptable. The polymer may be a polysaccharide. Cellulose polymers include hydroxypropylmethylcellulose. Hydroxyethylcellulose, Hydroxyethylmethylcellulose, Hyd Roxypropylcellulose, methylcellulose, carboxymethylcellulose and / or Sodium carboxymethylcellulose may also be used. The polymer is polyethylene oxide and / or may contain polyvinylpyrrolidone. The polymer matrix is ​​polyethylene. It may contain oxides and / or polysaccharides. The polymer matrix is ​​polyethylene oxy It may contain hydroxypropyl methylcellulose and / or polysaccharides. - The matrix consists of polyethylene oxide, cellulosic polymers, polysaccharides and / or poly It may contain vinylpyrrolidone.

[0036] This polymer matrix contains at least one polymer selected from the following group. Possible ingredients: pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate Polyurethane, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, Acacia gum, gum arabic, polyacrylic acid, methyl methacrylate copolymer, calcium Boxy vinyl copolymer, starch, gelatin, ethylene oxide or propylene oxide Hxidocopolymer, collagen, albumin, polyamino acids, polyphosphazenes, polysaccharides , chitin, chitosan, and their derivatives.

[0037] In one embodiment, the pharmaceutical composition may further contain a stabilizer. The stabilizer is Antioxidants capable of preventing undesirable oxidation of raw materials, forming chelate complexes, otherwise A metal ion chelating agent that can deactivate trace amounts of metal ions that might otherwise act as catalysts, Emulsifiers and surfactants that can stabilize emulsions, and materials that protect from the harmful effects of irradiated ultraviolet light. UV stabilizers that can protect against UV radiation, which absorbs irradiated UV light and prevent it from penetrating the composition. UV absorbers, being chemical substances, dissipate radiant energy as heat without breaking chemical bonds. A quencher capable of eliminating free radicals, or a scavenger capable of eliminating free radicals, It can include.

[0038] The prodrug is variable or customizable, for example, to target a desired target The structure is designed to ensure metabolic stability or protection from enzymatic cleavage until it reaches its destination. This yeast can alleviate certain side effects and / or enhance efficacy. Elementary cleavage can also be the result of endogenous enzymes, for example. In certain cases, the enzyme can be, for example It can also be intentionally added to the body to boost metabolism.

[0039] In yet another embodiment, the pharmaceutical composition is linked by bonding with hydrophilic sugars, and is hydrophobic A suitable non-toxic, non-ionic alkyl glycoside having a lukyl group is selected from the following: These are substances that combine with mucosal delivery promoters: (a) aggregation inhibitors; (b) charge modifiers; (c) pH adjusters. (d) Drug-reducing agents; (e) Mucolytic agents or mucolytic agents; (f) Ciliary motility inhibitors (ciliost (g) Membrane penetration enhancer selected from the following: (i) Surfactant; (ii) Bile salt; (ii) (iii) Lipid additives, mixed micelles, liposomes, or carriers; (iii) alcohol; (iv) energy (v) Nitric oxide donor compounds; (vi) Long-chain amphiphilic molecules; (vii) Low molecular weight hydrophobic permeation enhancers (viii) sodium or salicylic acid derivative; (ix) glycerol acetoacetate ester (x) Cyclodextrin or β-cyclodextrin derivative; (xi) Medium-chain fatty acid; (xii) Ki (xiii) Amino acids or salts thereof; (xiv) N-acetylamino acids or salts thereof; (x v) Degrading enzymes for selected membrane components; (ix) Inhibitors of fatty acid synthesis; (x) Cholesterol Synthetic inhibitors; and any combination of the membrane penetration enhancers listed in (xi)(i) to (x); (h) epithelium (i) a modifier of the physiological function of binding; (j) a vasodilator; (k) a selective transport promoter; and (k) the compound is a modifier of the physiological function of binding; (i) a vasodilator; (j) a selective transport promoter; and (k) a compound that Effectively combined, associated, contained, encapsulated, or bound together with , providing a vehicle that stabilizes delivery, resulting in the stabilization of compounds for enhanced transmucosal delivery. , carrier, mucosal adhesive substance, support, or complex-forming species, where the compound and the above Combining this compound with a transmucosal delivery enhancer increases the bioavailability of this compound in the target blood plasma. It is something that is provided.

[0040] Broadly speaking, the treatment method for the disease involves a pharmaceutical composition containing a prodrug, which is an active pharmaceutical ingredient. This may include administering an effective dose. The active pharmaceutical ingredient may include epinephrine. Epinephrine is administered as a prodrug, such as dipivefrin or other prodrugs. This may be done. This prodrug may include natural or synthetic prodrugs. The prodrug may be selected and designed based on the active pharmaceutical compound. In order to penetrate membrane barriers, intercellular spaces or intracellular spaces, and basement membranes to reach the vascular system, It can be designed to have a fixed permeability parameter. Prodrugs can also have 1 or more Metabolized by an enzymatic process to produce one or more active compounds, which are then found in tissues or biological fluids. It can also have sufficient hydrolysis parameters to be absorbed internally. The data acquisition can range from very fast to very slow. In some embodiments, uptake is controlled to uniquely enhance pharmacokinetic performance or profile. It can be custom-designed for specific or different pharmacodynamic effects.

[0041] Therefore, the treatment method for the disease involves administering an effective amount of a pharmaceutical composition containing a polymer matrix. This may include, where this pharmaceutically active ingredient is one or more prodrugs, permeation enhancers This may include sensors or combinations thereof in specific ratios. In one embodiment, the medical condition may include cardiac function. Brain impairment, pulmonary dysfunction, dermatitis, type I-IV hypersensitivity reactions, hypotension, cardiac arrest, heart failure, anaphylaxis Xysine, pupillary dilation, cardiac arrest, pulseless electrical activity, ventricular fibrillation, pulseless ventricular tachycardia, bradycardia, arrhythmia, upper This may include ventricular tachycardia or exacerbation of asthma.

[0042] In one embodiment, the pharmaceutical film comprises a polymer matrix, and within the polymer matrix... The pharmaceutically active ingredients contained are epinephrine or one or at least one p A pharmacoactive ingredient containing a drug alone or in combination with epinephrine, adrenaline It can be included together with receptor interacting substances.

[0043] The active ingredients and / or prodrugs within this pharmaceutical film have a Tmax of 1 second to 240 minutes, and a concentration of 0.1 ng / It can have a Cmax of 2 ng / ml. In one embodiment, Tmax is 40 minutes or less. In that case, Cmax is 0.1 ng / ml or more. In one embodiment, Tmax is 35 minutes or less, and its C max is 0.15 ng / ml or more. In one embodiment, its Tmax is 30 minutes or less, in which case C The maximum value is 0.2 ng / ml or higher.

[0044] Cmax is 0.1 ng / ml~2 ng / ml, 0.15 ng / ml~2.5 ng / ml, 0.2 ng / ml~1.0 ng / ml, 0.2 n g / ml to 1.2 ng / ml, and 0.2 ng / ml to 1.3 ng / ml are also acceptable. Cmax is greater than 0.1 ng / ml and 0.15 ng / ml. It is also acceptable to have values ​​greater than ml, greater than 0.2 ng / ml, greater than 0.4 ng / ml, greater than 0.5 ng / ml, greater than 1.0 ng / ml, or greater than 1.2 ng / ml. C The maximum value may be less than 3 ng / ml, less than 2 ng / ml, or less than 1.5 ng / ml.

[0045] Tmax is set to 1 second to 240 minutes, 10 to 60 minutes, 20 to 40 minutes, 12 to 15 minutes, and 5 to 10 minutes, as well as 15 seconds to 5 minutes. But that's fine. Tmax can be less than 120 minutes, 90 minutes, 60 minutes, 45 minutes, 35 minutes, 25 minutes, less than 20 minutes, 15 minutes, or 12 minutes. Less than, and less than 10 minutes may also be used. Monophase, biphase, and polyphase pharmacokinetic curves are used in the present invention. In this context, multiple different Tmax and Cmax, as well as partial or complete AUC (area under the curve or drug exposure), It is understood that it can be created in Russia.

[0046] Other aspects, embodiments, and features will be apparent from the following description, drawings, and claims. It is likely. [Brief explanation of the drawing]

[0047] (Brief explanation of the drawing) [Figure 1] Figures 1A and 1B show the plasma concentrations of EpiPen against dipivefrin-soluble film (DSF). [Figure 2] Figures 2A and 2B show the plasma concentrations over time for various doses of dipivefrin. [Figure 3] Figures 3A and 3B show the plasma epinephrine concentrations converted from dipivefrin and AQEP-10 prodrugs.

[0048] [Figure 4] Figure 4 shows the plasma epinephrine concentrations converted from dipivefrin and the AQEP-04 and AQEP-05 prodrugs. [Figure 5] Figure 5 shows the plasma epinephrine concentrations converted from dipivefrin and the AQEP-03, AQEP-06, and AQPE-07 prodrugs. [Figure 6] Figures 6A and 6B show the plasma epinephrine concentrations converted from dipivefrin and the AQEP-01, AQEP-02, AQEP-03, and AQEP-04 prodrugs. [Figure 7] Figures 7A and 7B show the plasma epinephrine concentrations converted from dipivefrin and the AQEP-03 and AQEP-05 prodrugs.

[0049] [Figure 8] Figures 8A-8C show the plasma epinephrine concentrations measured in relation to the prodrug conversion of L-dipivefrin administered intramuscularly (IM) and subcutaneously (SC), and compare the pharmacokinetic profiles of L-dipivefrin administered via the intramuscular (IM) and subcutaneous (SC) routes with those of epinephrine (EpiPen, 0.3 mg). [Figure 9] Figures 9A, 9B, and 9C compare the pharmacokinetic profiles of L-dipivefrin administered intramuscularly (IM) and subcutaneously (SC).

[0050] [Figure 10] Figure 10 shows the mean dipivefrin plasma concentrations over time, measured with IM and SC administration. [Figure 11] Figure 11A shows the conversion of dipivefrin to epinephrine for IM administration of 0.6 mg, 1 mg, and 2 mg of dipivefrin. Figure 11B shows the conversion of dipivefrin to epinephrine for SC administration of 0.6 mg, 1 mg, and 2 mg of dipivefrin.

[0051] [Figure 12] Figure 12A shows a graph comparing dipivefrin administered via intra-implantation (IM) and intra-sodium (SC) compared with EpiPen. Figure 12B shows a graph illustrating the dose-response (epinephrine plasma levels) obtained as a result of the administration route. Figure 12C also shows a graph illustrating the dose-response (epinephrine plasma levels) as a result of the administration route.

[0052] [Figure 13]In Figure 13A, the graph shows the epinephrine concentration (ng / ml) in human plasma over time (minutes) as a result of prodrugs AQEP-08, AQEP-09, and AQEP-10 tested against L-dipivefrin. In Figure 13B, the graph shows the epinephrine concentration (ng / ml) in human plasma over time (minutes) as a result of prodrugs AQEP-11, AQEP-12, and AQEP-13 tested against dipivefrin. In Figure 13C, the graph shows a comprehensive comparison of epinephrine concentration (ng / ml) in human plasma over time (minutes) as a result of various prodrugs tested against dipivefrin.

[0053] [Figure 14] Figure 14A shows a graph illustrating a comprehensive comparison of epinephrine concentrations (ng / ml) in human plasma over time (minutes) as a result of various prodrugs tested against dipivefrin. Figure 14B shows graphs illustrating the in vitro permeability data of AQEP-09 compared to L-dipivefrin. Figures 14C and 14D show graphs illustrating the in vitro permeability data of AQEP-09 compared to L-dipivefrin for film compositions with varying polysaccharide and starch content.

[0054] [Figure 15] Figure 15 shows a comparative study of in vitro human whole blood hydrolysis data for prodrugs with acceptable permeability levels. [Figure 16] In Figure 16, the graph shows the results of the permeation flux study as a function of carbon chain length. [Figure 17] In Figure 17, the graph shows the effect of sodium fluoride on drug absorption. [Figure 18] In Figures 18A and 18B, the graphs show the results of using the combination of two prodrugs in preclinical trials. [Modes for carrying out the invention]

[0055] (Detailed explanation) Prodrugs can provide enhanced delivery of active pharmaceutical ingredients, such as epinephrine. The mucosal surface, such as the oral mucosa, is a convenient route for drug delivery to the body, and for that reason These are highly angiogenic and permeable, and do not pass through the digestive system, thus bypassing the first transit barrier. Based on the fact that it offers high bioavailability and rapid onset of action in order to avoid accidents. In particular, the oral buccal tissue and sublingual tissue provide advantageous sites for drug delivery, and for that reason These are areas of the oral mucosa that are highly permeable, allowing drugs to diffuse from the oral mucosa. This is because it has direct access to the systemic circulation. This also leads to increased convenience, As a result, it improves patient medication compliance. This permeability is 10 on some mucosal surfaces. 0% is also acceptable, but also, oral cavity (buccal side), gums, sublingual area, esophagus, stomach, intestines, skin, epithelium, nasal passages, ears, In some cases, small amounts of certain drugs may be absorbed through one or more mucosal sites, such as the bronchi and colon. In the case of substances or pharmaceutically active ingredients, permeability enhancers complement the overcoming of mucosal barriers and improvement of permeability. It can help. Permeation enhancers have the ability to penetrate the barrier layer in a way that is advantageous for drug absorption. It reversibly regulates force. Permeation enhancers facilitate the transport of molecules through tissues. Absorption The film size and absorption rate are not limited to those listed below, but depend on the film size and drug load. Load, enhancer type / load, release rate from polymer matrix, mucosal residence time, etc. Depending on various parameters, and at least one active pharmaceutical ingredient alone or in combination of one or more It can be controlled and regulated by using it in combination with rodrugs.

[0056] The pharmaceutical composition is systematically adapted to deliver a prodrug for the pharmaceutically active ingredient. It can be designed in this style. U.S. Patent Applications No. 15 / 717,859 and 15 / 791,249, and WO Each of the PCT applications PCT / US2018 / 053042, published as PCT / US2019 / 067670, is cited by It is incorporated within this specification.

[0057] (Prodrug design) The delivery of certain active compounds, such as epinephrine, is characterized by specific and unique challenges. This compound is hydrophilic, endogenous, highly mutable, and requires rapid delivery to blood vessels. It promotes shrinkage. Therefore, the delivery concentration and timing are often very important to control. It is not easily achieved. An effective approach to epinephrine delivery is that this compound is used A system that allows penetration into the mucosal barrier may be used. This includes cutaneous cells, intercellular spaces, and basement membranes. For epithelial cells, an osmotic enhancer or This can be overcome with a permeability enhancer. Intercellular spaces can be overcome with a cosolvent or fatty acid. Finally, in the basement membrane, the absorption of this compound is slower but not hindered, enhancing permeation. It can be delivered with a siphon, and a co-solvent or fatty acid, or a combination thereof. Transmucosal delivery of nephrin may be effective, but in many cases it is not sufficiently rapid and does not reach the blood vessels. The contraction may result in a pharmacokinetic (PK) profile that fluctuates up and down in a wave-like pattern, and swallowed epinephrine may cause this. Flin may not be absorbed and could cause epigastric pain (e.g., 7.5 mg to 30 mg).

[0058] Prodrug design is an alternative means for the delivery of epinephrine, and in fact, other active pharmaceutical ingredients. It can also provide alternative means for the delivery of the ingredients. Prodrugs are improved and less sparse. It can exhibit aqueous properties, better permeability, reduced dosage, and enhanced absorption rate. It can also provide alternative compositions having unique stability profiles. For example, Epine While flin is stabilized by sodium metabisulfite, the prodrug dipiveflin It was found to be unstable in sodium metabisulfite. Other prodrugs are similar. It may also have stability, or the desired stability profile shown with certain additives. It may be designed based on the file. Prodrugs that are not absorbed in the stomach are also a side effect of epigastric pain. The effects can be avoided, minimized, or eliminated. Furthermore, prodrugs can also affect adrena This can lead to a decrease in phosphorus receptor binding, resulting in reduced variability and improved stability of vasoconstriction. The expected drawback of the epinephrine prodrug approach is the prodrug's effect on blood circulation. Often, a conversion is required, and the rate of this conversion causes a delay in epinephrine exposure. There is a possibility that it may cause problems, and its molecular weight is often larger than that of the active pharmaceutical ingredient. Therefore, a greater drug load may also be necessary (for example, if prodrugs are active). If the molecular weight of the active pharmaceutical ingredient is twice that of the active ingredient, twice the drug load will be required.

[0059] Prodrugs are metabolizable, for example, by hydrolysis. Metabolism utilizes the prodrug's properties. This can be done by enzymatic conversion, such as by hydrolytic enzymes, to convert it into a sexual compound. Drugs can be converted in the body at various times and in various ways. Prodrugs are those that are converted as desired. Depending on the location and time, it can be designed based on a target approach in any appropriate way. In some cases, the conversion of prodrugs can occur systemically (e.g., in the circulatory system). In some cases, the conversion of prodrugs occurs within the cell (for example, antiviral nucleoside anal). (e.g., lipid-lowering statins). In some cases, prodrug conversion can occur extracellularly (e.g., For example, in digestive fluids or other extracellular fluids.

[0060] Prodrugs can be administered orally. They may be in sublingual or oral buccal form, or These two may be administered in combination. In one embodiment, it may be a chewable or These include gelatin-based dosage forms, inhalation forms, capsules, lyophilized solid dose units, and mist. , administered as powder, spray, liquid, gum, gel, cream, film or tablet. That's good too.

[0061] In one embodiment, at least half of the administered prodrug is altered in less than 240 minutes. It is replaced. In one embodiment, at least half of the administered prodrug is replaced within 120 minutes. It is converted to less than. In other embodiments, at least half of the administered prodrug is , converted in less than 60 minutes. In other embodiments, at least of the administered prodrug Half are converted in less than 30 minutes. In other embodiments, a small amount of the administered prodrug At least half are converted in less than 15 minutes. In other embodiments, the administered prodrug At least half of it is converted in less than 10 minutes. In other embodiments, the administered prod At least half of the lag is converted in less than 5 minutes. In other embodiments, the administered At least half of the prodrugs are converted in less than a minute.

[0062] In one embodiment, the prodrug is converted to an activated compound between 20 pg / ml and approximately 40 ng / ml. The substance concentration can be designed to develop within 120 minutes. The prodrug is converted to 20 pg / m³. The system can be designed so that active compound concentrations between 1 and approximately 40 ng / ml are achieved in less than 60 minutes. The lag is converted, resulting in active compound concentrations between 20 pg / ml and approximately 40 ng / ml within less than 30 minutes. It can be designed to do so. The prodrug is converted to an activated concentration between 20 pg / ml and approximately 40 ng / ml. The substance concentration can be designed to develop within 15 minutes. The prodrug is converted to 20 pg / ml The system can be designed to produce active compound concentrations of approximately 40 ng / ml in less than 10 minutes. The buck is converted, and an active compound concentration between 20 pg / ml and approximately 40 ng / ml is produced in less than 5 minutes. It can be designed to do so. The prodrug is converted to an activation level between 20 pg / ml and approximately 40 ng / ml. The system can be designed so that the compound concentration is generated in less than one minute.

[0063] Other prodrugs for the delivery of active pharmaceutical compounds are explored and described herein. For example, A drug is a compound of formula (I); [ka] Alternatively, any salt that is acceptable as a medicine may be used.

[0064] In formula I, each R 1a , R 1b , R 2 and R 3 These are independently H, C1-C16 acyl, alkylaminocarb Nyl, alkyloxycarbonyl, phenacyl, sulfate or phosphate It may be present, or R 1a , R 1b , R 2 and R 3 As long as one of them is not H, R 1a and R1b but To, R 1a and R 2 Both, R 1a and R 3 Both, R 1b and R 2 Both, R 1b and R 3 together, or R 2 and R 3 Both have rings containing dicarbonyl, disulfate, or diphosphate components. It forms a morphological structure. In a favorable situation, R 2 and R 3 H is H, and each R 1a and R 1b C 1-C16 acyls, e.g., ethanol, n-propanoyl, isopropanoyl, n-butanoyl, Isobutanoyl, sec-butanoyl, tert-butanoyl, n-pentanoyl, isopentanoyl It may also be sec-pentanoyl, tert-pentanoyl, or neopentanoyl. In that case, each R 1a and R 1b They are identical and not H, and R 2 and R 3 It is H. In that case, R 1a and R 1b Neither of them is pivaloyl.

[0065] The compound of formula I may also be a pharmaceutically acceptable salt. A pharmaceutically acceptable salt is an acid-containing salt. Salt addition or base addition salt may also be used. Acid addition salts are made by adding a purified compound in the form of a free base to an appropriate organic acid or It can be prepared by reacting it with an inorganic acid and isolating the resulting salt. Pharmaceutically acceptable. Examples of possible acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid. and inorganic acids such as perchloric acid, or acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid This includes salts formed from organic acids such as citric acid or malonic acid and amino groups. (Base addition salts) The purified acidic compound is reacted with a suitable organic or inorganic base to form a salt. It can be prepared by isolation. Such salts include, but are not limited to, alka Metallic metals (e.g., sodium, lithium, and potassium), alkaline earth metals (e.g., magnesium) (Gene and calcium), ammonium, alkylammonium, substituted alkyl Ammonium and N + (C 1-4 It contains alkyl(4) salts. This alkyl is hydroxyal Kill is also acceptable. Other pharmaceutically acceptable salts of this compound include adipine and alginate. Ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate , borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanpropyl Onates, digluconates, dodecyl sulfates, ethanesulfons, formates, fumarates , glucoheptone salt, glycerophosphate salt, glycolate salt, gluconate salt, glycol Acid salts, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobroms, aqueous iodide Salts, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, Lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthol Talenolsulfonates, nicotinates, nitrates, oleates, oxalates, palmitic acid Salt, palmoate, pectinate, persulfate, 3-phenylpropionate, ri Salicylate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecane It may contain salts and valerates.

[0066] For epinephrine delivery, the R of epinephrine 1a , R 1b , R 2 and R 3 The following modifications to the base Certain prodrug compounds were tested. 1a and R 1b The groups are esters, amides, and ka It may contain carbonates and carbamates, orthoesters, or acetals. These groups include, for example, alkyl esters, chloroalkyl esters, amides, alkyl groups. May contain mids and chloroalkylamides. 2 The base is modified with a benzyl alcohol. It can include R 3 The group may include amine modification or oxazolidine. Ideally A prodrug must possess one or more of the following attributes: it must be biologically acceptable and penetrate one or more mucous membranes. It will be stable and will have attributes that allow it to be converted in the body, tissues, or blood. In this case, the prodrug does not require any permeation enhancer at all, and rather is sufficiently permeable on its own. It can also be overdone. The conversion of prodrugs to active ingredients is R 1a , R 1b , R 2 and R 3 The original chain length It cannot be predicted based on this. In particular, R 1a , R 1b , R 2 or R 3 A tertiary group located on the second atom of a group. The permeability of the drug is also R 1a , R 1b , R 2 and R 3 It cannot be predicted based on the basis. [ka]

[0067] The prodrug selection process for active pharmaceutical ingredients involves first selecting prodrugs with various substituents. We synthesized the sac, conducted permeability studies in vitro, and then tested them in biological fluids (e.g., human whole blood). This was performed by subjecting the assay to in vitro hydrolysis.

[0068] (synthesis) The following general synthesis procedure was used for the synthesis of epinephrine prodrugs. [ka]

[0069] (Preparation of Compound 2) A mixture of (-)-epinephrine (5 g) in water (50 ml) and THF (25 ml) is mixed with NaHCO3 (4.6 g, 2 units). Add (amount), stir at 0-5°C for 5 minutes, then N-(benzyloxycarbonyloxy)sucrine A solution of imide (6.82 g, 1 equivalent) in THF (25 ml) was slowly added, and the mixture was stirred at room temperature for 12 hours. Remove the solvent using a rotary evaporator, and the slide residue is sterilized with ethyl acetate (100 mL). Extract with HCl, wash with 2N HCl (50 mL), then wash with saline solution (100 mL), and then with anhydrous sodium sulfate. After drying and removal of the solvent, compound 2 (8.5 g) was obtained as a dark brown syrup.

[0070] (General procedure for preparing esters 3a-3f) Compound 2 (1 equivalent), triethylamine (3 equivalents), and dichloromethane (30 volumes relative to Compound 2) The corresponding acid chloride (1.8 equivalents) was added dropwise to the solution at 0-5°C. Next, the mixture was gradually... The mixture was heated to room temperature and stirred for 12 hours. The reaction mixture was then mixed with a saturated solution of NaHCO3 (30 units per 2 units of compound). Quenched with a compound. The organic phase was separated, dried with anhydrous sodium sulfate, and concentrated to obtain the residue. The solution was purified by column chromatography, and clean samples 3a-3f (approximately 60% yield) were isolated as an oily substance. The monosubstituted epinephrine prodrug (not shown in the scheme above) was subjected to acid chloride. It was synthesized using a smaller equivalent amount of [ingredient].

[0071] (General procedure for preparing 4a-4f) 3a-3f in methanol (approx. 20 vol), oxalic acid (1 equivalent), 10% Pd / C (50% wet, starting material) In contrast, a 20% by weight mixture was stirred for 12 hours under a hydrogen atmosphere (using a balloon), and then TLC was performed. The reaction was then completed. The catalyst was filtered through a Celite bed, and the filtrate was concentrated and dried. The solid is suspended in methyl tert-butyl ether (5 vol), stirred for 30 minutes, and the solid is filtered. The samples were dried. Samples 4a-4F were isolated as white solids and identified by NMR and mass spectrometry.

[0072] (Synthesis of viscarbonate 6) [ka]

[0073] (Compound 5) The same procedure as in 3a-3f was followed. (Compound 6) The same procedure as in 4a-4f was followed.

[0074] Representative prodrugs are shown in the table below. [Table 1] TIFF2026048683000007.tif224170TIFF2026048683000008.tif114170

[0075] Monoesters AQEP-14 and AQEP-15 are mixtures of two positional isomers.

[0076] (General permeability procedures - in vitro permeability research experiment protocols) Franz-type diffusion cells are used in formulation development to identify the most active permeation enhancers. This is a device used for in vitro tissue permeability assays. It is a Franz-type expander. The dispersion cell apparatus consists of two chambers separated by a single membrane. Permeability research experiments are conducted using this apparatus. The procedure was performed using the buccal mucosa of the oral cavity of pigs obtained from a slaughterhouse. Tissue was typically collected at a thickness of 300-500 μm. The sample was then placed on a vertical Franz-type diffusion cell maintained at 37°C. The tissue membrane was then dissolved in a permeation enhancer solution. A donor compartment containing the drug mixed with the liquid, and selected to provide sink conditions during the experiment. The receptor compartment containing the collection medium is separated. The permeation rate is used to determine the drug concentration in the receptor medium. We observed it over several hours by analyzing it.

[0077] In example 1, the permeation procedure is performed as follows: Set the bath to 37°C, and the receiver Place the medium in the water bath, adjust the temperature, and start degassing. Obtain a Franz-type diffusion cell. Prepare the following: A Franz-type diffusion cell consists of a donor compound, a donor chamber, a membrane, and a sampling device. It comprises a port, a receptor chamber, a stirring bar, and a heater / circulator. The stirring bar is Insert into a Franz-type diffusion cell. Place the test tissue over the Franz-type diffusion cell, and The tissue overlaps on the glass joint, completely and reliably covering the entire region. Top of the diffusion cell Place it on top of the tissue and clamp the top and bottom of the cell. Receptor medium approximately Load 5 mL into the receiver area and ensure that no air bubbles are trapped in the receiver portion of the cell. Ensure that this is the case. This means that all 5 mL can be reliably contained within the receiver area. Start mixing and allow the temperature to equilibrate for approximately 20 minutes. Meanwhile, perform high-performance liquid chromatography (HPLC). Label the vials by cell number and time point. Then, degassing occurs from the solution during heating. Since this is likely to happen, we need to check again to make sure there are no air bubbles.

[0078] When testing the film, you can then perform the following steps: (1) Fill Weigh the material, punch it to match (or smaller than) the diffusion area, reweigh it, and punch it. (2) Record the weight before and after ching; (3) Moisten the donor area with approximately 100 μL of phosphate buffer. (3) Place the film on the donor surface and cover it with 400 μL of phosphate buffer, then tie Start the MA.

[0079] For solution research experiments, the following steps can be performed: (1) Micropipette Dispense 500 μL of solution into each donor cell using the following method and start the timer; (2) At the following time (time) Sample 200 μL at intervals of 0, 20, 40, 60, 120, 180, 240, 300, and 360 minutes. Ring the vial, label it, place it inside the sealed HPLC vial, and tap the sealed vial to remove any air bubbles. (3) Ensure that it is not trapped at the bottom of the ial; (5 mL) at each sampling time (To maintain) replace with 200 μL of receptor medium; (4) Once all time points are complete, Disassemble the cell and dispose of all materials properly.

[0080] (In vitro permeability evaluation) Typical in vitro permeability evaluations are as follows: 1. Cut out a new tissue sample and immerse it in liquid at 4°C (for example, overnight). 2. Process the tissue and freeze it at -20°C for up to 3 weeks before use. 3. Take a sample of the tissue to the precise thickness. 4. Add approximately 5 mL of receiver medium to the receiver compartment. This medium will maintain the sink conditions. Choose to ensure it is correct. 5. The tissue is then used with the donor compound, donor chamber, membrane, sampling port, and receptor. It is placed in a Franz-type diffusion cell, which includes a chamber, a stirrer, and heater / circulator. . 6. Apply approximately 0.5 mL of donor solution to an 8 mm circular film, and then add 500 μL of PBS buffer. Moisten it with water. 7. Take samples from the receiver chamber at predetermined intervals and replace them with fresh medium. El.

[0081] (Transparency Enhancer) The in vivo solubility and permeability of the active pharmaceutical ingredient are considerably different, especially in the oral cavity of the target organism. It can fluctuate. Certain types of permeability enhancers affect the in vivo uptake of pharmacoactive ingredients. and its bioavailability can be improved. In particular, when delivered to the mouth via film. In this case, the permeability enhancer improves the permeability of the active pharmaceutical ingredient that passes through the target mucous membrane into the bloodstream. It can be done. The permeation enhancer controls the absorption rate and amount of the pharmaceutical active ingredient in the composition. Depending on the other ingredients, over 5%, over 10%, over 20%, over 30%, over 40%, over 50%, over 60%, over 70% Over 20%, over 80%, over 90%, over 100%, over 150%, approximately 200%, or more, or less than 200% Less than 150%, less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40% Full, less than 30%, less than 20%, less than 10%, or less than 5%, or a combination of these ranges. And it can be improved.

[0082] In one embodiment, the pharmaceutical composition is linked by bonding with hydrophilic sugars, and hydrophobic A suitable non-toxic, non-ionic alkyl glycoside having a lukyl group is selected from the following: These are substances that combine with mucosal delivery promoters: (a) aggregation inhibitors; (b) charge modifiers; (c) pH adjusters. (d) Drug reduction; (e) Degrading enzyme inhibitors; (f) Mucolytics or mucolytics; (g) Ciliary movement inhibitors; (g) The following Membrane penetration enhancers selected from: (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixtures (iii) Micelles, liposomes, or carriers; (iv) Alcohols; (iv) Enamines; (v) Nitric oxide (vi) Donor compounds; (vii) Long-chain amphiphilic molecules; (vii) Low molecular weight hydrophobic permeation enhancers; (viii) Sodium (ix) Glycerol acetoacetate ester; (x) Cyclodextrin Phosphorus or β-cyclodextrin derivatives; (xi) medium-chain fatty acids; (xii) chelating agents; (xiii) a (xiv) N-acetylamino acids or their salts; (xv) Selected membrane components (ix) Degrading enzymes; (x) Inhibitors of fatty acid synthesis; (x) Inhibitors of cholesterol synthesis; and (xi) Any combination of membrane penetration enhancers listed in (i) to (x); (h) Modulation of epithelial connective physiological function Agents; (i) vasodilators; (j) selective transport promoters; and (k) agents which the compound effectively combines with them. Enhanced transmucosal delivery by being combined, associated, contained, encapsulated, or bound together. Vehicles, carriers, and mucosal adhesion stabilize the delivery of compounds, providing stability for their application. A substance, support, or complex-forming species, wherein the compound and the above-mentioned transmucosal delivery promoter This formulation provides increased bioavailability of the compound in the target blood plasma. The osmotic enhancer is described in the literature by J. Nicolazzo et al., J. of Controlled Disease, 105(2005) 1-1 It is described in section 5, which is incorporated herein by reference.

[0083] In one embodiment, the matrix is ​​1000:1 to 1:1000 for the permeable enhancer. It has a weight ratio relative to the rag. In one embodiment, the production of the permeation enhancer The weight ratio to the g is 100:1 to 1:100. In one embodiment, the enhancer's prod The weight ratio to the rag is 50:1 to 1:50. In one embodiment, the permeation enhancer The weight ratio to the prodrug is 50:1 to 1:1. In one embodiment, the permeation enhancer The weight ratio of the prodrug is 50:1 to 10:1. In one embodiment, the permeation The weight ratio of the enhancer to the prodrug is 10:1 to 1:10.

[0084] (oral mucosa) There are many reasons why the oral mucosa would be an attractive site for delivering therapeutic drugs into the systemic circulation. For direct blood drainage from the internal buccal epithelium to the internal jugular vein, the first passage in the liver and intestines Overmetabolism can be avoided. The first-pass effect when administered orally affects several compounds. This can be the main reason for poor bioavailability. In addition, the mucous membrane covering the oral cavity is easily It is accessible, which means the dosage form can be applied to the site where it is needed, and it is urgent. In this case, ensure that it can be easily removed. However, as with the skin, the buccal mucosa inside the mouth It acts as a barrier to the absorption of xenobiotics, which prevents compounds from passing through this tissue. It can interfere with penetration. As a result, the identification of safe and effective penetration enhancers has become a major goal in the search for improved drug delivery and / or prodrug delivery across the oral mucosa.

[0085] A chemical penetration enhancer is a substance that controls the penetration rate of a co-administered drug through a biological membrane. In extensive research, the focus has been on obtaining a better understanding of how penetration enhancers alter intestinal and transdermal permeability, but little is known about the mechanisms involved in enhancing penetration on the buccal and sublingual sides of the oral cavity. The buccal mucosa in the oral cavity exists across the inner back wall of the cheek and the area between the gums and the upper and lower lips, and has an average surface area of 100 cm². The surface of the buccal mucosa in the oral cavity consists of stratified squamous epithelium,

[0086] which is separated from the underlying connective tissue (lamina propria and submucosa) by a gently undulating basement membrane (a continuous layer of extracellular material approximately 1 - 2 μm thick). This stratified squamous epithelium consists of layers of differentiated cells, and these cells change in size, shape, and contents as they migrate from the basal region to the surface region, where the cells are shed. Since there are approximately 40 - 50 cell layers, 2 the thickness of the buccal mucosa in the oral cavity is 500 - 600 μm.

[0087] Structurally, the sublingual mucosa is similar to the buccal mucosa in the oral cavity, but the thickness of this epithelium is 100 - 200 μm. This membrane is also not keratinized and is relatively thin, indicating that it is more permeable than the buccal mucosa in the oral cavity. Blood flow to the sublingual mucosa is slower compared to the buccal mucosa in the oral cavity, on the order of 1.0 ml / min / cm². -1 / cm² -2 ​

[0088] The permeability of the buccal mucosa inside the oral cavity is greater than that of the skin, but less than that of the intestines. Sexual differences are a result of structural differences between tissues. In the intercellular spaces of the buccal mucosa inside the oral cavity, tissue Because there are no keratinized lipid lamellae, compared to keratinized skin epithelium, foreign compounds are present. While significant permeability occurs, the buccal mucosa of the oral cavity, which is thicker and lacks tight junctions, It has lower permeability than intestinal tissue.

[0089] The primary barrier characteristics of the oral cavity buccal mucosa are considered to be the result of the contribution of the upper 1 / 3 to 1 / 4 of the oral cavity buccal epithelium. These researchers also found that the permeability barrier of the non-keratinized oral mucosa, which extends beyond the surface epithelium, is also This is a result of the contribution of contents pushed out from the granules covering this membrane into the intercellular spaces of the epidermal cells. I discovered that I could gain something.

[0090] The intercellular lipids in the non-keratinized areas of the oral cavity are more abundant than the lipids in the epidermis, palate, and gums. These lipids possess polarity, and differences in their chemical properties are observed between these tissues. This will contribute to differences in permeability. Therefore, this will create a more effective barrier. Not only is the degree of intercellular lipid filling within the stratum corneum of keratinized epithelium greater, but the barrier It is clear that this is also a chemical property of the lipids present within.

[0091] (Paracellular transport and transcellular transport) Due to the presence of hydrophilic and lipophilic regions within the oral mucosa, researchers have found that the buccal mucosa inside the oral cavity is Assuming the existence of two drug transport pathways: a paracellular (intercellular) pathway and a transcellular (intracellular) pathway. did.

[0092] Drug delivery through the oral buccal mucosa is limited by the barrier properties of the epithelium and the area available for absorption. Therefore, various enhancement strategies are needed to deliver a therapeutically appropriate amount of drug into the systemic circulation. This is necessary, including the use of chemical permeation enhancers, prodrugs, and physical methods. Various methods can be used to overcome the barrier properties of the oral cavity's buccal mucosa.

[0093] Chemical permeation enhancers or absorption promoters can cause damage to the membrane and / or toxicity. Without causing harm, in order to increase the membrane permeability or absorption rate of co-administered drugs, pharmaceutical formulations It is a substance added to the chemical penetration enhancer, which passes through the skin, nasal mucosa, and intestines. Many research experiments have been conducted to investigate the effects on the delivery of materials. In recent years, more Attention has been paid to the effects of these drugs on the permeability of the oral buccal mucosa. Since permeability through the buccal mucosa in the lumen is considered to be a passive diffusion process, the steady-state flux (Jss) increases with increasing donor chamber concentration (CD), according to Fick's first law of diffusion. It should happen.

[0094] In one embodiment, the pharmaceutically active form of the prodrug has a Tmax of less than 240 minutes. In one embodiment, the prodrug has a Tmax of less than 120 minutes. In one embodiment, The aforementioned prodrug has a Tmax of less than 60 minutes.

[0095] In one embodiment, the prodrug has a Cmax greater than 0.1 pg / ml. The lag may have a Cmax greater than 1 pg / ml. The prodrug may have a Cmax greater than 10 pg / ml. It may have a Cmax of more than 100 pg / ml. It can be achieved. The prodrug can have a Cmax exceeding 1000 pg / ml. The pro drug can have a Cmax exceeding 10,000 pg / ml. The prodrug can have a Cmax exceeding 20,0 00 pg / ml. The prodrug can have a Cmax exceeding 30,000 pg / ml. The prodrug can have a Cmax exceeding 40,000 pg / ml. The prodrug can have a Cmax less than 50,000 pg / ml.

[0096] The prodrug can be designed to have any particle size that enables its effective delivery. In some embodiments, the prodrug has a particle size not exceeding 200 microns. In some embodiments, the prodrug has a particle size not exceeding 300 microns, and the prodrug has a particle size not exceeding 400 microns. In some cases , the prodrug may be completely solubilized or partially solubilized, completely or partially suspended, or completely or partially emulsified within the matrix.

[0097] The prodrug can be designed in a manner that enables effective metabolism or hydrolysis into the active compound. For example, in one embodiment, the prodrug is an ester of the pharmaceutically active form of the prodrug. In one embodiment, the prodrug includes an alkyl ester of the pharmaceutically active form of the prodrug. In one embodiment, the prodrug includes a butyl ester of the pharmaceutically active form of the prodrug. In one embodiment, the prodrug includes an isopropyl ester of the pharmaceutically active form of the prodrug. In one embodiment The prodrug comprises an ethyl ester of the pharmaceutically active form of the prodrug. In this embodiment, the prodrug contains an amide of the pharmaceutically active form of the prodrug. In this embodiment, the prodrug comprises a carbonate of the pharmaceutically active form of the prodrug. nothing.

[0098] (Surfactants, bile salts, and other permeation enhancers) Surfactants and bile salts are used in both in vitro and in vivo studies on a variety of compounds. It has been shown to enhance permeability through the buccal mucosa of the oral cavity. These research experiments have shown that The data suggests that the increased permeability is due to the action of surfactants on the intercellular lipids of the mucous membrane. This strongly suggests that the permeation enhancer may be a synthetic compound. In some embodiments, the permeation enhancer may be a biosynthetic compound. The sir may be a natural compound. In other embodiments, the permeation enhancer is one or more of these compounds. It may include combinations of compounds selected from hybrid species.

[0099] Fatty acids have been shown to enhance the permeability of many drugs through the skin, and this is Differential scanning calorimetry and Fourier transform infrared spectroscopy were used to increase the fluidity of intercellular lipids. Related findings have been shown.

[0100] Furthermore, pretreatment with ethanol allows tritium-labeled water and albumin to pass through the ventral lingual mucosa. It has been shown to enhance permeability, and also to enhance caffeine permeability through the buccal mucosa of the oral cavity of pigs. It has been found that Azone (registered trademark) enhances the permeability of compounds through the oral mucosa. Several reports have been made regarding this. Furthermore, there are reports on chito, a biocompatible and biodegradable polymer. Sun has been shown to enhance drug delivery through various tissues, including the intestinal and nasal mucosa. Yes, they are.

[0101] Oral transmucosal drug delivery (OTDD) is a method of delivering drugs through the oral mucosa to achieve systemic effects. This involves the administration of a target activator. For example, see the passage pathways and predictive models for OTDD in M. Sattar's text. Submission: "Oral transmucosal drug delivery - current status and future outlook" Journal of Pharmaceutics, 4. This is described in 7(2014) 498-506, and this document is incorporated herein by reference. OTDD continues to attract the attention of academic and industrial scientists. It is administered via the skin and nose. Despite the limited characterization of the permeation pathways within the oral cavity compared to other pathways, ion Recent advances in our understanding regarding the extent to which chemical molecules penetrate the buccal epithelium of the oral cavity, and The emergence of new analytical techniques for studying and experimenting with the oral cavity, and the permeability of the oral cavity, buccal and sublingual areas. The outlook is bright, thanks to the progress in the development of in silico models to predict this.

[0102] In one embodiment, the matrix is ​​1000:1 to 1:1000 for the permeable enhancer. It has a weight ratio relative to the rag. In one embodiment, the production of the permeation enhancer The weight ratio to the g is 100:1 to 1:100. In one embodiment, the enhancer's prod The weight ratio to the rag is 50:1 to 1:50. In one embodiment, the permeation enhancer The weight ratio to the prodrug is 50:1 to 1:1. In one embodiment, the permeation enhancer The weight ratio of Sir to prodrug is 50:1 to 10:1.

[0103] In one embodiment, the prodrug contains 0.01 to 90% by weight of the matrix. In one embodiment, the prodrug contains 0.1 to 50% by weight of matrix. The permeation enhancer contains 1 to 50% by weight of matrix. In one embodiment, the permeation enhancer Hansers contain 5-25% by weight of matrix.

[0104] For a wider range of drugs to be delivered through the buccal mucosa of the oral cavity, the barrier function of this tissue is necessary. A reversible method to reduce this should be used. The necessary condition is the permeability of the oral buccal mucosa. To facilitate research and experimentation with penetration enhancers that safely modify transient constraints. Toru is a bile salt, surfactant, fatty acid and its derivatives, chelating agent, cyclodextrin Various types of transmucosal and transdermal penetration enhancers, such as torin and chitosan, are used. It has been shown that this can be improved by [doing something]. This is used to enhance drug permeability. Among these chemical substances, bile salts are the most common.

[0105] In vitro research experiments on the enhancing effect of bile salts on the oral buccal permeability of compounds were conducted. Sevda Senel's paper, "Enhancement of drug perfusion through the oral buccal pathway: possibilities and limitations (Drug perfusion "meation enhancement via buccal route: possibilities and limitations)", Journal This is discussed in Controlled Release 72 (2001), pp. 133-144, and this document is cited by This is incorporated herein. This document also contains dihydroxybile salts, glycodeoxy Sodium sicholate (SGDC) and sodium taurodeoxycholate (TDC), and tri Hydroxybile salts, sodium glycocholate (GC), and sodium taurocholate (TC) Regarding the latest research on the effect of a concentration of 100 mM on the permeability of the oral cavity buccal epithelium, This study includes the changes in permeability related to the chemical action of fluorescein isothiocyanate. Nate (FITC) and morphine sulfate were used as model compounds, respectively. Chitosan was also used. In both physical models and human volunteers, polar small molecules and peptide / protein drugs were detected in the nasal mucosa. It has been shown to promote absorption through the intestinal mucosa and cultured Caco-2 cells. It exhibits an enhancing effect on the penetration of compounds.

[0106] The permeation enhancer may be a plant extract. The plant extract is obtained by distillation of the plant material. It may also be an essential oil or composition containing essential oils. In some cases, plant extracts are plant materials. Includes synthetic analogs of compounds extracted from materials (i.e., compounds created by organic synthesis). The plant extract may contain phenylpropanoids, such as phenylalanine. Eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester, cinnamaldehyde, hi It may contain derosilicic acid, chavicol, or safrole, or a combination thereof. The plant extract is an essential oil extract of the clove plant, for example, the leaves, stems or Essential oils extracted from flower buds may also be used. The clove plant mentioned above is the clove tree (Syzygium aromum). (Aticum) may also be used. The aforementioned plant extract contains 20-95% eugenol and 40-95% eugenol Contains genol, containing 60-95% eugenol, for example, 80-95% eugenol. The extract may also contain 5% to 15% eugenol acetate. The extract may also contain caryophyllene up to 2.1%. It may contain α-humulene. Other volatile compounds present in clove essential oil at low concentrations. These include β-pinene, limonene, farnesol, benzaldehyde, 2-heptanone, and he Ethyl xanate may also be used. Another permeation enhancer is used to improve drug absorption, composition It may be added to substances. Suitable permeation enhancers are natural or synthetic bile salts, such as fusi. Sodium sodium sulfate; glycocholic acids or deoxycholic acids and their salts, etc.; fatty acids and and derivatives, such as sodium laurate, oleic acid, oleyl alcohol, monooleic acid N, and palmitoylcarnitine, etc.; chelating agents, for example, disodium EDTA, citrate Sodium phosphate and sodium lauryl sulfate, azone, sodium cholate, 5-methoxysodium Sodium lycylate, sorbitan laurate, glyceryl monolaurate, octoxin Nyl-9, Laureth-9, Polysorbate, Sterol, or Glycerides, e.g., Capriloca It contains proyl polyoxylglycerides, such as labrasol. The permeation enhancer is plant It may contain derivatives of the extract and / or monolignols. The permeation enhancer also Fungal extracts are also acceptable.

[0107] Some natural products of plant origin are known to have vasodilatory effects. There are several mechanisms or ways in which plant-based products can cause vasodilation. For the review article, see the references of JR McNeill and T. See M. Jurgens's work, Can. J. Physiol. Pharmacol. 84:803-821 (2006). Physically, the vasodilating effect of eugenol has been reported in numerous animal studies. For example, the works of S. Lahlou et al. and J. Card, each incorporated herein by reference, are examples of the works of which. iovasc. Pharmacol. 43:250-57 (2004), literature by CEN Damiani et al., Vascular Pharmacol. 40:59-66 (2003), the literature by H. Nishijima et al., Japanese J. Pharmacol. 79:327-334 (1998), and See also WR Hume's literature, J. Dent Res. 62(9):1013-15(1983). Calcium Channel blockade is vasodilation induced by plant essential oils or their main component, eugenol. It has been suggested that this is the cause. LRL I incorporated herein by reference See the literature by nteraminense et al., Fundamental & Clin. Pharmacol. 21: 497-506 (2007). sea ​​bream.

[0108] Fatty acids can be used as inactive components in drug formulations or drug vehicles. Fatty acids can also be used as, Due to their special functional effects and biocompatibility properties, they are used as pharmaceutical ingredients. It is also possible. Fatty acids in lipids, both as free lipids and as part of complex lipids, are major metabolic factors. Fuel (storage and transport energy) and an essential component of all membranes and gene regulatory factors. The review articles are incorporated herein by reference by AC Rustan and CA Drevon's literature, "Encyclopedia of Life Sciences, Fatty Acids: Structures and Properties" See "and Properties, Encyclopedia of Life Sciences" (2005). The essential fatty acids that are metabolized include two families, ω-3 and ω-6 polyunsaturated fatty acids (PUFAs). Yes, it exists. If the first double bond is found between the third and fourth carbon atoms from the ω-carbon. These are called ω-3 fatty acids. The first double bond is located between the sixth and seventh carbon atoms. These are collectively called omega-6 fatty acids. PUFAs are formed by the addition and desaturation (removal of hydrogen) of carbon atoms. It is further metabolized in the body by (decongestion). Linoleic acid, an omega-6 fatty acid, is converted into gamma-linolenic acid and diphosphate. Homo-γ-linolenic acid, arachidonic acid, adrenaline, tetracosatetraenoic acid, tetracosa It is metabolized into pentaenoic acid and docosapentaenoic acid, and alpha-linolenic acid, an omega-3 fatty acid, Tatecatetraenoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid Docosahexaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and docosahexaenoic acid It is metabolized into acid (DHA).

[0109] Fatty acids such as palmitic acid, oleic acid, linoleic acid, and eicosapentaenoic acid are Na + K + - Through a mechanism involved in the activation of the APTase pump, relaxation of porcine coronary artery smooth muscle cells and Hyperpolarization was induced, and as the degree of cis-unsaturation of the fatty acids increased, higher efficacy was achieved. It has been reported that it possessed. SI Pompository, incorporated herein by reference. See the literature by ello et al., Hypertension 31:615-20 (1998). Interestingly, Linoh The pulmonary vascular response to arachidonic acid, a metabolite of uric acid, depends on the dosage, animal species, and arachidonic acid. Depending on the method of acid administration and the tone of pulmonary circulation, it will be either vasoconstrictive or vasodilatory. It is possible. For example, arachidonic acid is both cyclooxygenase-dependent and cyclooxygenase-independent. It has been reported to cause pulmonary vasodilation. Each of these is incorporated herein by reference. This is based on the literature of CO Feddersen et al., J. Appl. Physiol. 68(5):1799-808(1990); and , the literature by E.W. Spannhake et al., J. Appl. Physiol. 44:397-495 (1978) and the text by TC Wicks et al. See the reference, Circ. Res. 38:167-71 (1976).

[0110] Many research experiments have shown that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be taken orally. The effects on vascular responsiveness after administration in an ingestible form have been reported. The study showed that EPA-DHA or EPA alone can reduce the vasoconstrictive effect of norepinephrine in the forearm microcirculation. We discovered that it either suppressed the use of the substance or enhanced the vasodilatory response to acetylcholine. The following is incorporated herein by reference: JPF Chin et al., Hypertension 21:2 See 2-8 (1993), and the literature by H. Tagawa et al., J Cardiovasc Pharmacol 33:633-40 (1999). I would like to. Another study showed that both EPA and DHA increase systemic arterial compliance. It was discovered that this tends to lower pulse pressure and total vascular resistance. The reference incorporated in the specification is that of P. Nestel et al., Am J. Clin. Nutr. 76:326-30 (2002). See also. On the other hand, one research experiment showed that DHA, not EPA, was beneficial for hyperlipidemia in overweight individuals. We discovered that in the microcirculation of the male forearm, this enhanced the vasodilatory mechanism and attenuated the vasoconstrictive response. The following is incorporated herein by reference: TA Mori et al., Circulation 102 See 1264-69 (2000). Another research experiment involved isolated human coronary artery in vitro. We discovered the vasodilatory effect of DHA on the rhythmic contraction of the cerebral arteries. This is incorporated herein by reference. See also the literature by KT Wu et al., Chinese J. Physiol. 50(4):164-70(2007). sea ​​bream.

[0111] (Adrenaline receptors) Adrenaline receptors (or adrenoceptors) are receptors for catecholamines, particularly norepinephrine. G proteins are targets of furin (norepinephrine) and epinephrine (adrenaline). It is a type of coupled receptor. Epinephrine (adrenaline) is a type of α- and β-adrenoceptor. It interacts with both of them, causing vasoconstriction and vasodilation, respectively. The α receptor interacts with epinephrine. Although less sensitive to furin, peripheral α1 receptors are more sensitive than β-adrenoceptors. Since there are many of them, when α receptors are activated, these are due to β-adrenoceptors This takes precedence over vasodilation mediated by vasodilation. As a result, high levels of circulating epinephrine in the blood Tubal constriction occurs. At lower levels of circulating epinephrine, β-adrenoceptor stimulation occurs. It is dominant, leading to vasodilation and a subsequent decrease in peripheral vascular resistance. α1-adrenoleceptor - This includes smooth muscle contraction, pupil dilation, vasoconstriction in the skin, mucous membranes and abdominal organs, and the gastrointestinal (GI) tract and It is well known regarding bladder sphincter contraction. The α1-adrenergic receptor is G q Protein-coupled It is a member of the receptor superfamily. Activation involves the heterotrimeric G protein G q It activates phospholipase C (PLC). Its mechanism of action is through interaction with calcium channels. It alters intracellular calcium content through interaction. For a review, please refer to this document by citation. The following reference is included in the book: RS Smith et al., Journal of Neurophysiology 102(2): See 1103-14 (2009). Many cells possess these receptors.

[0112] The α1-adrenergic receptor can be the primary receptor for fatty acids. For example, Saw palmetto extract (SPE), widely used in the treatment of benign prostatic hyperplasia (BPH), contains α1-adrenergic ions. Phosphate receptors, muscarinic receptors, and 1,4-dihydropyridine (1,4-DHP) calcium receptors It has been reported to bind to nel antagonist receptors. Each of these is cited herein by reference. The following are incorporated within: the literature by M. Abe et al., Biol. Pharm. Bull. 32(4) 646-650 (2009), and See also the literature by M. Suzuki et al., Acta Pharmacologica Sinica 30:271-81 (2009). PE contains lauric acid, oleic acid, myristic acid, palmitic acid, and linoleic acid. It contains various fatty acids. Lauric acid and oleic acid are involved with α1-adrenergic receptors. Non-competitive targeting of scalinic receptors and 1,4-DHP calcium channel antagonist receptors. They can be combined in a specific way.

[0113] In one embodiment, the permeation enhancer may be an adrenaline receptor interacting substance. Adrenaline receptor interacting substances are substances that modify the action of adrenaline receptors. This refers to compounds or substances that cause changes. For example, adrenaline receptor interacting substances are By increasing or decreasing the receptor's binding capacity, it is possible to prevent receptor stimulation. Such interacting substances can be provided in either a short-acting or long-acting form. Certain short-acting interacting substances can act rapidly, but their effects It only lasts for a few hours. Certain long-acting interacting substances take longer to act. In short, these effects are more long-lasting. This interacting substance is, for example, desired Delivery and dosage, active pharmaceutical ingredients, permeability modifiers, permeability enhancers, matrix, and Adrenaline receptors can be selected and / or designed based on one or more of the symptoms being treated. The body-interacting substance may also be an adrenergic receptor blocker. The properties are terpenoids, terpenes (for example, derived from isoprene units, found in plant essential oils) A volatile unsaturated hydrocarbon, or a C3-C22 alcohol or acid, preferably a C7-C18 alcohol. Alcohol or acid, or aromatic or aliphatic alcohol may also be used. In one embodiment, Adrenergic receptor interacting substances include farnesol, linoleic acid, arachidonic acid, and It may contain cosahexanoic acid, eicosapentanoic acid, and / or docosapentanoic acid. The acid may be a carboxylic acid, phosphoric acid, sulfuric acid, hydroxamic acid, or a derivative thereof. This derivative may also be an ester, amide, or carbonate. For example, an adrenaline receptor The substance interacting with the drug may be a fatty acid or an aliphatic alcohol.

[0114] The C3-C22 alcohol or acid may be a straight-chain C3-C22 hydrocarbon chain, for example, optionally having at least 1 double bond, at least 1 triple bond, or at least 1 double bond and 1 triple bond-containing C3-C22 hydrocarbon chain; the hydrocarbon chain may be optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, hydroxyl, hal o, amino, nitro, cyano, C 3-5 cycloalkyl, 3- to 5-membered heterocycloalkyl, mono cyclic aryl, 5- to 6-membered heteroaryl, C 1-4 alkylcarbonyloxy, C 1-4 alkyl oxycarbonyl, C 1-4 alkylcarbonyl, or formyl; and , further optionally, -O-, -N(R a )-, -N(R a )-C(O)-O-, -O-C(O)-N(R a )-, -N(R a )-C(O)-N(R b )-, or -O-C(O)-O- is interposed. Each of R a and R b is independently hydrogen, alkyl, al kenyl, alkynyl, alkoxy, hydroxyalkyl, hydroxyl, or haloal kyl.

[0115] Fatty acids with high unsaturation are effective candidates for enhancing drug permeability. Unsaturated fatty acids showed higher enhancement than saturated fatty acids, and the enhancement increased with the number of double bonds. By reference incorporated herein, the literature of A. Mittal et al., "Skin Penetration Enhancers" The Status of Fatty Acids as Skin Penetration Enhancers - Review See "A Review)", Current Drug Delivery, 2009, 6, pp. 274-279. Double bond The position of the double bond also affects the enhancement of fatty acid activity. The differences in the physicochemical properties of the acids determine the efficacy of these compounds as skin penetration enhancers. It is most likely that the position of the double bond will shift to the hydrophilic end, and the skin will The dispersion increases. Fatty acids with double bonds at even positions are more effective than fats with double bonds at odd positions. It acts more rapidly than acids on the disruption (perturbation) of the structure of both the stratum corneum and the dermis. It has also been reported that cis-unsaturation within the chain tends to increase activity.

[0116] Adrenaline receptor interacting substances can also be terpenes. Terpenes in essential oils lower blood pressure. Activity has been reported. The text by I.A. Menezes et al. is incorporated herein by reference. See reference to Z. Naturforsch. 65c:652-66 (2010). In one embodiment, permeation enhancement The sensor may also be a sesquiterpene. A sesquiterpene consists of three isoprene units. , experimental formula C 15 H 24 It is a type of terpene that possesses [a certain characteristic]. Like monoterpenes, it is a sesquiterpene. These can be acyclic or may contain rings in many unique combinations. Oxidation or conversion Biochemical modifications such as those at the position of the sesquiterpenoid generate related sesquiterpenoids.

[0117] Adrenaline receptor interacting substances may also be unsaturated fatty acids such as linoleic acid. In this embodiment, the permeation enhancer may be farnesol. Farnesol is an acyclic permeation enhancer. It is a skiterpene alcohol, a 15-carbon organic compound, and this is farnesyl pylori. It is a naturally occurring dephosphorylated form of farnesol. Under standard conditions, farnesol is a colorless liquid. It is hydrophobic and therefore insoluble in water, but miscible with oil. Farnesol is sit It can be extracted from plant oils such as lonella, neroli, cyclamen, and night-blooming fragrant. Yes, it is possible. This is an intermediate in the biosynthesis of cholesterol from mevalonic acid in vertebrates. It has a delicate floral scent or a weak citrusy lime-like scent, and the fragrance and flavor are It is used. Farnesol selectively targets acute myeloid leukemia blasts and leukocyte cell lines. It has been reported that they preferentially kill these cells over hematopoietic cells. See also the reference by A. Rioja et al., FEBS Lett 467(2-3): 291-5(2000). Vasoactive properties of farnesyl analogs have been reported. These are incorporated herein by reference. See the literature by JBRoullet et al., J. Clin. Invest., 1996, 97:2384-2390. I want to. Farnesol, and N-acetyl-S-trans,trans-farnesyl-L-cyste Both (AFC), a synthetic mimic of the carboxyl terminus of farnesylated proteins, are , inhibited vasoconstriction in the rat aortic ring. In one embodiment, the interacting substance was a Porphyrin alkaloids are also acceptable. For example, the interacting substance could be dicentrin.

[0118] Generally, the interacting substance may also be a vasodilator or therapeutic vasodilator. It is a drug that opens or widens blood vessels. It is usually used to treat hypertension, heart failure, and angina. It is used to treat, but it is also used to treat other conditions, such as glaucoma. It can also be done. Several vasodilators (arteriovenous dilators) that primarily act on resistance vessels are used for hypertension. It is used for heart failure and angina, but reflex cardiac stimulation can cause some arterial dilation. The medication is unsuitable for angina. Venous dilators are very effective for angina and are sometimes used for heart failure. It is used, but not as a first-line treatment for hypertension. Vasodilators affect both arteries and veins. In that it expands the vasodilator, it can be a mixed (or balanced) vasodilator, and therefore, It can be widely applied to hypertension, heart failure, and angina pectoris. Several vasodilators have different effects. Due to the mechanism, it may be possible to enhance their therapeutic usefulness in some cases. It also has another important effect that can provide several additional therapeutic benefits. For example, Some calcium channel blockers not only dilate blood vessels but also affect the mechanical function of the heart. By reducing their electrical function, their antihypertensive effects can be enhanced. It can provide additional therapeutic effects, such as blocking arrhythmias.

[0119] Vasodilators are classified based on their site of action (arterial and venous contrast) or by their mechanism of action. They can be classified as follows. Some drugs primarily dilate resistance blood vessels (arteriovenous agents; for example) (For example, hydralazine) On the other hand, other drugs primarily affect the capacity of venous vessels (venodilators; e.g., For example, nitroglycerin. Many vasodilators, such as phentolamine, are mixed-type. , having arterial and venous dilating properties (mixed dilators; for example, α-adrenoceptor antagonists) (Angiotensin-converting enzyme inhibitors).

[0120] However, classifying vasodilators based on their main mechanisms of action is more effective. This is common. The figure on the right shows the types of important mechanisms of action of vasodilators. These drug types, and Other types that cause vasodilation include: α-adrenoceptor antagonists (α-blockers); Angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); β2-adreno Scepter agonists (β2-agonists); calcium channel blockers (CCBs); centrally acting sympathetic Nerve blocking agents; direct-acting vasodilators; endothelin receptor antagonists; ganglion blocking agents; ni Trodiastolants; phosphodiesterase inhibitors; potassium channel openers; or renin inhibitors It is included.

[0121] Generally, active or inactive components or materials produce increased blood flow or tissue flushing. This enables modification or difference (increase or decrease) in the transmucosal uptake of the API, and / or , having positive or negative heat of dissolution and for modifying (increasing or decreasing) transmucosal uptake It may also be a substance or compound used as an aid.

[0122] (Order of one or more permeation enhancers and active pharmaceutical ingredients) Arrangement of the permeation enhancer and active pharmaceutical ingredient (API) delivered to the desired mucosal surface. The order (ent), sequence, or sequence is used to deliver the desired pharmacokinetic profile. It may be varied. For example, initially, the transmission enhancer can be applied by film or by swag. It is applied by a spray, gel, rinse, or by the first layer of film, and then The API is applied by a single film, by a swab, or by a second layer of film. It can be applied. This order is, for example, first by the API by film or swab By or by the first layer of the film, then the transmission enhancer, By the film, by a swab, spray, gel, rinse, or by the second layer of the film Therefore, by applying it, it can be reversed or modified. In another embodiment, The permeation enhancer can be applied using a film, and the drug can be applied using a separate film. For example, depending on the desired pharmacokinetic profile, the API can be transmitted under a film containing the API. An enhancer film may be placed, or a film containing a transparent enhancer may be placed underneath. A film containing API may be placed.

[0123] The arrangement, order, or sequence of one or more prodrugs delivered to a desired mucosal surface. The pharmacokinetic profile may be varied to deliver the desired pharmacokinetic profile. For example, one prodrug A combination of one or more prodrugs, applied via film, swab, spray, or gel. It can be applied by rinsing or by a film layer. In another example, first The prodrug can be administered via film, swab, spray, gel, or rinse. Alternatively, apply by a film layer, then apply the prodrug by film or swab. It can be applied by spray, gel, rinse, or by a film layer. The next prodrug may be a different prodrug from the first prodrug. In another example... The first prodrug and the following one or more prodrugs may be the same compound. In the example, one or more permeation enhancers are first applied by film, swab, or spray. , applied by gel, rinse, or by the first layer of film, followed by one or more The prodrug is administered by a single film, by a swab, or by a second layer of film. This can be applied by, for example, starting with one or more prodrugs. This is applied by film, by swab, or by the first layer of film, Next, one or more permeation enhancers are applied by film, swab, spray, or gel. By rinsing or by applying the second layer of film, the opposite can be done. It can also be modified. In another embodiment, one or more transmission enhancers are used in a film. The drug may be applied by different films. For example, the desired pharmacokinetic profile Depending on the file, one or more transmissions containing prodrugs are placed under the film. An enhancer film may be placed, or a film containing one or more transmission enhancers may be placed. A film containing one or more prodrugs may be placed beneath the film.

[0124] For example, one or more penetration enhancers as a pretreatment, either alone or at least one Used in combination with an API or prodrug, to enhance the absorption of one or more APIs into the mucous membrane. Preconditioning can be performed. Following this treatment, one or more neat penetrations are carried out. Continue with another treatment with the enhancer, and then proceed to the application of at least one of the APIs to the mucosa. This can be done as a separate procedure (film, gel, solution, swab, etc.) or It can be applied as one layer in a multilayer film structure of one or more layers. Similarly, this previous The treatment is carried out within separate domains of a single film designed to dissolve and release into the mucous membrane. It may include, followed by a second which may or may not include one or more penetration enhancers or APIs. Domain release occurs. Subsequently, the active ingredient is used alone or in addition to the second treatment. Alternatively, they may be delivered in combination with multiple penetration enhancers in different ratios or other proportions. In any ratio different from the total treatment load, an additional one or more infiltration enhancers and / or There is at least one API or a third procedure or domain that delivers a prodrug. This is acceptable. This makes it possible to obtain a tailored pharmacokinetic profile. In this manner, the product achieves its intended pharmacokinetic profile and / or pharmacodynamic effect. The order of application, composition, concentration, or A single or multiple penetration enhancer and API that can vary the total load. It may have multiple domains.

[0125] The configuration of this film may be oriented so that the sides are not separate, or The film has at least one side of a multilayer film that shares an edge with the edge ( They may be oriented to have or join a boundary or limit of a passage.

[0126] This pharmaceutical composition is available in chewable or gelatin-based dosage forms, sprays, gums, gels, and creams. The composition may be in the form of a foam, tablet, liquid, or film. For example, the surface may have microneedles or It may include textures such as micro-protrusions. Recently, regarding the increase in skin permeability, The use of the Ronscale needle has been shown to significantly increase transdermal delivery, particularly of polymers. Most drug delivery research experiments emphasize solid microneedles, and they are widespread. It has been shown to increase in vitro skin permeability for surrounding molecules and nanoparticles. In vivo research experiments showed that oligonucleotide delivery and insulin-induced reduction of blood glucose levels were observed. Furthermore, the induction of immune responses from protein vaccines and DNA vaccines has been clarified. For these research experiments, needle arrays are used to create holes in the skin to diffuse or iontophoresis. Used to increase transport by oleolysis, or from the microneedle surface coating. It is used as a drug carrier to release drugs into the skin. Hollow microneedles are also used. It has been developed and shown to allow for microinjection of insulin into diabetic rats. For the actual application of the needle, the ratio of the microneedle's breaking strength to its skin insertion strength is ( In other words, it was found that the safety margin is optimal for needles with a small tip radius and a large wall thickness. Microneedles inserted into human skin have been reported to be painless. These results suggest that microneedles have an applicability range for delivering therapeutic compounds to the skin. This suggests it will be a promising technology for internal delivery. The path of the microelectronics industry. Using tools, microneedles are produced in various sizes, shapes, and materials. Icloneedles, for example, deliver encapsulated drugs in a minimally invasive manner using microplastics. A needle can be used, but other suitable materials can also be used.

[0127] Using microneedles, drugs can be delivered through the oral mucosa, particularly together with the claimed composition. Delivery may be enhanced. Microneedles create micron-sized pores in the oral mucosa. This can enhance the delivery of drugs through the mucous membrane. Solid type, hollow type, and This allows for the fabrication of soluble microneedles using suitable materials, including metals and polypropylene. This includes, but is not limited to, rimmer, glass, and ceramic. The fabrication process involves photolithography, silicon etching, laser cutting, and metal electrolysis. This may include plating, metal electropolishing, and molding. The microneedles pre-treat the tissue. It may also be a solid used for that purpose and removed before the application of this film. The revealed drug-carrying polymer film is the matrix material of the microneedles themselves. It can be used as a material. These films are made on their surface and then injected into the mucous membrane. It may have microneedles or fine protrusions that dissolve after forming a cross-channel, The drug can pass through the microchannels.

[0128] The term "film" refers to any shape of film, including rectangles, squares, or other desired shapes. It may include films and sheets. The films may be of any desired thickness and size. In a preferred embodiment, the film can be administered to the user, for example, into the user's oral cavity. It can have a thickness and size that allows it to be placed. The film is approximately 0.0025 mm thick to approximately The film may have a relatively thin thickness of 0.250 mm, or the film may be slightly thicker, from about 0.250 mm to about 1.0 mm. It can also have a thicker thickness. In some films, the thickness is even greater, i.e., approximately The film may be thicker than 1.0 mm, or it may be relatively thin, i.e., less than approximately 0.0025 mm. It can be a layer, or the film can be a laminated film or a multiple cast film. It may be multilayered, including a film. The permeation enhancer and pharmaceutically active ingredients are combined within a single layer. Even if each is contained in separate layers, or even if each is contained in separate regions of the same dosage form It may be done. In one embodiment, the pharmaceutically active ingredient contained in the polymer matrix is They may be dispersed within the matrix. In one embodiment, within the polymer matrix The contained permeation enhancer may be dispersed within the matrix.

[0129] Oral dissolvable films are divided into three main categories: immediately dissolvable, moderately dissolvable, and slowly dissolvable. It is possible. Oral dissolvable films also include any combination of the above categories. It can be used. The fast-dissolving film can be used in the mouth for more than 1 second, more than 5 seconds, more than 10 seconds, more than 20 seconds, or It can dissolve in approximately 1 to 30 seconds, including less than 30 seconds. The moderately soluble film can be used in the mouth for 1 minute. It can be dissolved in approximately 1 to 30 minutes, including over 5 minutes, over 10 minutes, over 20 minutes, or less than 30 minutes. Dissolvable films can dissolve in the mouth over a period of more than 30 minutes. Generally, immediate dissolution is more common. The film is made of a low molecular weight hydrophilic polymer (for example, having a molecular weight of approximately 1,000 to 9,000 daltons). It contains (or consists of) a polymer, or a polymer having a molecular weight of up to 200,000 daltons. This is possible. Conversely, slow-dissolving films are generally made of high molecular weight polymers (e.g., molecular weights of several million). (Having) includes. Moderately soluble films are immediately soluble films and slowly soluble films. It will likely tend to fall somewhere in between.

[0130] It is sometimes preferable to use a film that has moderate solubility. The film can dissolve fairly quickly, yet it also has a good level of adhesion to mucous membranes. The highly soluble film is also flexible, can be quickly wetted, and is generally irritating to the user. It does not undergo this process. Such moderately soluble films dissolve quickly, most preferably in about 1 minute to about 2 minutes. While it can offer a dissolution rate of 0 minutes, once placed in the user's mouth, fill To provide an acceptable level of mucosal adhesion that prevents the substance from easily peeling off. This ensures that the active ingredient is delivered to the user.

[0131] A pharmaceutical composition may contain one or more pharmaceutically active ingredients. These pharmaceutically active ingredients may be single The pharmaceutical ingredients or combinations thereof may also be used. The active pharmaceutical ingredients include anti-inflammatory analgesics and steroids. Idoid anti-inflammatory drugs, antihistamines, local anesthetics, disinfectants, antiseptics, vasoconstrictors, hemostatic agents, Chemotherapy drugs, antibiotics, keratolytic agents, cauterizing agents, antiviral drugs, antirheumatic drugs, antihypertensive drugs, Bronchodilators, anticholinergics, anxiolytics, antiemetics, hormones, peptides, proteins or A vaccine would also be acceptable. This pharmaceutically active ingredient is a pharmaceutically acceptable salt or prodrug of a drug. These may be derivatives, drug conjugates, or drug analogs.

[0132] The term "prodrug" refers to a drug that can be metabolized in the body to produce biologically active substances. , refers to a biologically inactive compound, or, "prodrug" refers to a biologically active compound. In addition to its inherent biological activity, when metabolized, it develops other biological activities or This may result in a drug having more desirable biological activity. In one embodiment, A drug may have its own biological activity, which may be similar to or different from that of the active substance. It can also have a prodrug, for example, an ester of epinephrine, for example, hydrolyzed. Dipivefrin, which is broken down into epinephrine, is also acceptable. For example, see the literature by J. Anderson et al. Intraocular hydrolysis sites of the prodrug dipivefrin, and its intraocular metabolism and its parent compound E Comparison with that of pinephrine (Site of ocular hydrolysis of a prodrug, dipivefrin, and a comparison of its ocular metabolism with that of the parent compound, epineph See "rine)" Invest., Ophthalmol. Vis. Sci. July 1980.

[0133] In some embodiments, the film may contain more than one pharmaceutically active ingredient. The active ingredients include ACE inhibitors, anti-anginal drugs, antiarrhythmic drugs, anti-asthma drugs, and anticholesterolemia drugs. Dispensing of medicines, analgesics, anesthetics, anticonvulsants, antidepressants, antidiabetic drugs, antidiarrheal drugs, antidepressants, antihistamines, antihistamines. Staminas, antihypertensives, anti-inflammatory drugs, anti-lipid drugs, anti-manic drugs, anti-nausea drugs, anti-stroke drugs Antithyroid drugs, amphetamines, antitumor drugs, antiviral drugs, acne drugs, alkaloids, Mino acids, cough suppressants, antiuricemia agents, antivirals, anabolic compounds, systemic and non-systemic Physical anti-infective drugs, antineoplastic drugs, antiparkinson's disease drugs, antirheumatic drugs, appetite stimulants, blood modifiers Drugs, bone metabolism regulators, cardiovascular drugs, central nervous system stimulants, cholinesterase inhibitors, contraception Medications, decongestants, nutritional supplements, dopamine receptor agonists, endometrial regulators, enzymes, Erectile dysfunction medication, fertility aids, gastrointestinal medications, homeopathic remedies, hormones, high-calcium content Drugs for the management of umciemia and hypocalcemia, immunomodulators, immunosuppressants, migraine medications, motion sickness medications. Drugs for treating uterine contractions, muscle relaxants, obesity control drugs, osteoporosis medications, uterine contraction drugs, parasympathetic nerve blocking drugs, parasympathetic Neuromimetic drugs, prostaglandins, psychotropic drugs, respiratory drugs, sedatives, smoking cessation aids Drugs, sympathetic nerve blockers, tremor countermeasures, urethral drugs, vasodilators, laxatives, antacids, ion exchange resins Lipids, antipyretics, appetite suppressants, expectorants, anti-anxiety drugs, anti-ulcer drugs, anti-inflammatory substances, coronary vasodilators, brain Vasodilators (cerebral vasodilators), peripheral vasodilators, psychotropic drugs, stimulants, antihypertensive drugs, vasoconstrictors, hemiplegia Pain relievers, antibiotics, tranquilizers, antipsychotics, antitumor drugs, anticoagulants, antithrombotic drugs, Hypnotics, antiemetics, anticardiac drugs, anticonvulsants, neuromuscular drugs, hyperglycemia and hypoglycemia drugs, thyroid and Antithyroid drugs, diuretics, seizure suppressants, uterine relaxants, anti-obesity drugs, erythropoiesis-producing drugs, anti-asthma drugs, Cough suppressants, mucolytics, DNA and genetic modification agents, diagnostic agents, contrast agents, dyes, or tracers, Or combinations thereof. Suitable active ingredients used in the films of this specification are: This includes, but is not limited to, the following types of treatments: ACE inhibitors, adrenaline-based drugs. Adrenocortical steroids, adrenocortical inhibitors, aldosterone antagonists, alkaloids Amino acids, anabolic drugs, stimulants, analgesics, anesthetics, appetite suppressants, anti-acne drugs, anti-addictive drugs Renaline drugs, anti-allergic drugs, anti-amoebic drugs, anti-anemia drugs, anti-angina drugs, anti-anxiety drugs, anti Antiarthritis drugs, antiarrhythmic drugs, anti-asthma drugs, anti-atherosclerotic drugs, anticholesterolemia drugs Antibiotics, anticholinergics, anticoagulants, anticonvulsants, antidepressants, antidiabetic drugs, antiperspirants Laxatives, antidiuretics, antidotes, antiemetics, anticonvulsants, antifibrinolytics, antifungals, hemostatics, Antihistamines, antihyperlipidemia drugs, antihypertensive drugs, vasopressors, anti-infective drugs (both systemic and non-systemic) Anti-inflammatory drugs, anti-lipid drugs, anti-manic drugs, antimicrobial drugs, anti-migraine drugs, mitotic inhibitors, antifungal drugs Antinausea-inducing heart drugs, antineoplastic drugs, antineutropenic drugs, anti-obesity drugs, antiparasitic drugs, anti-Parkinson's disease drugs Drugs, antiproliferative drugs, antipsychotics, antipyretics, antirheumatic drugs, antiseborrheic drugs, secretory inhibitors, seizure inhibitors Antistroke drugs, antithrombotic drugs, antithyroid drugs, antitumor drugs, cough suppressants, antiulcer drugs, antiuricemia drugs, anti-uricemia drugs Virus drugs, appetite suppressants, appetite stimulants, biological response modifiers, blood glucose regulators, blood modifiers, blood Fluid metabolism regulators, bone resorption inhibitors, bronchodilators, cardiovascular drugs, central nervous system stimulants, cerebrovascular drugs Dilatants, contraceptives, coronary vasodilators, cholinergics, antitussives, decongestants, inhibitors, diagnostic aids Drugs, nutritional supplements, diuretics, dopamine agonists, enzymes, estrogen receptor agonists Endometrial regulators, expectorants, erectile dysfunction medications, erythropoiesis, ibrinolytic (i Brinolytic, pregnancy-inducing drugs, fluorescent agents, free radical oxygen scavengers, gastric acid suppressants, Gastrointestinal motility effectors, gene modifiers, glucocorticoids, hair growth stimulants, hemostatic agents, Stamin H2 receptor antagonist, homeopathic remedy, hormone, hypercalcemia Drugs for managing symptoms, drugs for managing hypocalcemia, drugs for reducing hypocholesterolemia, drugs for lowering blood glucose, drugs for lowering lipids Antihypertensive drugs, ion exchange resins, contrast agents, immunotherapy drugs, immunomodulatory drugs, immunostimulants, immunomodulatory drugs, immunostimulants, immunotherapy drugs Epidemic suppressants, keratolytics, laxatives, LHRH agonists, mood regulators, motion sickness medications, mucus Dissolving agents, muscle relaxants, pupil dilators, nasal congestion decongestants, neuromuscular blocking agents, neuroprotective agents, NMDA antagonists Sterol derivatives, non-hormonal sterol derivatives, osteoporosis treatment drugs, uterine contraction drugs, parasympathetic nerve blockers Parasympathetic agonist mimics, plasminogen activators, platelet-activating factor antagonists Nistol, platelet aggregation inhibitors, prostaglandins, psychotropic drugs, antipsychotics, radiopharmaceuticals, Respiratory drugs, scabies insecticides, sclerosing agents, sedatives, sedative-hypnotics, selective agents Denosine A1 antagonist, serotonin antagonist, serotonin inhibitor, serotonin Receptor antagonists, smoking cessation medications, steroids, stimulants, sympathetic nerve blockers, Therin (t Thyroid relaxants, thyroid hormones, thyroid inhibitors, thyroid mimetic drugs, tranquilizers Rizer, tremor treatment drugs, amyotrophic lateral sclerosis drugs, cerebral ischemia drugs, Paget's disease drugs, unstable angina Symptomatic drugs, vasoconstrictors, vasodilators, weight management drugs, wound healing drugs, xanthine oxidase inhibitors Medicines, and combinations thereof.

[0134] Examples of suitable active ingredients used herein include antacids, H2 antagonists, and analgesics. It contains. For example, the dosage of antacids contains calcium carbonate as a single ingredient, or magnesium hydroxide. It may also be prepared using components combined with cium and / or aluminum hydroxide. Furthermore, antacids may be used in combination with H2 antagonists.

[0135] Analgesics include opioids and opioid derivatives, such as oxycodone (Oxycontin (registered trademark) Available on the market as (Trademark); Ibuprofen (Motrin®, Advil®, Motrin Children's (registered trademark), Motorin IB (registered trademark), Advil Children's (registered trademark), Motorin In fants' (registered trademark), Motrin Junior (registered trademark), Ibu-2 (registered trademark), Proprinal (registered trademark) Ibu-200 (registered trademark), Midol Cramp Formula (registered trademark), Bufen (registered trademark), Motrin Migr (Available on the market as aine Pain®, Addaprin®, and Haltran®) , aspirin (Empirin®, Ecotrin®, Genuine Bayer® and Ha Available on the market as lfprin (registered trademark), acetaminophen (Silapap Infant's (registered trademark) Tylenol, Silapap Children's (registered trademark), Tylenol Children 's (registered trademark), Tylenol Extra Strength (registered trademark), Tylenol Infants' Original nal (registered trademark), Tylenol Infants' (registered trademark), Tylenol Arthritis (registered trademark) T-Painol (registered trademark), Q-Pap (registered trademark), Cetafen (registered trademark), Dolono (registered trademark), Tyco Available on the market as lene (registered trademark), APAP (registered trademark), and Aminofen (registered trademark), and These include combinations that may optionally contain caffeine. The pain relievers include meperidine hydrochloride (available on the market as Demerol®), and capsaicin. Syn (available on the market as Qutenza®), morphine sulfate, and naltrexone hydrochloride Salt (available on the market as Embeda®), hydromorphone hydrochloride (Dilaudid®) (Available on the market as) propoxyfen napsylate and acetaminophen (Darvoce Available on the market as tN (registered trademark), fentanyl (Duragesic (registered trademark), Onsolis (registered trademark) (Trademark), and available on the market as Fentora (registered trademark), sodium hyaluronate (Euflexxa (Available on the market as registered trademark), adalimumab (available on the market as registered trademark Humira) , sumatriptan succinate (available on the market as Imitrex®), iontopho Fentanyl for resis (available on the market as Ionsys®), Orphenadol Salic acid salt (available on the market as Norgesic®), magnesium salicylate tetrahydrate (Novas Available on the market as al(registered trademark), oxymorphone hydrochloride (Opana ER(registered trademark)) (Available on the market), methocarbamol (available on the market as Robaxin®), carisopro Dol (available on the market as Soma®), Tramadol hydrochloride (Ultracet®) (and available on the market as Ultram®), morphine sulfate (MS Contin®) (Available on the market), metaxalone (available on the market as Skelaxin®), oxycod Acetaminophen / oxycodone hydrochloride (available on the market as OxyContin®), Hydrochloride (available on the market as Percocet®), oxycodone / aspirin (Percodan( Available on the market as a registered trademark, hydrocodone bitartrate / acetaminophen (Vicodi Available on the market as n(registered trademark), hydrocodone bitartrate / ibuprofen (Vicoprof Available on the market as en (registered trademark), Nepafenac (available on the market as Nevanac (registered trademark)) It may also contain (and pregabalin (available on the market as Lyrica®)).

[0136] The films disclosed herein may further contain drugs such as NSAIDs, which are examples of... For example, etodolac (available on the market as Lodine®), ketrolactromethamine (Acu Available on the market as lar (registered trademark) or Acuvail (registered trademark), naproxen sodium (An Available on the market as aprox (registered trademark) and Naprosyn (registered trademark), flurbiprofen (Ansai Available on the market as d(registered trademark), diclofenac sodium / misoprostol (Arthro Available on the market as tec (registered trademark), celecoxib (available on the market as Celebrex (registered trademark)). Possible), Sulindac (available on the market as Clinoril®), Oxaprozin (Daypro( (Available on the market as a registered trademark), Piroxicam (Available on the market as Feldene (registered trademark)) , indomethacin (available on the market as Indocin(registered trademark)), meloxicam (Mobic(registered trademark) Available on the market as a trademark, mefenamic acid (available on the market as Ponstel®), toru Methine sodium (available on the market as Tolectin®), magnesium trisalicylate Nesium (available on the market as Trilisate®), diclofenac sodium (Voltar Available on the market as en (registered trademark), diclofenac potassium (Cambia (registered trademark) or Zips (Available on the market as or (registered trademark), and misoprostol (Cytotec (registered trademark) on the market) (Available locally) This includes opioid agonists and antagonists, such as buprenorph. Ingredients such as ylamine and naloxone are further examples of drugs used in the present invention.

[0137] Other drugs for use with other active ingredients as described herein include antidiarrheal agents, such as loperamide. (Imodium AD(registered trademark), Imotil(registered trademark), Kaodene(registered trademark), Imperim(registered trademark), D iamode (registered trademark), QC Anti-Diarrheal (registered trademark), Health Care America Anti-Diarrhea Available on the market as l(registered trademark), Leader AD(registered trademark), and Imogen(registered trademark), Nita Zoxanide (available on the market as Alinia®) and diphenoxylate hydrochloride / ato Lopin sulfate (available on the market as Lomotil®), etc., antihistamines, cough suppressants, etc. Contains blood-thinning agents, vitamins, and breath fresheners. For colds, pain, fever, cough, congestion, runny nose, and Common drugs used alone or in combination for allergies, such as acetaminophen Ibuprofen, chlorpheniramine maleate, dextromethorphan, de Xtromethorphan HBr, Phenylephrine HCl, Pseudoephedrine HCl, Diphenephrine Dramine and related materials, such as dextromethophan HBr and phenyl The present invention involves a combination with refrin HCl, etc. (available as Triaminic®), etc. It can be included in the composition.

[0138] Other active ingredients available in this specification include, but are not limited to, alcohol dependence. Treatments for the disease, such as acamprosate calcium (available on the market as Campral®); Allergy medications, such as promethazine hydrochloride (available on the market as Fenelgan®), are available on the market. Possible), bepotastine besilate (available on the market as Bepreve®), hydrocodone Polystyrene / Chlorpheniramine Polystyrene (Tussionex (registered trademark) is sold in the market) (Available on the market), cetirizine hydrochloride (available on the market as Zyrtec®), cetirizine salt Pseudoephedrine hydrochloride (available on the market as Zyrtec-D®), Prometha Zin hydrochloride / codeine phosphate (available on the market as Fenelgan-Codeine®), Pemirolast (available on the market as Alamast®), fexofenadine hydrochloride (Alle Available on the market as gra (registered trademark), meclizine hydrochloride (available on the market as Antivert (registered trademark)). Available), azelastine hydrochloride (available on the market as Astelin®), nizatidine (A Available on the market as xid (registered trademark), desloratadine (available on the market as Clarinex (registered trademark) (Available on the market), cromolyn sodium (available as Crolom®), epinastine Hydrochloride (available on the market as Elestat®), Azelastine hydrochloride (Optivar®) (Available on the market as) Prednisolone phosphate sodium (Orapred ODT (Registered Trademark) Olopatadine hydrochloride (available on the market as Patanol®), , ketotifen fumarate (available on the market as Zaditor®), and montelucas Sodium tonazolate (available on the market as Singulair®); and antihistamines, for example Diphenhydramine HCl (available as Benadryl®), loratadine (Claritin) (Available as registered trademark), Astemizole (Available as Hismanal (registered trademark)), Nab Meton (available as Relafen®), diphenydramine HCl (The (Available as raFlu®) and clemastine (available as Tavist®) It is included.

[0139] The film of this disclosure further relates to Alzheimer's treatments, such as tacrine hydrochloride (Cognex (Registered (Available on the market as a trademark), galantamine (available on the market as Razadyne (registered trademark)), Nepezil hydrochloride (available on the market as Aricept®), rivastigmine tartrate (Exel (Available on the market as a registered trademark), Caprylidene (Available on the market as a registered trademark Axona) , and memantine (available on the market as Namenda®); anemia treatments, such as cyanoco Balamin (available on the market as Nascobal®) and Fermoxyl (Feraheme®) Available on the market as a registered trademark); anesthetics, e.g., antipyrine-benzocaine (Auralgan (Registered Trademark)); Available on the market as trademarks, Aurodex® and Auroto®; angina treatment drugs, e.g. For example, amlodipine besylate (available on the market as Norvasc®), nitroglycerin (Nitro-Bid (registered trademark), Nitro-Dur (registered trademark), Nitrolingual (registered trademark), Nitrostat ( (Registered trademark), available on the market as Transderm-Nitro (Registered trademark), isosorbide mononitrate (Imdu Available on the market as r (registered trademark), and isosorbide dinitrate (marketed as Isordil (registered trademark)). Available locally); cough suppressants, e.g., guaifensin; anti-Alzheimer's drugs, e.g. For example, nicergoline; and CaH -Antagonists, for example, nifedipine (Procardia (Registered Trademark) This may also include (Mark) and (Available on the market as Adalat®).

[0140] The active ingredients that can be used in this disclosure are also anti-asthmatic drugs, such as albuterol sulfate (Proventil Available on the market as (registered trademark), ipratropium bromide (marketed as Atrovent (registered trademark)). Available), salmeterol xinafoate (available on the market as Serevent®), The Filulkast (available on the market as Accolate®), Flunisolid (AeroBid®) (Available on the market as a trademark), methaproterenol sulfate (available on the market as Alupent (registered trademark)) (Available by hand), albuterol inhalation (available on the market as Ventolin®), terbutari Sulfates (available on the market as Brethine®), formoterol (Foradil®) Available on the market as (), cromolyn sodium (available on the market as Intal (registered trademark)), Bualbuterol hydrochloride (available on the market as Xopenex®), Zillowton (Zyflo® (Available on the market as a registered trademark), fluticasone propionate / salmeterol (Adva Available on the market as IR (registered trademark), albuterol sulfate / triamcinolone acetonide (Available on the market as Azmacort(registered trademark)), Dimethylxanthine (Theophylline(registered trademark)) (Available on the market as) and beclomethasone (Beclovent®, Beconase®) Available on the market as Qvar(registered trademark), Vancenase(registered trademark), Vanceril(registered trademark); blood A drug for treating tubular edema, for example, a CI esterase inhibitor (human) (marketed as Berinert®). (Available on the market) and ecalantide (available on the market as Kalbitor®); and antimicrobial therapeutics For example, trimethoprim / sulfamethoxazole (available on the market as Bactrim®) (Potential), mupirocine (available on the market as Bactroban®), metronidazole (Flagyl( (Available on the market as a registered trademark), Acetylsulfisoxazole (Gantricin (Registered trademark) (Available on the market as) Bismuth subsalicylate and metronidazole / tetracycline Phosphate hydrochloride (available on the market as Helidac Therapy®), nitrofurantoin (Macr (Available on the market as odantin (registered trademark)), norfloxacin (available on the market as Noroxin (registered trademark)) (Available on-site), Erythromycin ethyl succinate / acetyl sulfisoxazole (Available on the market as Pediazole®), and levofloxacin (Levaquin®) It may also include (available on the market as).

[0141] The films of this disclosure may further contain one or more antibiotics, including amoxicillin Phosphorus (available on the market as Amoxil®), Ampicillin (Omnipen®, Polyci Amoxicillin / Crab (Available on the market as llin® and Principen®), Potassium lanate (available on the market as Augmentin®), moxifloxacin hydrochloride ( Available on the market as Avelox (registered trademark), besifloxacin (as Besivance (registered trademark)) (Available on the market), clarithromycin (available on the market as Biaxin®), ceftib Ten (available on the market as Cedax®), cefuroxime axetil (Ceftin®) (Available on the market as), cefprodil (available on the market as Cefzil®), ciprof Roxacin hydrochloride (available on the market as Ciloxan® and Cipro®), Clin Damycin phosphate (available on the market as Cleocin T®), doxycycline Nhicrat (available on the market as Doryx (registered trademark)), dilithromycin (Dynabac (registered trademark) Available on the market as a trademark, erythromycin (EES®, E-Mycin®, Er YC (registered trademark), Ery-Tab (registered trademark), Erythrocin (registered trademark), and PCE (registered trademark) are registered trademarks of the city. (Available on-site), topical erythromycin (A / T / S (registered trademark), Erycette (registered trademark), T-Stat ( Available on the market as a registered trademark, Gemifloxacin (Available on the market as Factive (registered trademark)) (Potential), ofloxacin (Ocuflox®, publicly known as Floxin®), telisthromycin Syn (available on the market as Ketek (registered trademark)), lomefloxacin hydrochloride (Maxaquin (registered trademark) Available on the market as (trademark), minocycline hydrochloride (available on the market as Minocin®). ), fosfomycin tromethamine (available on the market as Monurol®), penicillin - Potassium (Penicillin VK®, available on the market as Veetids®), Trimetho Prim (available on the market as Primsol®), ciprofloxacin hydrochloride (Proquin XR) (Available on the market as a registered trademark), rifampin, isoniazid and pyrazinamide (Rifa Available on the market as ter (registered trademark), cefditoren (available on the market as Spectracef (registered trademark) (Available on the market), cefixime (available on the market as Suprax®), tetracycline (Achr (Available on the market as omycin V (registered trademark) and Sumycin (registered trademark)), tobramycin (Tobre (Available on the market as x(registered trademark)), Rifaximin (Available on the market as Xifaxan(registered trademark)) (Potential), Azithromycin (available on the market as Zithromax®), Azithromycin Turbidity (available on the market as Zmax®), Linezolid (available on the market as Zyvox®) Possible), benzoyl peroxide and clindamycin (available on the market as BenzaClin®). (Potentially), erythromycin and benzoyl peroxide (available on the market as Benzamycin®). ), dexamethasone (available on the market as Ozurdex®), ciprofloxacin and de Xamethasone (available on the market as Ciprodex®), polymyxin B sulfate / neomyxin Syn sulfate / hydrocortisone (available on the market as Cortisporin®), colistin Sulfate / Neomycin sulfate / Hydrocortisone acetate / Tonzonium bromide (Cortispo Available on the market as rin-TC Otic (registered trademark), cephalexin hydrochloride (Keflex (registered trademark) (Available on the market as), cefdinir (available on the market as Omnicef®), and gatif Contains roxacin (available on the market as Zymar®).

[0142] Other usable active ingredients include cancer drugs, such as cyclophosphamide (Cytoxan®). (Available on the market as) Methotrexate (Rheumatrex® and Trexal®) (Available on the market as) Tamoxifen citrate (Available on the market as Nolvadex®) ), bevacizumab (available on the market as Avastin (registered trademark)), everolimus (Afinitor ( (Available on the market as registered trademark), pazopanib (Available on the market as Votrient (registered trademark)), and anastrozole (available on the market as Arimidex®); leukemia treatment, for example Ofatumumab (available on the market as Arzerra®); antithrombotic drugs, e.g., Antitron Vinn genetically modified freeze-dried powder (available on the market as Atryn®), prasugrel (Ef Available on the market as ient(registered trademark); anticoagulants, e.g., aspirin-sustained-release dipyridamone. (Available on the market as Aggrenox (registered trademark)), warfarin sodium (Coumadin (registered trademark) Available on the market as (marked), dipyridamole (available on the market as Persantine®), Dalteparin (available on the market as Fragmin®), Danaparoid (Orgaran®) (Available on the market as) Enoxaparin (Available on the market as Lovenox®), Hepa Phosphate (available on the market as Hep-Lock, Hep-Pak, Hep-Pak CVC, Heparin Lock Flush), Chin Zaparin (available on the market as Innohep®), and clopidogrel bisulfate (Plavix) Available on the market as (registered trademark); antiemetics, e.g., granisetron hydrochloride (Kytril (registered trademark) (Available on the market as) and Navilon (Available on the market as Cesamet®), Trimeth Benzamide hydrochloride (available on the market as Tigan®) and ondansetron hydrochloride Salt (available on the market as Zofran®); antifungal drugs, e.g., ketoconazole (Nizora) Available on the market as (registered trademark), posaconazole (available on the market as Noxafil (registered trademark)) (Potential), cyclopirox (available on the market as Penlac®), griseofulvin (Gris-P Available on the market as EG (registered trademark), oxiconazole nitrate (as Oxistat (registered trademark)) (Available on the market), fluconazole (available on the market as Diflucan®), seltaconazole Zole nitrate (available on the market as Ertaczo®), terbinafine hydrochloride (Lamisil( (Available on the market as a registered trademark), Cyclopirox (Available on the market as Loprox (registered trademark)) , Nystatin / Triamcinolone acetonide (available on the market as Mycolog-II (registered trademark)) ), econazole nitrate (available on the market as Spectazole®), itraconazole ( Available on the market as Sporanox (registered trademark), and terconazole (Terazol (registered trademark)). (Available on the market), including.

[0143] The active ingredient is further an anti-inflammatory drug, such as hydroxychloroquine sulfate (Plaquenil (registered) Available on the market as a trademark, fluticasone propionate (Cutivate (registered trademark) and (Available on the market as) canakinumab (available on the market as Llaris®), amsinoni (Available on the market as Cyclocort®), Methylprednisolone (Medrol®) (Available on the market as), budesonide (available on the market as Entocort EC®), anarchy Nra (available on the market as Kineret (registered trademark)), diflorasone diacetate (Psorcon (registered trademark) Available on the market as a registered trademark, and etanercept (available on the market as a registered trademark of Enbrel). (Ability); seizure suppressant drugs, e.g., phenobarbital / hyosciamine sulfate / atropine sulfate) / Scopolamine hydrobromide (available on the market as Donnatal®); antiviral drug For example, oseltamivir phosphate (available on the market as Tamiflu®); antiparasitic treatment Therapeutic drugs, for example, tinidazole (available on the market as Tindamax®); appetite suppressants, for example For example, megestrol acetate (available on the market as Megace ES®), phentermine hydrochloride. Salt (available on the market as Adipex-P (registered trademark)), and diethylpropion hydrochloride (Tenuate ( Available on the market as a registered trademark); arthritis medication, for example, leflunomide (Arava (registered trademark) and (Available on the market as Cetolizumab pegol (available on the market as Cimzia®), Clofenac sodium (available on the market as Pennsaid®), golimumab (Simponi (Available on the market as a registered trademark), and tocilizumab (Available on the market as Actemra (registered trademark)). Possible); bladder control drugs, such as trospium chloride (available on the market as Sanctura®). (Potential), desmopressin acetate (available on the market as DDAVP®), tolterodine tartrate (Available on the market as Detrol®), oxybutynin chloride (Ditropan® or G Available on the market as elnique (registered trademark), dalifenacin (available on the market as Enablex (registered trademark)) (Available on the market), and solifenacine succinate (available on the market as VESIcare®); blood Tuberoconstrictors, such as methylergonovine maleate (marketed as Methergine®), Possible to use); plasmauric managers, such as rasburicase (Elitek®). Available on the market as; iron deficiency anemia treatment, e.g., fermoxytol (Feraheme (registered trademark) Available on the market as a registered trademark); lymphoma treatment drugs, such as pralatrexate (Folotyn (registered trademark) (Available on the market as) Romidepsin (Available on the market as Isodax®); Malaria Therapeutic drugs, such as artemether / lumefantrine (available on the market as Coartem®). ;A drug for treating hyponatremia, for example, tolvatpan (Samsca®, a registered trademark) Available on the market; treatment for von Willebrand disease (available on the market as Wilate®); Antihypertensive drugs, such as treprostinil (available on the market as Tyvaso®), free Lafil (available on the market as Adcirca®); cholesterol-lowering drugs, for example, Recalcitol (available on the market as Altocor®), Pitavastatin (Livalo®) (Available on the market as a trademark), lovastatin, niacin (Available on the market as Advicor (registered trademark) (Available on the market), Colestipol hydrochloride (available on the market as Colestid®), Rosvasta Calcium tin (available on the market as Crestor®), fluvastatin sodium (Le Available on the market as scol (registered trademark), atorvastatin calcium (Lipitor (registered trademark) (Available on the market as), lovastatin (Available on the market as Mevacor®), niacin (Available on the market as Niaspan (registered trademark)), Pravastatin sodium (Pravacol ( Available on the market as a registered trademark, pavastatin sodium-buffered aspirin Phosphorus (available on the market as Pravigard PAC (registered trademark)), Cholestyramine (Questran (registered trademark) Simvastatin and niacin (marketed as Simcor®) are available on the market as registered trademarks. (Available on the market), atenolol, chlorthalidone (available on the market as Tenoretic®), Atenolol (available on the market as Tenormin®), fenofibrate (Tricor® Available on the market as a registered trademark, fenofibrate (available on the market as Triglide (registered trademark)) Possible), ezetimibe / simvastatin (available on the market as Vytorin®), cholecebe Lamb (available on the market as WelChol®), bisoprolol fumarate (Zebeta® Available on the market as a trademark, ezetimibe (available on the market as Zetia (registered trademark)), bisop Lorol fumarate / hydrochlorothiazide (available on the market as Ziac®), and This may include simvastatin (available on the market as Zocor®).

[0144] The active ingredients contained herein are also used in the treatment of chronic kidney disease, such as paricalcitol (Zempl). Available on the market as ar(registered trademark); contraceptives, e.g., etonogestrel (Implanon(registered trademark) (Available on the market as) norethindrone acetate, ethinylestradiol (Loe Available on the market as strin 24 FE (registered trademark), ethinylestradiol, norugues Tromin (available on the market as Ortho Evra (registered trademark)), Levonorgestrel (Plan B (registered trademark) (Available on the market as a trademark), levonorgestrel and ethinylestradiol (Preven( (Available on the market as a registered trademark), levonorgestrel, ethinylestradiol (Season nique (registered trademark) is available on the market, and medroxyprogesterone acetate (Dep Available on the market as o-Provera®; COPD treatment, e.g., alformoterol tartrate Salts (available on the market as Brovana®) and ipratropium bromide, albutero Tefl sulfate (available on the market as Combivent®); cough suppressants, e.g., benzonatate (Tes Salon (registered trademark) is available on the market, along with guaifenesin, codeine phosphate (Tussi-Org Available on the market as anidin NR (registered trademark), and acetaminophen-codeine phosphate ( Available on the market as Tylenol-Codeine®; diabetes medication, e.g., Piogli Tazone hydrochloride, metformin hydrochloride (available on the market as ACTOplus met®), bro Mocriptine mesylate (available on the market as Cycloset®), liraglutide (Victo Available on the market as za (registered trademark), saxagliptin (available on the market as Onglyza (registered trademark) (Available on the market), pioglitazone hydrochloride (available on the market as Actos®), glimepiride (A Available on the market as maryl (registered trademark), rosiglitazone maleate, metformin hydrochloride Salt (available on the market as Avandaryl(registered trademark)), rosiglitazone maleate (Avandaryl( Available on the market as a registered trademark, rosiglitazone maleate (as Avandia (registered trademark)) (Available on the market), exenatide (Available on the market as Byetta®), exenatide (By Available on the market as dureon (registered trademark), chlorpropamide (as Diabinese (registered trademark)) Available on the market), pioglitazone hydrochloride, glimepiride (marketed as Duetact®) (Available on the market), metformin hydrochloride (available on the market as Glucophage®), Glyp Zide (available on the market as Glucotrol®), Glybride, Metformin (Glucovance (Available on the market as registered trademark and Fortamet), metformin hydrochloride (Glumetza (Available on the market as a registered trademark), sitagliptin (Available on the market as Januvia (registered trademark) (Potential), detemir (available on the market as Levemir®), glipizide, metformin hydrochloride Salt (available on the market as Metaglip®), Glybride (available on the market as Micronase®) (Available on the market), repaglinide (available on the market as Prandin (registered trademark)), acarbose (Pre Available on the market as cose (registered trademark), nateglinide (available on the market as Starlix (registered trademark)). (possible), plumlintide acetate (available on the market as Symlin®), canagliflozin (Available on the market as Invokana (registered trademark)), Linagliptin (as Tradjenta (registered trademark)) (Available on the market), dapagliflozin (available on the market as Farxiga®), insulin Ngralgin (available on the market as Lantus® or Toujeo®), insulin Aspart (available on the market as Novolog®), insulin lispro, Empagli Flozin (available on the market as Jardiance (registered trademark)) and Trazamide (Tolinase (registered trademark) This may include (available on the market as a standard).

[0145] Other usable active ingredients include digestive agents, such as sulfasalazine (Azulfidine®). (Available on the market as) Rabeprazole sodium (Available on the market as AcipHex®) (B), lubiprostone (available on the market as Amitiza®), dicyclomine hydrochloride (B Available on the market as entyl (registered trademark), and scralfate (available on the market as Carafate (registered trademark)). (Available on the market), lactulose (available on the market as Chronulac (registered trademark)), doxart (Col Available on the market as ace (registered trademark), balsalazid disodium (as Colazal (registered trademark)) (Available on the market), losartan potassium (available on the market as Cozaar®), Orsa Sodium radin (available on the market as Dipentum®), chlordiazepoxide hydrochloride Salt, clidinium bromide (available on the market as Librax®), esomeprazole magnesium Cium (available on the market as Nexium®), Famotidine (as Pepcid®) (Available on the market), lansoprazole (available on the market as Prevacid®), lansoprazole Razole and naproxen (available on the market as Prevacid NapraPAC®), Amoxi Sicillin / Clarithromycin / Lansoprazole (available on the market as Prevpac®) ), omeprazole (available on the market as Prilosec®), pantoprazole Thorium (available on the market as Protonix®), Metoclopramide hydrochloride (Reglan® Available on the market as registered trademark (or Metozolv(registered trademark)), cimetidine (Tagamet(registered trademark) and (Available on the market as), ranitidine hydrochloride (available on the market as Zantac®), and Omeprazole, sodium bicarbonate (available on the market as Zegerid®); diuretics For example, spironolactone, hydrochlorothiazide (marketed as Aldactazide®) (Available on the market), spironolactone (available on the market as Aldactone®), bumetanide (Bum (Available on the market as ex (registered trademark)), Torsemid (Available on the market as Demadex (registered trademark)) , chlorothiazide (available on the market as Diuril®), furosemide (Lasix®) (Available on the market as), Methrazone (Available on the market as Zaroxolyn®), and Hid Contains lochlorothiazide and triamterene (available on the market as Dyazide®). It is possible.

[0146] The active ingredients available herein are also emphysema treatments, such as tiotropium bromide (Spiriva). Available on the market as (registered trademark); fibromyalgia treatment, e.g., milnacipran hydrochloride (Savel Available on the market as la (registered trademark); gout treatment drugs, such as colchicine (Colcrys (registered trademark) and (Available on the market as) and febuxostat (available on the market as Uloric®); enemas Intestinal therapeutic drugs, for example, aminosalicylic acid (as Mesalamine® and Rowasa®) Available on the market; epilepsy medications, for example, valproic acid (available on the market as Depakene®). (possible), Felbatol (available on the market as Felbatol®), Lamotrigine (Lamict Available on the market as al(registered trademark), primidone (available on the market as Mysoline(registered trademark)). ), oxcarbazepine (available on the market as Trileptal®), zonisamide (Zonegra n (available on the market as registered trademark), levetiracetam (available on the market as registered trademark Keppra) This includes (and phenytoin sodium (available on the market as Dirantin®)). It is possible.

[0147] The active ingredients available herein also include ophthalmic and therapeutic agents, such as dipivefrin hydrochloride. Salt (available on the market as Propine®), valganciclovir (Valcyte® and (Available on the market as Zirgan®); Potastine besilate (available on the market as Bepreve®), besifloxacin (Besi Available on the market as Vance (registered trademark), Bromfenac (available on the market as Xibrom (registered trademark)) (Available on the market as FML®), fluorometholone (available on the market as FML®), pilocarpine hydrochloride (P ilocar (registered trademark) is available on the market, cyclosporine (registered trademark Restasis) is available on the market (Available on the market), brimonidine tartrate (available on the market as Alphagan P®), Dorzo Lamid hydrochloride / timolol maleate (available on the market as Cosopt®), bimato Prost (available on the market as Lumigan®), Timolol maleate (Timoptic( (Available as a registered trademark), Travoprost (Available on the market as Travatan (registered trademark)), Latanoprost (available on the market as Xalatan®), ecothiophate iodide (Phos Available on the market as pholine Iodide (registered trademark), and ranibizumab (Lucentis (registered trademark)) Available on the market as; fluid regulators, e.g., acetazolamide (Diamox®) on the market Available; gallstone treatment drugs, e.g., ursodiol (available on the market as Actigall®). ; Gingivitis treatment drugs, for example, chlorhexidine gluconate (marketed as Peridex®) Possible); headache medications, e.g., butarvital / codeine phosphate / aspirin / caffeine ( Fiornal (registered trademark) - available on the market as codeine), naratriptan hydrochloride (Amerge (registered trademark) (Available on the market as a trademark), Almotriptan (Available on the market as Axert (registered trademark)), Ergotamine tartrate / caffeine (available on the market as Cafergot®), butarbit Tar / acetaminophen / caffeine (available on the market as Fioricet®), porcine Rubital / Aspirin / Caffeine (available on the market as Fiorinal®), Frobath Liptan succinate (available on the market as Frova®), rizatriptan benzoate ( Available on the market as Maxalt (registered trademark), isometeptene mucinate / dichloral phenazo / Acetaminophen (available on the market as Midrin®), dihydroergotamine Mesylate (available on the market as Migranal®), Eletriptan hydrobromide (Rel Available on the market as pax (registered trademark), and zolmitriptan (available on the market as Zomig (registered trademark)). Available; influenza treatments, e.g., Haemophilus b conjugate vaccine; tetanus toxoi Conjugates (available on the market as Hiberix®); and cardiac medications, such as quinidine. Sulfate, isosorbide disnitrate / hydralazine hydrochloride (available on the market as BiDil®) , digoxin (available on the market as Lanoxin®), flecainide acetate (Tamboco Available on the market as r (registered trademark), mexiletine hydrochloride (available on the market as Mexitil (registered trademark) (Available on the market), disopyramide phosphate (available on the market as Norpace®), procaine Mid hydrochloride (available on the market as Procanbid®), and propafenone (Rythmol® This may include (available on the market as a registered trademark).

[0148] Other usable active ingredients include hepatitis medications, such as entecavir (Baraclude®) (Available on the market as) Hepatitis B immunoglobulin (Available on the market as HepaGam B (registered trademark)) , and Copegus / Rebetol / Ribasphere / Vilona / Virazole (Ri Available on the market as baviline (registered trademark); herpes treatment, e.g., valacyclovir hydrochloride (Available on the market as Valtrex (registered trademark)), penciclovir (available on the market as Denavir (registered trademark)) (Available on the market), acyclovir (available on the market as Zovirax®), and famcyclovir Vir (available on the market as Famvir®); antihypertensive drugs, e.g., enalaprilat (Vaso Available as tec (registered trademark), captopril (available as Capoten (registered trademark)) and Lisinopril (available as Zestril®), verapamil hydrochloride (Calan®) (Available as), ramipril (marketed as Altace®), olmesartan Medoxomil (available on the market as Benicar®), amlodipine / atorvastatin (Available on the market as Caduet®), nicardipine hydrochloride (as Cardene®) Available on the market), diltiazem hydrochloride (available on the market as Cardizem®), quinap Ryl hydrochloride (available on the market as Accupril®), quinapril hydrochloride / hydrochlorochloride Thiazide (available on the market as Accuretic®), Perindopril Erbumine (Aceon( (Available on the market as a registered trademark), candesartan cilexetil (as Atacand (registered trademark) (Available on the market), Candesartan Cilexetil / Hydrochlorothiazide (Atacand HCT (Registered) Available on the market as a trademark, Irbesartan / hydrochlorothiazide (Avalide (registered trademark)) (Available on the market as), Irbesartan (Available on the market as Avapro®), AMRO Dipine besylate / olmesartan medoxomil (available on the market as Azor®), Levobunolol hydrochloride (available on the market as Betagan®), betaxolol hydrochloride ( Available on the market as Betoptic (registered trademark), Nebibolol (available on the market as Bystolic (registered trademark)) Available on the market as captopril / hydrochlorothiazide (Capozide®). (Potentially), doxazosin mesylate (available on the market as Cardura®), clonidine hydrochloride Salt (available on the market as Catapres®), carvedilol (available on the market as Coreg®) (Available on the market), Nadrol (Available on the market as Corgard®), Nadrol / Bend Loflumethiazide (available on the market as Corzide (registered trademark)), valsartan (Diovan (registered trademark) (Available on the market as a trademark), Isradipine (Available on the market as DynaCirc (registered trademark)), G Anabenz acetate (available on the market as Wytensin®), guanfacine hydrochloride (Ten Available on the market as ex(registered trademark) or Intuniv(registered trademark), losartan potassium / hydro Chlorothiazide (available on the market as Hyzaar®), propranolol hydrochloride (Inder Available on the market as a (registered trademark), propranolol hydrochloride / hydrochlorothiazide (Inde Available on the market as ride (registered trademark), Eplerenone (available on the market as Inspra (registered trademark)) (Ambicentan), Ambrisentan (available on the market as Letairis®), Enalaprilmaray Ferodipine (available on the market as Lexxel®), Metoprolol tartrate ( Available on the market as Lopressor (registered trademark), benazepril hydrochloride (Lotensin (registered trademark) and (Available on the market), Benazepril hydrochloride / hydrochlorothiazide (Lotensin HCT (registered trademark) (Available on the market as) Amlodipine / Benazepril Hydrochloride (Marketed as Lotrel®) (Available on the market), indapamide (available on the market as Lozol®), trandolapril (Mav Available on the market as ik (registered trademark), telmisartan (available on the market as Micardis (registered trademark)). (Possible), Telmisartan / hydrochlorothiazide (available on the market as Micardis HCT®) (possible), prazosin hydrochloride (available on the market as Minipress®), amiloride, hi Dichlorothiazide (available on the market as Moduretic®), Hoshinoprilus (Available on the market as ZZXT Monopril®), Hosinopril sodium / hydrochloride Rothiazide (available on the market as Monopril-HCT®), pindol (Visken (registered trademark) Available on the market as (trademark), felodipine (available on the market as Plendil®), sil Denafil citrate (available on the market as Revatio®), Nisoldipine (Sular®) Available on the market as a registered trademark, trandolapril / verapamil hydrochloride (Tarka (registered trademark) and (Available on the market as), Aliskiren (Available on the market as Tekturna®), Eprosa Lutan mesylate (available on the market as Teveten®), eprosartan mesylate / Hydrochlorothiazide (available on the market as Teveten HCT®), moexipryl salt Salt / hydrochlorothiazide (available on the market as Uniretic®), moexipril Hydrochloride (available on the market as Univasc®), Enalapril maleate / hydrochloride Rothiazide (available on the market as Vaseretic®), and lisinopril / hydrochloride Contains rothiazide (available on the market as Zestoretic®).

[0149] The films disclosed herein can be used as active ingredients for HIV / AIDS treatment, such as ampoule. Navir (available on the market as Agenerase®), Tipranavir (Aptivus®) (Available on the market), Efavirenz / Emtricitabine / Tenofovir (Atripla (registered trademark)) (Available on the market as) Lamivudine / Zidovudine (Available on the market as Combivir®) , indinavir sulfate (available on the market as Crixivan®), lamivudine (Epivir (registered trademark) (Available on the market as a registered trademark), Saquinavir (Available on the market as Fortovase (registered trademark)), Zalcitabine (available on the market as Hivid®), lopinavir / ritonavir (Kaletra( Available on the market as a registered trademark, fosamprenavir calcium (Lexiva (registered trademark)) (Available on the market), ritonavir (available on the market as Norvir (registered trademark)), zidovudine (Re Available on the market as trovir (registered trademark), atazanavir sulfate (as Reyataz (registered trademark)) Available on the market), efavirenz (available on the market as Sustiva®), abacavir / Lamivudine / zidovudine (available on the market as Trizivir®), didanosine (Videx®) Available on the market as a registered trademark, nelfinavir mesylate (Viracept (registered trademark)) is available on the market. (Available on the market), nevirapine (available on the market as Viramune®), tenofovir disop Roxyl fumarate (available on the market as Viread®), Stabzine (Zerit®, registered trademark) Available on the market as (marked) and abacavir sulfate (available on the market as Ziagen®). Homocysteene scavenging agents, such as anhydrous betaine (Cystadane® and Available on the market); pharmaceuticals, such as insulin (Apidra®, Humalog®, Humulin®, Iletin®, Tresiba®, and Novolin® Available on the market; as well as HPV treatments, such as the human papillomavirus vaccine (Gardas Available on the market as il (registered trademark) or human papillomavirus bivalent vaccine (Cervarix ( Available on the market as a registered trademark); immunosuppressants, such as cyclosporine (Gengraf(registered trademark)); Neoral (registered trademark), Sandimmune (registered trademark), and Apo-Cyclosporine (registered trademark) are registered trademarks of the city. (Available on site) can be included.

[0150] The active ingredients available in this disclosure are further prolactin inhibitors, such as bromocriptine. Silates (available on the market as Parlodel®); adjunct medicine for stress testing, e.g., Gadenosone (available on the market as Lexiscan®); a treatment for alopecia, e.g., finasteride Lido (available on the market as Propecia® and Proscar®); pancreatitis treatment, for example Gemfibrozil (available on the market as Lopid®); hormone therapy, e.g., Nor Etindrone acetate / ethinylestradiol (available on the market as femHRT®) (possible), goserelin acetate (available on the market as Zoladex®), progesterone gel (Available on the market as Prochieve®), progesterone (as Prometrium®) (Available on the market), salmon calcitonin (available on the market as Miacalcin®), calcium Triol (available on the market as Rocaltrol®), Syntroid (Levothroid®) Available on the market as trademarks, Levoxyl (registered trademark), Unithroid (registered trademark), testosterone (Testopel (registered trademark), Androderm (registered trademark), Testoderm (registered trademark), and AndroGel (registered trademark) Available on the market as a trademark); antimenopausal medication, e.g., estradiol / norethindrone vinegar. Acid ester (available on the market as Activella®), drospirenone / estradiol (Available on the market as Angeliq (registered trademark)), estradiol / levonorgestrel (Cli Available on the market as mara Pro (registered trademark), estradiol / norethindrone acetate Tel (available on the market as CombiPatch (registered trademark)), estradiol (Estrasorb (registered trademark) Available on the market as (Registered Trademark), Vagifem® and EstroGel®, Esterified E Trogen and methyltestosterone (available on the market as Estratest®), Est Rogen (Alora (registered trademark), Climara (registered trademark), Esclim (registered trademark), Estraderm (registered trademark)) Available on the market as Vivelle (registered trademark) and Vivelle-Dot (registered trademark), estropipate ( Available on the market as Ogen (registered trademark), conjugated estrogen (available on the market as Premarin (registered trademark)). (Available on the market) and medroxyprogesterone acetate (marketed as Provera®) Available; menstrual medications, e.g., leuprolide acetate (available on the market as Lupron Depot), Tranexamic acid (available on the market as Lysteda®) and norethindrone acetate Tel (available on the market as Aygestin); and muscle relaxants, such as cyclobenzaprine hydrochloride. Salt (available on the market as Flexeril®), tizanidine (available on the market as Zanaflex®) (Available on the market), and containing hyoscyamine sulfate (available on the market as Levsin®). It is possible.

[0151] The active ingredients available herein are also osteoporosis treatments, such as sodium ibrandronate. Um (ibrandronate sodium) (available on the market as Boniva®), risedronate (Ac Available on the market as tonel (registered trademark), raloxifene hydrochloride (Evista (registered trademark), Forti Available on the market as cal(registered trademark), and sodium alendronate (Fosamax(registered trademark)) Available on the market as; ovulation stimulants, such as clomiphene citrate (Serophene®). Available on the market as Clomid® and Serophene®; a treatment for Paget's disease. For example, disodium etidronate (available on the market as Didronel®); pancreatic enzyme deficiency Disease treatment drugs, for example, pancrelipase (marketed as Pancrease® or Zenpep®) Available on-site); Parkinson's disease treatment drugs, for example, pramipexole dihydrochloride (Mirapex (Registered Trademark) Available on the market as (Registered Trademark), Ropinirole hydrochloride (Available on the market as Requip®), Carvidopa / Levodopa (available on the market as Sinemet CR®), Carvidopa / Levodopa / Entacapone (available on the market as Stalevo(registered trademark)), selegiline hydrochloride (Zelapar(registered trademark) (Available on the market as a registered trademark), Rasagiline (Available on the market as Azilect (registered trademark)), E Ntacapone (available on the market as Comtan®), and selegiline hydrochloride (Eldepryl® Available on the market as a registered trademark); multiple sclerosis treatment drug, for example, dalfampridine (Ampyra( (Available on the market as a registered trademark) and interferon β-Ib (Extavia (registered trademark) Available on the market; prostate medications, such as flutamide (available on the market as Eulexin®). , Niltamide (available on the market as Nilandron®), Dutasteride (Avodart® (Available on the market as a trademark), Tamsulosin hydrochloride (Available on the market as Flomax® registered trademark) , terazosin hydrochloride (available on the market as Hytrin®) and alfuzosin hydrochloride (Uro This may include Xatral (a registered trademark available on the market).

[0152] The film disclosed herein further contains information on antipsychotic drugs, such as alprazolam (Niravam®), Available as Xanax (registered trademark), clozopine (available as Clozaril (registered trademark)) (Available as), haloperidol (available as Haldol®), fluoxetine hydrochloride (Pr Available as ozac (registered trademark), sertraline hydrochloride (available as Zoloft (registered trademark)) ), asenapine (available on the market as Saphris®), iloperidone (Fanapt®) (Available on the market as) and paroxtine hydrochloride (Paxil®) (Available for use), aripiprazole (available on the market as Abilify®), guanfacine (I Available on the market as ntuniv (registered trademark), amphetamine and methamphetamine (Adderall (Available on the market as registered trademark and Desoxyn), clomipramine hydrochloride (Anafran Available on the market as il (registered trademark), buspirone hydrochloride (available on the market as BuSpar (registered trademark)). Possible), citalopram hydrobromide (available on the market as Celexa®), duloxet Ritalin hydrochloride (available on the market as Cymbalta®), methylphenidate (Ritalin, Dayt Available on the market as rana (registered trademark), divalproex sodium (valproic acid) (Depako Available on the market as te (registered trademark), dextroamphetamine sulfate (Dexedrine (registered trademark) Available on the market as (trademark), venlafaxine hydrochloride (available on the market as Effexor® registered trademark) (Potential), selegiline (available on the market as Emsam®), carbamazepine (Equetro®) Available on the market as a trademark, lithium carbonate (available on the market as Eskalith® registered trademark), f Luboxamine maleate / dexmethylphenidate hydrochloride (as Focalin®) Available on the market), ziprasidone hydrochloride (available on the market as Geodon®), mesylate Ergoloid (available on the market as Hydergine®), escitalopram oxalate ( Available on the market as Lexapro (registered trademark), chlordiazepoxide (as Librium (registered trademark)) (Available on the market), morindone hydrochloride (available on the market as Moban®), fenellum Sulfates (available on the market as Nardil®), thiothixene (as Navane®) (Available on the market), desipramine hydrochloride (available on the market as Norpramin®), Ben Zodiazepines (e.g., those available as oxazepam®), nortriptyline Hydrochloride (available on the market as Pamelor®), Tranexypromine sulfate (Parnate (registered trademark) Available on the market as a registered trademark, prochlorperazine, mirtazapine (Remeron (registered trademark) and (Available on the market as), risperidone (available on the market as Risperdal (registered trademark)), que Chiapine fumarate (available on the market as Seroquel®), doxepine hydrochloride (Sineq Available on the market as UAN (registered trademark), atomoxetine hydrochloride (as Strattera (registered trademark)) (Available on the market), Trimipramine maleate (Available on the market as Surmontil®) , olanzapine / fluoxetine hydrochloride (available on the market as Symbyax®), imipu Lamin hydrochloride (available on the market as Tofranil®), protriptyline hydrochloride (Vivac Available on the market as til (registered trademark), bupropion hydrochloride (Wellbutrin (registered trademark), Wellb (Available on the market as utrin SR (registered trademark) and Wellbutrin XR (registered trademark), as well as Ora This may include nazapine (available on the market as Zyprexa®).

[0153] The active ingredients available herein are also uric acid-lowering agents, such as allopurinol (Zylopri). Available on the market as m(registered trademark); seizure medications, e.g., gabapentin (Neurontin(registered trademark) (Available on the market as) ethotoin (Available on the market as Peganone®), Vigabat Phosphate (available on the market as Sabril®), and Topiramart (as Topamax®) Available on the market); treatments for shingles, such as the live shingles vaccine (Zostavax®) Available on the market); skincare therapeutics, for example, calcipotriene (as Dovonex®). (Available on the market), ustekinumab (available on the market as Stellara®), televancein (televancin) (available on the market as Vibativ (registered trademark)), isotretinoin (Accutane (registered trademark) Available on the market as a registered trademark, hydrocortisone / iodoquinol (Alcortin (registered trademark) and (Available on the market as Avar(registered trademark)), Sodium sulfacetamide / sulfur (Available on the market as Avar(registered trademark)) Possible), azelaic acid (available on the market as Azelex® and Finacea®), peracid Benzoyl benzoyl (available on the market as Desquam-E (registered trademark)), adapalene (Differin (registered trademark) (Available on the market as a registered trademark), fluorouracil (available on the market as Efudex®), pi Mecrolimus (available on the market as Elidel®), topical erythromycin (A / T / S (registered trademark) Available on the market as registered trademarks, Erycette (registered trademark), T-Stat (registered trademark), hydrocortisol (Available on the market as Cetacort®, Hytone®, and Nutracort®) , metronidazole (available on the market as MetroGel®), doxycycline (Orace Available on the market as a (registered trademark), tretinoin (Retin-A (registered trademark) and Renova (registered trademark) Available on the market as (trademark), Mequinol / Tretinoin (available on the market as Solage (registered trademark) (Ability), acitretin (available on the market as Soriatane®), calcipotriene hydrate / Betamethasone dipropionate (available on the market as Taclonex®), Taza Rotenoid (available on the market as Tazorac®), fluocinonide (as Vanos®) (Available on the market), desonide (available on the market as Verdeso®), miconazole nitrate Salt / zinc oxide (available on the market as Vusion®), ketoconazole (Xolegel®) (Available on the market as) and efalizumab (Available on the market as Raptiva®) It can include.

[0154] Other active ingredients available in this specification include sleep disorder medications, such as zaleplon (Sonata ( (Available as a registered trademark) and eszopiclone (available as Lunesta® registered trademark), sol Pidem tartrate (marketed as Ambien®, Ambien CR®, and Edluar®) (Available on the market), lorazepam (available on the market as Ativan®), flurazepam hydrochloride (Da Available on the market as lmane (registered trademark), triazolam (available on the market as Halcion (registered trademark)). Possible), clonazepam (available on the market as Klonopin®), barbiturates (e.g.) Phenobarbital (registered trademark), modafinil (available on the market as Provigil (registered trademark)). ), temazepam (available on the market as Restoril (registered trademark)), rameltheone (Rozerem (registered trademark) Available on the market as (Tranxene®), dipotassium chlorazepate (available on the market as Tranxene®). Possible), diazepam (available on the market as Valium®), quazepam (Doral®) (Available on the market as) and estazolam (Available on the market as ProSom®) Smoking cessation medications, such as varenicline (available on the market as Chantix®), nicotine, For example, Nicotrol® and bupropion hydrochloride (available on the market as Zyban®) (Ability); and steroids, such as alclomethasone dipropionate (Aclovate ( (Available on the market as a registered trademark), betamethasone dipropionate (Diprolene (Registered Trademark) Mometasone furoate (Elocon®), available on the market as a registered trademark. (Available on the market), Fluticasone (Flonase®, Flovent®, Flovent Disk (Available on the market as US (registered trademark), Flovent Rotadisk (registered trademark), fluocinonide (Lide Available on the market as x (registered trademark), mometasone furoate monohydrate (Nason Available on the market as ex (registered trademark), desoximethasone (available on the market as Topicort (registered trademark)). (Available), clotrimazole / betamethasone dipropionate (Lotrisone (Registered Trademark) (Available on the market as a trademark), Prednisolone acetate (Pred Forte®, Prednisone ( It is marketed as (registered trademark), Budesonide Pulmicort (registered trademark), and Rhinocort Aqua (registered trademark). (Available for purchase), Prednisolone phosphate sodium (marketed as Pediapred®) (Available on the market), desonide (available on the market as Tridesilon®), and halo propionate This may include betasol (available on the market as Ultravate®).

[0155] The film of the present invention further contains active ingredients that can be used to treat thyroid diseases, such as hormone TC and Available on the market as TD (Armour Thyroid® registered trademark); Potassium deficiency treatments, such as potassium chloride (available on the market as Micro-K®); Triglyceride regulators, such as ω-3 fatty acid ethyl esters (marketed as Omacor®), are available. available); Urinary tract medications, such as phenazopyridine hydrochloride (available on the market as Pyridium®). and methenamine, methylene blue / phenyl salicylate / benzoic acid / atropine sulfate / Hydrochloride Sucamine (available on the market as Urised®); Vitamin supplements for pregnant women (Advanced Natalcare®, Materna®, Natalins®) Available on the market as a trademark, Prenate Advance (registered trademark); Weight control drugs, such as orlistat (available on the market as Xenical®) and It may contain butramine hydrochloride (available on the market as Meridia®).

[0156] Reputable H2-antagonists intended for use herein include cimetidine, lanolin Tidine hydrochloride, famotidine, nizatidien, ebrotidine, miphentidine Roxatidine, pisatidine, and aceroxatidine (roxatidine acetate) (Ster) is included.

[0157] The active antacid ingredients are not limited to the following: aluminum hydroxide, dihydrogen hydroxide hydroxyaluminum aminoacetate, aminoacetic acid, aluminum phosphate, dihydrox Sodium aluminum carbonate, bicarbonate, bismuth aluminate, bismuth carbonate, subcarbonate Bismuth acid, bismuth subgallate, bismuth subnitrate, bismuth subsilicylate silate, calcium carbonate, calcium phosphate, citrate ions (acid or salt), aminoacetic acid Magnesium aluminate sulfate hydrate, Magaldorate, Magnesium aluminosilicate Magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide M, magnesium trisilicate, milk solids, monobasic or dibasic aluminum calcium phosphate Um, tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate It contains magnesium aluminosilicate, tartaric acid, and salts.

[0158] The activators used in the present invention are allergens or antigens, and are not limited to the following: However, there is no plant pollen from grasses, trees, or ragweed; skin and hair of cats and other furry animals. Animal dander, which consists of tiny scales that fall from animals; insects, such as house dust mites, honeybees, and wasps; Furthermore, it may include drugs, such as penicillin.

[0159] Examples of specific active ingredients include, but are not limited to, the following: 16-α-fluoroxtra Diol (fluorocstradiol), 16-α-gitoxin, 16-epiestriol, 17-α-dihydro Roechirenine, 17-α-estradiol, 17-β-estradiol, 17-hydroxypro Gesterone, l-α-hydroxyvitamin D2, 1-dodecpyrrolidinone ), 20-epi-1,25-dihydroxyvitamin D3, 22-oxacalcitriol, 2CVV, 2'-nor-c GMP, 3-isobutylGABA, 5-ethinyluracil, 6-FUDCA, 7-methoxytacrine, abamec Chin, avanokil, avecarnil, abiraterone, abulkast, abulkastsodium Acadecin, acamprosate, acarbose, acebutrol, acecainide hydrochloride Salt, aceclysine, aceclofenae, acedapsone, aceglutamide Luminium, acemannan, acetaminophen, acetazolamide, acetohexamide, Acetohydroxamic acid, acetomepregenol, acetophenazine maleate, acetos Sodium rufonate, acetylcholine chloride, acetylcysteine, acetyl-L-carnitine Acetylmetadol, Acifran, Acipimox, Acitemate, Acito Retin, Asibicin, Acralubicin, Aclatonium, Acodazole Hydrochloride, Aconia Zid, Acrizolsine, Acribastine, Acronin, Actisomid, Actodigin, A Cyclovir, Acylfluben, Adafenoxate, Adapalene, Adapalene, Adathan Serine, Adathanserine hydrochloride, Adesipenol, Adesipenol, Adefovir, Adele Midrol, ademethionine, adenosine, azinazolam, adipheinine ) Hydrochloride, adiposin, adzeresin, adrafinil, adrenaline, ailbutamine ( airbutamine, aracepril, alamesin, alanine, alaproclate, alaptide, Albendazole, arborablin, albuterol, arbutoin, alclophenae (alclofenae), alclomethasone dipropionate, alcloxa, aldekalma Isine, Aldesleukin, Aldioxa, Alendronate sodium, Alendronate Alentemol, Alentemol hydrobromide, Aretamin hydrochloride, Areerochloride Aleuronium chloride, alexidine, α-calcidol, alfentanil hydrochloride Alfuzosin, algestone acetonide, alglucerase, aliflurane, alinas Chin, Alipamid, Allantoin, Alobarbital, Allopurinol, ALL-TK Antagon Nist, alogliptin, aronimide, alosetron, alosetron hydrochloride, alovudine Alpertin, α-amylase, α-idosone, alpidem, alprazolam Alprenolol hydrochloride, alprenoxime hydrochloride, alprostadil, alrestatin Altanserine sodium, altanserine tartrate, alteplase, althiazide, altoretami Altromycin B, Alverinc citrate, Albilceptosdote Amazinone acetate, amantadine hydrochloride, ambamustine, ambomycin, ambul Tisine, ambuphylline, ambucid, amsinaphal, amcinonide, amdinosilline , amdinocillin pivoxil, amedalin hydrochloride, amelomethasone, ameltolide, ame Sergido, Amethantrone Acetate, Amezinium Methylsulfate, Amphebutamon, Amphe Nac sodium, amflutisol, amicycline, amidephrine mesylate, amidoc Amifloxacin, Amifostine, Amikacin, Amirolide hydrochloride, Aminacline Hydrochloride salt, potassium aminobenzoate, sodium aminobenzoate, aminocaproic acid, amine Noglutethimide, sodium aminohippurate, aminolevulinic acid, aminophylline, amino Rex, sodium aminosalicylate, aminosalicylic acid, amiodarone, amiodarone hydrochloride Relose, amikincin hydrochloride, amisulpride, amitraz, amitriptyline hydrochloride Anlexanox, amlodipine, amobarbital sodium, amodiaquine, amo Diaquin hydrochloride, amorolfine, amoxapine, amoxicillin, amfechloral amphetamine sulfate, amphomycin, amphotericin B, ampicillin, ampyro Xicam, ampidin sulfate, amquinate, amrinone, amrinone, amrubicin, A Musacrin, Amylin, Amichiamycin, Anagestone acetate, Anagrelide, Anakin La, Ananaine, Analytide, Analytide Acetate, Anastrozole, Anazolen Natri Um, Anclod, Andrografolide, Androstenedione, Angiogenesis inhibitors, An Diotensinamide, anidoxime, anilelysine, anilopam hydrochloride, aniracetam, Anilolac, methyl anisotropine bromide, anistreplase, anitrazafen, anno Rudrin, Antagonist D, Antagonist G, Antarelix, Antazolin Phosphate Anthermycin, anthraline, anthramycin, antiandrogen drugs, acetaps N, felbamate, anti-estrogen drugs, antineoplaston, antipyrine, anti Sense oligonucleotides, apadrin, apafant, aparcillin sodium, apa Apixifyllin, Apazon, Aphydicolinglycinate, Apixifyllin e) Apomorphine hydrochloride, apraclonidine, apraclonidine hydrochloride, apramycin aprindine, aprindine hydrochloride, aproslate sodium, aprotinin, male Aptazapine acetate, Aptiganel, Aprinic acid, Aprinic acid, Alanidipine, Alanoti Albaprostil, Arbekicin, Arbidol, Albutamine Hydrochloride Alclophenin, Aldeparin sodium, Argatroban, Arginine, Argip Lessin tannate, allildone, aripiprazole, arotinolol, albinoside (arpinocid), artefren, artilide fumarate, acimadrin, asparaton, as Paraginase, aspartic acid, aspartosin, asperfuran, as Pyrrhizin, aspoxylin, asprelin, astemizole, astromycin Sulfates, asracurin, atamestan, atenolol, atevirdin, atipamezole, Atiprosin maleate, Atorvastatin calcium, Atosiban, Atova Con, Atopenin B, Atracurium besylate, Atrimustin, Atrinositol, A Tropin, Auranofin, Aureobasidin A, Aurothioglucose, Abiramais Avocadoparcin, Abridine, Axid, Axinastatin 1, Axinasta Chin 2, Axinastatin 3, Azavon, Azacitidine, Azachlordine Hydrochloride, Azacona Zol, azadirachtin, azalanstat dihydrochloride, azaloxane fumarate, malein Azanator acid, azanidazole, azaperone, azalibine, azaserine, azasetron, Azatadine maleate, azathioprine, azathioprine sodium, azatoxin, A Zatyrosine, azelaic acid, azelastine, azelnidipine, azepindol, azetepa Azimilide, azithromycin, azurocillin, azolimine, azosemide, azotomycin Syn, Aztreonam, Azmoren sodium, Bacampicillin hydrochloride, Baccatin III bacitracin, baclofen, bacoside A, bacoside B, bactovoramine, varanol, Valadipon, Valhimycin, Balofloxacin, Valsalazid, Bambermycin, Bambuterol, bametan sulfate, bamifilin hydrochloride, bamidazole, bao Foside 1, balmastine, barnidipine, basifungin, batanoprid salt Salts, bateblast, baterapine maleate, batimastat, beaubellin, bateblast hydrochloride Canton, Becaprelmin, Becliconazole, Beclomethasone dipropionate Befloxatone, beinserazide, bellosdil, belladonna, bellox Samide, bemethetron, bemitrazine, bemoradan, benapridine hydrochloride, benazepril Hydrochloride, benazeprilat, bendakarol mesylate, bendazac, bendroflumetia Zid, Benflumethol, Benidipine, Benolterone, Benoxaprofen, Benoxap Lofen, benoxynate hydrochloride, bemperidol, bentazepam, benzomid, benu Restat, benzbromarone, benzethonium chloride, benzetimide hydrochloride, benzy bromide Rhonium, benzindopyrine hydrochloride, benzoisoxazole, benzocaine, benzo Lorin, benzothamine hydrochloride, benzodepa, benzidazoxane, benzonatate, Benzoyl oxide, benzoyl calcium, benzoyl staurosporine, benzkina Mid, benzthiazide, benztropine, benztropine mesylate, benzydamine hydrochloride Salt, benzylpenicilloyl polylysine, bepridil, bepridil hydrochloride, belactant, Beraprost, bereflin, perlaphenone, vertasamil, berithromycin, vesipin Ludin, β-aretin, betacramycin B, betamethasone, betamipron, betaxol Betaxolol hydrochloride, betanylene chloride, betanidine sulfate, betulinic acid, beban Trol, bevantrol hydrochloride, bezafibrate, bFGF inhibitor, bialamicol hydrochloride Salt, biapenem, bicalutamide, bicifadine hydrochloride, biclodil hydrochloride, bidisamide, Bifemeran, bifonazole, bimalim, bimithil, vindalit, vinira Mycin, Binospirone, Bioxalomycin α2, Bipenamol hydrochloride, Biperiden, Bifenamine hydrochloride, biliperone, bisanthren, bisalamil, bisaziridinyl spel Min, bis-benzoimidazole A, bis-benzoimidazole B, bisnafide, biso lactate Brin, bisoprolol, bispirithione, Magsulfex, bistramid D, bistra Mido K, Bistratin A, Sodium Bitisonolate, Bitolterol Mesylate, Vivari Luzin, Bizeresin, Bleomycin sulfate, Boranediol dipropionate, Boraste Ron, Undecylenate boldenone, Borzin, Borenol, Bormantalat, Bopindo Roll, Bosentan, Voxydin, Bleferdin, Bleflat, Blequinal Sodium Mu, Bretazeninil, Bretylium tosylate, Brifentanil hydrochloride, Brimonidine, B Linolase, Brocrecin, Broclinat, Brophoxin, Bromadrine maleate, B Romazepam, bromochlorenone, bromelain, bromfenac, brominidion (bromi nidione), bromocriptine, bromodifenhydramine hydrochloride, bromoxamide (bromo xamide), bromperidol, bromperidol decanoate, brompheniramine maleate n, broperamol, bropyrimin, brotizolam, bucainide maleate, bucindro Bucrizine hydrochloride, bucromarone, budesonide, budipine, budotitanium, buformin Bumetamide, Bunaprolast, Bunazosin, Bunolol hydrochloride, Bupicomethyl Bupivacaine hydrochloride, buprenorphine hydrochloride, bupropion hydrochloride, Bramart, Buserelin acetate, buspirone hydrochloride, busulfan, porcine barbital, porcine, Butacramole hydrochloride, butarbital, butamben, butamirto citrate, butapen Radin, Butaprost, Butedronate tetrasodium, Butenafine, Buteridine, Buti Onin sulfoxymine, butycasin, butylphenine, butyrosine sulfate, butyxylamine Butixocort propionate, butoconazole nitrate, butonate, butopamine, Topridine hydrochloride, butorphanol, butoxamine hydrochloride, buttriptyline hydrochloride, Kutinomycin, Cadexomer-iodine, Caffeine, Caranolid A, Calcifediol , calcipotriene, calcipotriol, calcitonin, calcitriol, undecyl Calcium lenate, carphostin C, carsterone, cambendazole, camonagrel, Camptothecin derivatives, canagliflozin, canariapox IL-2, candesartan, Ndicidine, candoxatril, candoxatril, caniglibose, Potassium canrenoate, Lennon, capecitabine, sodium capobenate, capobenic acid, capreomycin sulfate Capromab, capsaicin, captopril, capride, chalasemide, carbachol, Lubadox, carbamazepine, carbamide peroxide, carbantel lauryl sulfate, carbas Pyrin calcium, carbazelan, carbazomycin C, carbenicillin potassium, cal Benoxolone sodium, carbethimer, carbetocin, carbidopa, carbidopa-levo Dopa, carbinoxamine maleate, carbifen hydrochloride, carbochloral, carbo Cysteine, carbol-fuxin, carboplatin, carboprost, carbovir, Ruboxamide-aminotriazole, carboxyamidotriazole, carboxymethyl β-1,3-glucan, carbuterol hydrochloride, CaRest M3, carfentanyl citrate, Lisoprodol, Carmantadine, Carmustine, CARN 700, Camidazole, Caloxazo Carperitide, carfenadine maleate, carprofen, carsatrin succinate Cartazolate, carteolol, carteolol hydrochloride, cartilage-derived inhibitors, carbici Carbothrin hydrochloride, carmonam sodium, carvedilol, carbothrin, carbothrin salt Salts, carzeresin, casein kinase inhibitors (ICOS), castanospermine, caulmona Caurumonam, sevaracetam, cecropin B, sedefingol, cefaclor, cef Adoroxyl, Cephamandor, Cephaparol, Cephatrizine, Cephazafleur Sodium, cefazolin, cefbuperazone, cefcapene pivoxil, cefdallo tosylate Ximpentexyl, cefdinir, cefditoren pivoxil, cefepime, cefetameth Cefetechol, Cefixime, Cefluprenum, Cefinenoxime salt Salts, cefinetazole, cefminlox, cefozidime Cefoniside sodium, cefoperazone sodium, cefolamide, cef Foselis, cefotaxime sodium, cefotetan, cefotiam, cefoxitin, Cefozopran, cefpimisole, cefpyramide, cefpirome, cefpodoxime proxen Chil, cefprodil, ceffloxazine, cefslodin, ceftazidime, cefteram, cef Tibutene, ceftizoxime sodium, ceftriaxone, cefuroxime, cerastro Lu, Cericarim, Ceriprolol, Cepacidiine A, Cephacetri Lunatri Um, cephalexin, cephaloglysin, cephaloridine, cephalothin sodium, Cefapillin sodium, cefradin, cericlamine, cerivastatin, seronapril, Certoparin sodium, ceruretide, cetaben sodium, cetalkonium chloride, ceta Morol hydrochloride, cethiezil, cetirizine, cetofenicol, cetraxate hydrochloride, Cetrorelix, cetylpyridinium chloride, kenodiolus, clofedianol hydrochloride, ku Loral betaine, chlorambucil, chloramphenicol, chlordantoin, chlor Diazepoxide, chlorhexidine gluconate, chlorin, chlormadinone acetate Chloroorientisin A, chloroprocaine hydrochloride, chlorpropamide, chloroquine chloroquinoxaline sulfonamide, chlorothiazide, chlorotrianicene, chloro Chlorphenesin, Chloroxylenol, Chlorpheniramine Carbamate, Chlorpheniramine Maloyl Chlorpromazine, chlorpropamide, chlorprothixene, chlortethyl sulfate Lacycline, chlorthalidone, chlorzoxazone, cholestyramine resin, chromoral salts Salts, cibenzoline, cicaprost, cyclafrine hydrochloride, cyclazine dol, cicleso Nido, cicletanin, cyclopirox, cycloprofen, cycloprolol, sidohobi Lu, sidoxepin hydrochloride, cyfenlin, ciglitazone, siladopa hydrochloride, silancetro cilastatin sodium, cilazapril, cilnidipine, silobamine mesylate, silobamine Brazine, silofungin, cilostazol, simaterol, cimetidine, simeropide bromide Um, Cinalcast, Sinanserin Hydrochloride, Cinepazet Maleate, Synflumid, Syn Gestol, sinitaprid, cinnamedrine, cinnarizine, cinorazepam, cinoxa N, Synperene, Synlomid, Syntazone, Syntriamide, Scioteronel, Sipamphy Phosphorus, cyprefadol succinate, cyprosinonide, cyprofibrate, cyproflox Sacin, cyprosten, silamadol, cilolemycin, cisapride, cisator besylate Cryum, cisconazole, cisplatin, cis-porphyrin, cystinexin, citalo Plum, cytenamide, citicoline, citreamycin α, cladribine, claroxyquin salt Salts, clarithromycin, claucenmamide, potassium clavulanate, clazolam, Lazolimine, Clevopride, Clemastine, Clentheme maleate, Clizinyl bromide Clinafloxacin, clindamycin, clioquinol, cliooxamide (clioxam ide), criprofen, clobazam, clobetasol propionate, clobetazone butyrate, Crocoltrone acetate, clodanolene, clodazone hydrochloride, clodronate, clofazimine Clofibrate, clofyllium phosphate, chlorogestone acetate, chromacran phosphate, Clomegestone acetate, clometerone, clomethiazole, clomiphene analog, clomiphene Nolex, clomiphene, clomipramine hydrochloride, clonazepam, clonidine, clonitol Laat, clonixeryl, clonixin, clopamide, clopentixol, cloperidone Clopidogrel hydrochloride, clopimodide, clopipazan mesylate, clopirac, clopimodide Redonol, cloprostenol sodium, dipotassium chlorazepate, Chloretate, Chlorexolone, chloroperone hydrochloride, chlorprenaline hydrochloride, chlorthrone, chlor Theremine hydrochloride, Closantel, Clocilamine acetate, Clotiapine, Cryptophosphate Rotixamide, Cloticasone propionate, Clotrimazole, Cloxacillin benzate N, cloxiquin, clozapine, cocaine, coccidioidin, codeine, chodoxime, Colchicine, Colestimide, Colestipol Hydrochloride, Colestron, Colforcin, Pal Colphosseryl mitinate, sodium colistimate, colistin sulfate, colistin Syn A, Corismycin B, Corterol Mesylate, Combretastatin A4, Combretas Tatin analogs, Compressostatin, Conogenin, Conorfone hydrochloride, ContiGnasteroderon Corticostatin, Contortrostatin, Colmetasone acetate, Corticosteroid ophthalic acid, Trifluthate T, corticotropin, cortisone acetate, cortibazole, cortodoxone, cosaran, Costatride, Cosyntropin, Cotinine, Coumadin, Coumamycin, Clanbexidine 816, Kirromycin, Crisnatol, Cromitril Sodium, Cromolyn Sodium, Chlorothen, Cryptophycin 8, Cucumarioside, Cuprim Xine, Classin A, Cardlan Sulfate, Curiosin, Cyclacillin, Cyclazo Sin, Cyclazosin, Cyclic HPMPC, Cyclindole, Cycliramine Maleate , Cyclizine, Cyclobenzadazole, Cyclobenzaprine, Cyclobut A, Cyclobut G , Cyclocapron, Cycloguanil Pamoate, Cycloheximide, Cyclopentaanthracen one, Cyclopentiazide, Cyclopentolate Hydrochloride, Cyclophenazine Hydrochloride, Cycl ophosphamide, Cycloplatin, Cyclopropane, Cycloserine, Cyclosine, Cycl osporin, Cyclothiazaridine, Cyclothiazide, Cyclothiazomycin, Sheptamide , Sipeomycin, Sipenamine Hydrochloride, Ciprazepam, Cyproheptadine Hydrochloride, Cyproly dol Hydrochloride, Cyproterone, Cyproxamide, Cysteamine, Cysteine Hydrochloride, Cis tin, Cytarabine, Cytarabine Hydrochloride, Cytarabine Ocfosfate, Cytokinesis B , Cytolytic Factor, Cytostatic, Dacarbazine, Daclizumab, Dactinomycin(dacti micin), Dactinomycin, Daidzein, Daledarin Tosylate, Dalfopristin, Dal teparin Sodium, Daltroban, Dalbavancin, Danaparoid, Danazol, Dan trolene, Dapagliflozin, Daphlnodorin A, Dapiprazole, D pitant, Dapoxetine Hydrochloride, Dapsone, Daptomycin, Darglitazone Sodium , dalifenacin, darulcin A, darodipine, darcidomin, daunorubicin hydrochloride, Dazadrol maleate, dazepinyl hydrochloride, dazmegrel, dazopride fumarate, dazo Xyben hydrochloride, debrisoquin sulfate, decitabine, deferipron, deflazacort, Dehydrocholic acid, dehydrodidemnin B, dehydroepiandrosterone, delapril Delapril hydrochloride, delavirdine mesylate, derequamin, delfaprazine, derphaprazine acetate Lumadinone, Dermopinol, Delphinidin, Demepotassium bromide, Demeclocycline Demecycline, Demoxepam, Denofungin, Deoxypyridinoline, Depacote, De Prodone, Deprostil, Depsidomycin, Delamcycline, Dermatan sulfate, Desci Clovir, desinolone acetonide, desflurane, desipramine hydrochloride, decilzine, de Slanoside, Deslorerin, Desmopressin, Desogestrel, Desonide, Desoximet Zon, desoxoamiodarone, desoxycorticosterone acetate, decadymium tartaric acid Hydrogen salt, deterenol hydrochloride, detilelix acetate, debazepide, dexamethasone, dexa Misol, Dexbronpheniramine maleate, Dexchlorpheniramine maleate Dexcramol hydrochloride, dexetimide, dexfenfluramine hydrochloride, dexphos Dexifosfamide, deximafene, dexivacaine, dexketoprofen Dexroxiglumide, Dexmedetomidine, Dexormaplatin, Dexoxadrol Dexpanthenol hydrochloride, dexpemedlac, dexpropranolol hydrochloride, dex Srazoxane, dexsotalol, dextrin disulfate, dextroamphetamine, Dextromethorphan, dextrorphan hydrochloride, dextrothyroxine sodium Dexverapamil, dezaguanine, dezinamide, dezosin, diacetol hydrochloride, cy Diamocine clamate, diapamide, meglumine diatrizoate, diatrizoate, diabet Lysine, diazepam, diaziquan, diazoxide, dibenzepine hydrochloride, dibenzothio Fen, dibucaine, dichliorvos, dichloralphenazone, dichlor Fenamide, disylenone, diclofenac sodium, dicloxacillin, dicranin, Dicomarol, dicyclomine hydrochloride, didanosine, didemnin B, zidox, diene Strol, dienogest, diethylcarbamazine citrate, diethylhomospermine, Diethylnorspermine, diethylpropion hydrochloride, diethylstilbestrol, Phenoxidide hydrochloride, diphenoxine, diflorazone diacetate, difloxacin hydrochloride, Difluanine hydrochloride, diflucortolone, diflumidone sodium, diflunisal, dif Luprednate, diphthalone, digitalis, digitoxin, digoxin, dihexyberine Hydrochloride, dihydrolexidine, dihydro-5-azacitidine, dihydrocodeine bitartrate , dihydroergotamine mesylate, dihydroestosterone, dihydrostreptomycin 9-Dihydrotaxol, 9-Dihydrotaxol, Dirantin, Dilevalol Hydrochloride, diltiazem hydrochloride, dimefadan, dimefrine hydrochloride, dimenhydrinate, Dimercaprol, dimethadione, dimethindene maleate, dimethisterone, dimethyl Prostaglandin Al, Dimethyl Sulfoxide, Dimethyl Homospermine, Dimiracetam , dimoxamine hydrochloride, dinoprost, dinoprostone, dioxadrol hydrochloride, di Xamycin, diphenhydramine citrate, diphenidol, diphenoxylate hydrochloride Salt, diphenylspiromustine, dipivefin hydrochloride, dipivefrin, dip Dipliencyprone, zipraphenone, dipropylnorspermine, dipyri Damole, dipirithione, dipyrone, dylithromycin, discodermolide, disob Tamide, disofenine, disopyramide, disoxalil, disulfiram, ditexylene, di Valproex sodium, disosilpine maleate, dobutamine, docarpamine, doce Benone, docetaxel, doconazole, docosanol, dofetilide, drasetron, E Bastin, Eviratide, Ebrothidine, Ebselen, Ekabapid, Ekabet, Ecadotri Lu, ecdysterone, exetin, exestatin, iodide ecothiophate, maleic acid Eclanamine, Eclazolast, Ecomustine, Econazole, Ectainacidine 722, Edaravone, edatrexate, ederfosine, ediphorone acetate, edbacomab, edoc Sudin, edrecolomab, edrophonium chloride, edroxyprogesterone acetate (edroxyp rogesteone acetate), efegatran, eflornithine, efonidipine, eguarcene ( egualcen), erantrin, eleatonin, elemen, eletriptan, el Gojipin, Elibrozil, Elsamitolusine, Eltenae, Elcain, Emma Emalkalim, Emedastine, Emetine Hydrochloride, Emiglitate, Emite Tosylate Rium, Emiteflu, Emoctaquin, Empagliflozin, Enadrine hydrochloride, Enalaph Lil, Enalaprilat, Enalkiren, Enazadrem, Ensiplat, Endo mesylate Larazine, Endrison, Enflurane, Englitazone, Enilconazole, Enisop Rost, Enlimomab, Enloplatin, Enoflast, Enolicum sodium, Enoflast Xacin, enoxacin, enoxaparin sodium, enoxaparin sodium, enoxa Xymon, empyroline phosphate, emprophylline, empromart, entacapone, e Centrostatin, Enviraden, Enviroxime, Ephedrine, Epicillin, Epimeth Trol, epinephrine, epinephryl borate, epipropidine, Epirizole, Epirubicin, Epitetracycline hydrochloride, Epithiazide, Epoetin α, epoetin β, epoprostenol, epoprosterol sodium, epoxymec Threnone, epristeride, eprosartan, eptastigmine, ekirenine, ekirin , erbrozol, erdostein, ergoloid mesylate, ergonovine maleate, Ergotamine tartrate, elcentide, elsofermin, erythritol, tetranitrate Risrityl, erythromycin, esmolol hydrochloride, esorubicin hydrochloride, esprox Estradiol hydrochloride, estazolam, estradiol, estramustine, estramustine analgesic Log, estradiol hydrobromide, estriol, estroflate, estrogens Estrogen agonist, estrogen antagonist, estrogen, conjugated estrogen, es Estrone telamide, estropipate, espron, etafedrine hydrochloride, etanidazo Ethanol, etanterol, etalotene, etazolate hydrochloride, eterovalvul, etasidine, Sodium ethacrine, ethacrine, ethambutol hydrochloride, etamiban, etanol Luamine oleate, es-eflorvinol, ether, ethinyl ether Stradiol, ethiodized oil, ethionamide, etham nitrate, etopropazine salt Salts, ethosuximide, etotoin, ethoxazene hydrochloride, etibenzutropin, chloride Tyl, dibnate ethyl, ethylestrenol, ethindiol, ethinerone, diacetic acid Ethinodiol, etibendazole, etidocaine, disodium etidronate, etido Etizolam, etifenamin, ethintidine hydrochloride, etizolam, etodolac, etofenamer Etformin hydrochloride, etomidate, etonogestrel, etoperidone hydrochloride, eto Poside, Etopurine, Ethoxadrol Hydrochloride, Etozoline, Etravamin, Etretin Eto, etriptamine acetate, eucatropin hydrochloride, eugenol, euprosin hydrochloride ebeminocycline, examethadium, examorelin, exaprolol hydrochloride, ex Cemestan, Fadrozol, Feriefungin, Famciclovir, Famotidine, F Amplizine, Fantofaron, Fantridone hydrochloride, Faropenem, Fasidotri Lu, Fasudil, Fazarabine, Fedotodin, Felbamart, Felbinac, Ferro Dipine, felipresin, phenalamide, phenamol, fenbendazole, fenb Fen, phencibutyrol, fenclofenac, fenclonin, fenchlorac, Fendosar, Fenestrel, Phenethine hydrochloride, Fenfluramine hydrochloride, Fen Ngabin, Phenimide, Phenisolex, Fenmethozol hydrochloride, Fenmetramide, Phenobam, phenocthymine sulfate, fenofibrate, phenoldopam, phenopro Fen, fenoterol, fenpiparone, fenprinast hydrochloride, fenprostar Fenkisone, fenretinide, fenpiride, fentanyl citrate, fen Thiazac, fenticloride, fenticonazole, phenilipol hydrochloride, feprazino Felpiphosate sodium, Felisten, Felixan, sulfuric acid (1) Iron (dried), Fermoxides, Fermoxilate, Fethoxilate hydrochloride, Fexofen Nazin, fezolamine fumarate, fiacitabine, fiarlysine, fibrinogen I-12 5. Filgrastim, Philippines, finasteride, flavodilol maleate, flavodilol Bopiridol, flavoxate hydrochloride, flazalone, flecainide, flerobuterol, Freloxacin, Frecinoxane, Frestrol sulfate, Fretazepam, Frezelastine Flobufen, flocatafenin, flomoxef, flordipine, florfenicol , floriphenin, flosatidyl, furosekinan, floxacillin, floxuridine, Fluasterone, Fluazacort, Fluvanilate hydrochloride, Flubendazole, Flucin Dol, fluchloronide, fluconazole, flucytosine, fludaranine, fluda phosphate Ravin, fludazonium chloride, fludeoxyglucose F-18, fludrex, flud acetate Locortisone, flufenamic acid, fluphenisal, flumazenil, flumesinol, flu Lumekin, Flumeridone, Flumethasone, Flumetramide, Flumezapine, Fluminolec Flumizole, flumoxonide, flunarizine, flunidazole, flunisolide, flu Lunitrazepam, flunixin, fluocalcitriol, fluocinolone acetonide, Fluocinonide, fluorocortin butyl, fluorocortron, fluorescein, fluor Fluorodaunorunicin hydrochloride, Fluorodopa F-18, Fluorometholone, F Luoruracil, fluotracene hydrochloride, fluoxetine, fluoxymesterone, flu Paroxane, Flupera Mid, fluperolone acetate, fluphenazine decanoate, flupirin, fluprednisolone Fluproquazone, Fluprostenol sodium, Fluquazone, Fluradrin hydrochloride Salt, flurandrenolide, flurazepam hydrochloride, flurbiprofen, fluretofen, Flurithromycin, flurocitabine, flurofamide, flurogestone acetate, flurocitabine Lu, fluloxen, fluspiperone, fluspirelene, fluticasone propionate, flu Trimazole, Flutrolin, Fluvastatin, Fluvastatin sodium, Fluvox Min, fludinamide, folic acid, follicular regulatory protein, folliclostatin, fomepizole, Honadine mesylate, forasartan, forfenirmex, forfenirmex ), hormestan, formocortal, formoterol, hosalilat, hosazepam, ho Scarnetosodium, fosfomycin, phosphonetosodium, hosinopril, hosino Prilat, fosphenyloin, fosquidone, hostedil, hostriesin , fotemustine, basic fuchsin, fumoxicillin, fungimycin, flaprofen, Furazolidone, furazolium chloride, fraglerate sodium, phlobufen, phlodazo Glucoside, furosemide, sodium fusidate, fusidic acid, gabapentin, dimethic acid Glumine, gadobonic acid, gadobutrol, gadodiamide, gadolinium texaphylline, Gadopentetate dimeglumine, gadoteric acid, gadoteridol, gadobercetamide, galant Tamin, Galansetron, Galansetron hydrochloride, Galansetron triethiozide, Galansetron nitrate Ganfixin, gallopamil, gallocitabine, ganfexin, gamolenic acid, ganciclovir, gan Nirelix, gelatinase inhibitors, gemcadiol, gemcitabine, gemeprost, gem Fibrozil, gentamicin sulfate, gentian violet, gepilone, gestaclo Gestodene, gestolone caproate, gestrinone, gebotroline hydrochloride, glyso Pam, Graspimod, Glaucocalyxin A, Gremanserine, Gliamirid, Grivol Nulid, sodium glycetanyl, glyflumid, glimepiride, glipizide, gloxy Monam, glucagon, glutapyrone, glutathione inhibitors, glutethimid, glybride, Glycopine, glycopril, glycopyrrolate, glychexamide, glimidine sodium Glyoctamide, glyparaamide, gold Au-198, gonadoctrinins, gona Drelin, gonadotropin, goserelin, gramicidin, granisetron, grepafloxacin Sacin, Griseofulvin, Guayapato, Guachilin, Guanabenz, Guanabenz Vinegar Salts, guanadrel sulfate, guancidin, guanethidine monosulfate, guanfacine hydrochloride Salt, guanisoquine sulfate, guanochlor sulfate, guanoctine hydrochloride, guanoxabens , guanoxane sulfate, guanoxyfen sulfate, gusperimus trihydrochloride, harazepam, Halcinonide, halichondrin B, halobetazole propionate, halofantrin, Lophanthrine hydrochloride, halofenate, halofdinone hydrobromide, halomon, halope Mid, haloperidol, halopredone, haloprogesterone, haloprosin, halothan, Harukinol, Hamycin, Human (Han) Menopausal Gonadotropin, Hatomamycin, Hatoma Begin A, Hatmaru Begin B, Hatmaru Begin C, Hatmaru Begin D, Heparin Sodium, Hepsulfame, helegulin, hetacillin, heteronium bromide, hexachlorophene: Hydrogen oxide, hexafluorenium bromide, hexamethylene bisacetamide, hexedine, Hexobenzine, hexoprenaline sulfate, hexylresorcinol, histamine phosphate Salt, histidine, histoplasmin, histrelin, homatropin hydrobromide, hokidi Hydrochloride, human chorionic gonadotropin, hycanthone, hydralazine hydrochloride, hydralazine Polystyrene, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisol Hydroflumethiazide, hydromorphone hydrochloride, hydroxyamphetamine bromide Hydroxychloroquine sulfate, hydroxyphenate, hydroxycaproate Progesterone, hydroxyurea, hydroxyzine hydrochloride, hymechromone, hyosciamine ibuprofen, ipericin, ibafloxacin, ibandronate, ibogaine, ivopamine, ibuprofen Last, ibufenac, ibuprofen, ibutylide fumarate, icatibant acetate, i Chtamol, Icotidine, Idarubicin, Idoxifen, Idoxuridine, Hydra Iemefloxacin, Iesopitron, Ifetrova Ifosfamide, Ilepeimide, Ilimaquinone, Il Mofosin, Ilomast, Ilonidap, Iloperidone, Iloprost, Imafen hydrochloride Salt, imazodane hydrochloride, imidapril, imidazenil, imidazoacridone, imidecil Iodine, imidocarb hydrochloride, imidorin hydrochloride, imidourea, imiloxane hydrochloride, Mipenem, imipramine hydrochloride, imiquimod, immunostimulatory peptide, impromidine hydrochloride Indacrinone, indapamide, indecinide hydrochloride, inderoxazine hydrochloride, Indigotine disulfate sodium, indinavir, indocyanine green, indrapril Hydrochloride, Indolidan, Indomethacin, Indomethacin sodium, Indoprofen Indramin, indorenate hydrochloride, indoxol, indoliline hydrochloride, Inoco Terone, inogatoran, inorimomab, inositol nicotinate, insulin, interstitial Ferron, interleukin, intrazole, intriptyline hydrochloride, iovengua n, iobenzamic acid, iobitridol, iocalmic acid meglumine, iocalmic acid, io Cetam acid, iodamide, iodine, iodipamide meglumine, iodixanol, iodine Miloride, Iodoantipyrine I-131, Iodocholesterol I-131, Iododoxorubicin Syn, Iodohippurate sodium I-131, Iodopiracet I-125, Iodoquinol, Iodo Meglumine samate, Iodoxamic acid, Ioglycic acid, Iofetamine hydrochloride I-123, Iofractol, Ioglucol, Ioglucomi, Ioglucamic acid, Yogurt Lamide, Iohexol, Iomeprole, Iometine I-125, Iopamidol, Iopamidol Iopentol, iofendilate, ioprosemic acid, iopromide, iopro Iopidone, iopidone, iopyrrol, iocefamic acid, iocell Acids, ioslamid meglumine, iosmethic acid, iotasul, iotetolic acid, iotalamic acid Sodium, iotalamic acid, iotriside, iotrolan, iotroxic acid, iotyrosine I-131, Iobertol, Ioxagiate sodium, Ioxaglycerate Glumine, ioxaglucate, ioxiran, ioxotrizoic acid, ipazilide, ipenoxa Zon, ipidacrine, calcium ipodate, 4-ipomeanol, ipratropium bromide, Ipriflavone, Iprindol, Iprofenin, Ipronidazole, Iproplatin iproxamine hydrochloride, ipsapirone, irbesartan, irinotecan, illoxamine Iroplact, Ilsogladine, Iltemazole, Isalsteine, Isalsteine Moxol, isvogrel, isepamycin, isobengazole, isob Tamben, isocarboxazide, isoconazole, isoetalin, isofloxitepine, Isoflupredone acetate, isoflurane, isoflurofate, isohomohalichondrin (i sohomohalicondrin)B, isoleucine, isomazole hydrochloride, isomiramine hydrochloride, iso Niazide, isopropamide iodide, isopropyl alcohol, isopropyl unoprost Isoproterenol hydrochloride, isosorbide, isosorbide mononitrate, isothiquimid, Sotretinoin, isoxepac, isoxicam, isoxuprine hydrochloride, isradipine, Itamelin, Itasetron, Itazigrel, Itopride, Itraconazole, Ivermec Chin, Jaspraquinolide, Josamycin, Kahalalide F, Calafungin, Kanamayci Ketamine sulfate, ketamine hydrochloride, ketanserin, ketazosin, ketazolam, ketoxal, ke Tipramin fumarate, ketoconazole, ketoprofen, ketorphanol, ketrola K, ketotifen fumarate, kitasamycin, labetalol hydrochloride, lasidipine, lasidipine Dipine, lactitol, lactibicin, lacosamide, laennec, lafutidine, lamella Phosphate-N-triacetate, lamifibane, lamivudine, lamotrigine, lanoconazole, Lanoxine, Lamperison, Lanreotide, Lansoprazole, Latanoprost, Lateri Chin, Laurocaprum, Isoquinoline Laurylbromide, Labortidine Succinate, Lazabemide Recimivid, Reinamycin, Remildipine, Reminoprazole, Renercept, Reni Kinsin, Lenograstim, Lenperone, Lentinan sulfate, Leptin, Leptolstatin , relcanidipine, relgotril, rerisetron, retimide hydrochloride, letrazuril, leto Rosol, leucine, leucomycin, leuprolide acetate, leuprolide + estrogen N+ progesterone, leuprorelin, levanfetamine succinate, levanfetamine, levanfetamine, lac Levdobutamine tobionate, Leveromakalim, Levetiracetam, Levue Leveycloserine, levobetaxolol, levobunolol, levobupivakai Levocabastine, levocarnitine, levodopa, levodropropidine, levofloxacin Levoflaldadone, levofluratadone, levoleucovorin calcium, levometadil acetate, levometa Dil hydrochloride, levomoprolol, levonantradol hydrochloride, levonordefrine, levon Lugestrel, levopropoxyfen napsylate, levopropyl sylin potassium, levo Lumeloxifen, Levolfanol Tartrate, Levocimendan, Levosulpiride, Levo Thyroxine sodium, levoxadrol hydrochloride, lexipaphant, lexithromycetin Rhizole, Ribenzapril, Ridamidine hydrochloride, Lidocaine, Lidofenin, Ri Doflagin, Refaridin, Refibrate, Refibrol, Rinarotene, Rincomai Syn, linear polyamine analog, linoglylide, linopyridine, linotropan, linthi Domin, lynchitrypto, lintopride, liothyronine I-125, liothyronine sodium , Riotrix, Lilexapride, Lisinopril, Lisoclinamide 7, Lixadi Sulfate Non, lobaplatin, lobenzarit sodium, lobucavir, roderaven, rhodoxam Iodoxamide, lofemizole hydrochloride, lofentanil oxalate, lofepramine hydrochloride Salt, lofexidine hydrochloride, rombrisin, lomefloxacin, lomerizine, lometral rhizome hydrochloride, lometrexol, lomofungin, romoxicam, lomustine, lonapalene, Lonazolak, lonidamin, loperamide hydrochloride, loracalbef, loradumine hydrochloride, loradumine hydrochloride, loradumine Tadine, lorazepam, lorvamart, lorcainide hydrochloride, lorecresol, lorenad Loreinadol, lorglumide, lormetazepam, lornoxicam, lornoxicam, Lortalamine, Lorzafone, Losartan, Rosigamon, Rosoxantrone, Rosladine Salt Salts, loteprednol, lovastatin, lobilid, loxapine, loxolibine, Lebel Zole, rucanton hydrochloride, ruphylonil, lurosetron mesylate, lulutotecan, luteal form Adult hormones, lurasidone, lutetium, luterelin acetate, rudindol, liaporatina Thorium, lycetamin, ridicamycin, ridimycin, linestrenol, ripressin Lysine, lysophylline, lysostafine, soluble peptide, maduramycin, mafe Nido, Maginin 2-amide, Magnesium salicylate, Magnesium sulfate, Magnolol Mytansine, Maletamer, Malotochromene, Malotojaponin, Malochilate, Malo Thyrato, Mangahodipil, Manidipine, Maniwamycin A, Mannitol, Mannosta Tin A, Manumycin E, Manumycin F, Mapinastine, Maprotiline, Marimastate Martek 8708, Mar tek 92211, masoprocol, masupin, massetrid, matrilysin inhibitor, Mytan Syn, Mazapertine Succiniate, Mazindol, Mebendazole Mebeberine hydrochloride, mebrophenin, mebutamate, mecamillamine hydrochloride, mechloret Meclocycline hydrochloride, meclocycline, sodium meclofenamate, meclocalon, mecloli Songibutyrate, medazepam hydrochloride, medrionone, medroguestone, medroxalol, Medroxyprogesterone, Medrison, Meelizine hydrochloride, Mefenamic acid Mefenidyl, Mefenorex hydrochloride, Mefexamide, Mefloquine hydrochloride, Mefluside Megalomycin potassium phosphate, megestrol acetate, meglumine, megurt Melengestrol acetate, melitracene hydrochloride, melphalan, memotin hydrochloride, Menavitan hydrochloride, menoctone, menogalil, menotropin, meobentine sulfate, mepal Tricin, mepenzolate bromide, meperidine hydrochloride, mephentermine sulfate, mepheni Mephenyloin, mefobarbital, mepivacaine hydrochloride, meprobamate, Butazinol hydrochloride, Mekidox, Melalein sodium, Melvalon, Mercaptopri Merck phenol chloride, mercury sulfate, melisoprole Hg-197, meropenem, mesalamine Min, Mesecrazone, Mesolidazine, Mesterolone, Mestranol, Mespurine hydrochloride Metarol hydrochloride, metaproterenol polystyrene, metalaminol bitartrate Metaxalone, meteneprost, meterelin, metformin, methacholine chloride, metasa Ikurin, methadone hydrochloride, metazil acetate, meththiazide, methamphetamine hydrochloride, Metacarone, Metazolamide, Metodilazine, Metenamine, Metenolone acetate, Metetoin, Methicillin sodium, methimazole, methioninase, methionine, methisazone, meth Xen hydrochloride, methocarbamol, methexital sodium, metforin, methot Lexate, methotrimeprazine, methoxatone, methoxyflurane, Methoxate Tosuximide, meticlothiazide, methyl palmoxylate, methylatropine nitrate, chloride Methylbenzethonium, methyldopa, methyldopa hydrochloride, methylene blue, methylergono Bin maleate, R-α-methylhistamine, methylinosine monophosphate, methyl Phenidate hydrochloride, methylprednisolone, methyltestosterone, methinodiacetate Methicerzide, Methicerzide maleate, Methiamide, Methiapine, Methioprim Methipamide, Metipranolol, Metizoline hydrochloride, Methcefamide acetate, Metoclop Lamid, iodide methocrine, metogest, metrazone, metopimazine, methoprine, metto Prolol, Methoxin, Metrifonate, Metrizamide, Sodium Metrizoate, Meth Ronidazole, Metsuredepa, Metyrapone, Methylosine, Mexiletine hydrochloride, Mexileno Potassium acid, mezlocillin, mufonelic acid, mianserin hydrochloride, mibe Frazil, mibeflazil dihydrochloride, miboleron, mikeramine B, miconazole, micoco Phosphorus A, Midaflur, Midazolam hydrochloride, Midodrine, Mifepristone, Mihobart, Miglitol, mirasemide, miramelin, mildronate, myrenperon, miripertine Milnacipran, Milrinone, Miltefosine, Minban hydrochloride, Minaprin, Minakiso Lon, minoclomil, minocycline, minoxidil, myophradin hydrochloride, myocame Syn, mipragoside, milfentanil, mirimostim, milinkamycin hydrochloride, mare Myricetron inate, mirtazapine, mismatch double-stranded RNA, misonidazole, misopro Stole, Mitindomide, Mitocalcin, Mitochromin, Mitogyrine, Mitoguazone, Mi Tractor, Mitomarcin, Mitomycin, Mitonafide, Mitospel, Mitotan, Mitoxantrone, Mibacryl chloride, Mivazerol, Mixampril, Mixidine, Mi Zolastine, mizoribine, moclobemide, modafinil, modalin sulfate, modicainide, Moexipril, Mofalotene, Mofegiline hydrochloride, Mofezolac, Morglamostim , morinazone, morindone hydrochloride, morcidomin, mometasone, monatepil maleate, Monensin, monoctanoin, montelukast sodium, montilelin, mopidamol Moracidine, Morantel tartrate, Moricidine, Morniflumate, Morphine sulfate, Mol Sodium iodide, mosapramine, mosapride, motilide, motoretinide, moxalacta Munisodium, Moxazosin, Moxylaprine, Moxnidazole, Moxonidine, Mumps dermatological test antigen, mustard anticancer drug, muzolimin, micaperoxide B, mi Cophenolic acid, Myriapolon, Nabazenil, Nabilon, Navitan hydrochloride, Naboctart Hydrochloride, nabumetone, N-acetyldinaline, nadide, nadifloxacin, nadolol, Nadropalin calcium, naphadotolid, nafamostat, nafarelin, naphili Nafen sodium, naphenopine, nafimidone hydrochloride, naflocort, nafone malate, Nafoxidine hydrochloride, nafronil oxalate, naphtifine hydrochloride, naphtopidil, nagli Ban, Nagrestip, Nalbufine hydrochloride, Naldemedine, Nalidixate Thorium nalidixic acid, nalmefene, nalmexone hydrochloride, naloxone + pentazocine N, naltrexone, namoxylate, fenpropionate nandrolone, nantrador Napa hydrochloride, napactadine hydrochloride, napadisyl acids, napamezole hydrochloride, napabiin (nap Naphazoline hydrochloride, naphterpine, naproxen, naproxol, napsaga Tran, naranol hydrochloride, nalasin, naratriptan, naltograstim, nasalpra -ze, natamycin, nateplase, naxagolide hydrochloride, nebibolol, nebulamycin N, Nedaplatin, Nedocromil, Nefazodone hydrochloride, Neflumodide hydrochloride, Nehopam Hydrochloride, Nerezaprine maleate, Nemazoline hydrochloride, Nemorubicin, Neo palmitate Mycin, neostigmine bromide, neridronic acid, netylmycin sulfate, neutral endopeptide Dase, Neutramycin, Nevirapine, Nexeridine hydrochloride, Niacin, Nibroxa Nicardipine hydrochloride, nicergoline, niclosamide, nicorandil, nicotinyl Cole, nifedipine, nifirmerone, niflulidide, nifladen, ni Flurdezone, Nifratel, Nifratoron, Nifludazil, Niflmid, Niflupirino Nifluquinazole, Nifluthiazole, Niltamide, Nilvadipine, Nimazon, Nimo Dipine, nipelotidine, niborolin, niridazole, nisamycin, nisbutero mesylate Nisin, Nisobamat, Nisoldipine, Nisoxetine, Nisterim Acetate, Nital Son, nitazoxamide, nitecapone, nitrafdam hydrochloride, nitralamine Hydrochloride, nitramisol hydrochloride, nitrazepam, nitrendipine, nitrocycline, nitrazepam Trodan, nitrofurantoin, nitrofurazone, nitroglycerin, nitromelsol Nitromide, nitromiphene citrate, nitrous oxide, nitrogen oxide antioxidant, nitrulline (nitrullyn), nivazole, nibimedone sodium, nizatidine, novellastine, nocoda Zol, nogaramycin, norinium bromide, nomifensin maleate, noacimethad Norboreton, norepinephrine hydrochloride, norethindrone, norepinephrine bitartrate, norepinephrine Tinodrel, norfloxacin, norflurane, norgestimate, norgestmeth, no Lugestrel, nortriptyline hydrochloride, noscapine, novobiocin sodium, N-substituted Benzaiimide, nufenoxol, nilestriol, nystatin, O6-benzylgua Nin, ovidoxime chloride, ocaperidone, ocfentanil hydrochloride, osinapron, oc Tannic acid, octazamide, octenidine hydrochloride, octodrine, octreotide, phosphate Ctotriptyline, ofloxacin, Oformine, oxenone, olanzapine Ologenoids, olopatadine, olprinone, olsalazine, olsalazine sodium Rium, Orbanil, Omeprazole, Onapristone, Ondansetron, Ontazora Stomach, oocyte maturation inhibitors, opipramol hydrochloride, oracin, orconazole nitrate, Lugotein, Orlistat, Ormaplatin, Olmetprim, Ornidazole, Or Panoxin, Orphenadol trimethoate, Osateron, Otenzepad, Oxacillin Thorium, oxagrelate, oxaliplatin, oxamarin hydrochloride, oxamisol , oxamnicine, oxandrolone, oxantel pamoate, oxaprotiline hydrochloride, Oxaprozin, oxalvazole, oxatomide, oxaunomycin, oxazepam Oxcarbazepine, oxendron, oxethazaine, oxetron fumarate, oc Sufendazole, Oxfenicin, Oxybendazole, Oxconazole, Ox Dopamine, oxidronic acid, oxyfungin hydrochloride, oxilorphan, oxymonam, Oxymonam sodium, oxyperomide, oxyracetam, oxyramide, oxysura Oxmethidine hydrochloride, oxodipine, fenpropionate oxogestone, oxo Phosphate, oxprenolol hydrochloride, oxtriffine, oxybutynin chloride, oxy Chlorocene, oxycodone, oxymetazoline hydrochloride, oxymetholone, oxymorphone Hydrochloride, oxypertine, oxyfenbutazone, oxyprinol, oxytetrasulfate Ikurin, oxytocin, ozagrel, ozolinone, paclitaxel, paraamine, pa Luzimycin, palinavir, palmitoyl rhizoxine, sodium palmoxylate, pa Quesid, Pamatorol sulfate, Pamicogrel, Disodium pamidronate, Pamidronate Panadipron, Panamesin, Panoxytriol, Pancoprid, Pancuronium bromide Panipenem, Pannoline, Panomiphene, Pantethine, Pantoprazole, Papaverine Hydrochloride, parabactin, parachlorophenol, paraaldehyde, paramethasone acetate, Lanillin hydrochloride, parapenzolate bromide, pararosaniline pamoate, parbendazole, Parconazole hydrochloride, Paregoric, Pareptide sulfate, Pargiline hydrochloride, Parnapari Sodium, paramomycin sulfate, paroxetine, parthenolide, patricin, pau Romycin, Pazeliptin, Padinacrone, Pazoxide, Pazufloxacin, Pefloxacin Syn, Pegaspargaze, Pegolgotine, Peranserin hydrochloride, Perdesine, Perioma Icin, Perretin, Perlinone hydrochloride, Pemedrac, Pemerido nitrate, Pemirolast, Pemoline, penamecillin, penbutrol sulfate, penciclovir, penfluridol, Penicillin G benzathine, Penicillin G potassium, Penicillin G procaine, Penicillin G na Thorium, Penicillin V, Penicillin V Benzatine, Penicillin V Hydrabamine, Penicill Potassium V, pentabamate, pentaerythritol tetranitrate, pentafusid e) Pentamidine, pentamorphone, pentamustine, pentapiperium methylsulfate, pentamustine Pentazocine, pentetate, pentiapine maleate, pentigetide, pentisomycin, pentazocine Nthyzidone sodium, pentobarbital, pentomon, pentopril, pentosan, Pentostatin, pentoxifylline, pentrinitrol, pentrozol e) Pepromycin sulfate, pepstatin, perflubron, perfofamide de), perphosphamide, pergolide, perhexylline maleate, periryl alcohol Perindopril, Perindoprilat, Perlapine, Permethrin, Perospirone, Per Phenazine, phenasemide, phenaridine, phenazinomycin, phenazopyridine hydrochloride Salt, fenbutazone sodium glycerate, fencarbamide, phencyclidine hydrochloride Salt, fendimethrazine tartrate, phenelzine sulfate, fenmethrazine hydrochloride, fe Novalbital, phenoxybenzamine hydrochloride, fenprocum, fencelin, f Enskshinar (p hensuccinal, fenximide, phentermine, phentermine hydrochloride, fentra Minmesylate, phentoxifylline, phenyl aminosalicylate phenyl acetate, phenylalanine, phenylalanyl ketoconazole, phenylbutazo Phenylephrine hydrochloride, phenylpropanolamine hydrochloride, phenylpropanolamine Minpolistylex, pheniramidol hydrochloride, phenyloin, phosphatidyl -ase inhibitors, physostigmine, picenadol, picibanil, picotrin diolamine, Piclorib, picmeterol, pidotimod, pifamine, pilocarpine, pill Cicainide, pimagedin, pimetine hydrochloride, pimiruprost, pimobendan, pimozide, Pinacidyl, Pinadrine, Pindolol, Pinenol, Pinocebrin rin), pinoxepine hydrochloride, pioglitazone, pipemperone, pipezetate, pipec bromide Rhonium, piperacetazine, piperacillin sodium, piperamide maleate, piperacillin n, Pipobroman, Piposulfan, Pipothiazine palmitate, Pipoxolane hydrochloride, Piprozoline, Pikindone hydrochloride, Pikidyl hydrochloride, Piracetam, Pyrandamine hydrochloride, Pirarubicin, pyrazmonam sodium, pyrazolac, pyrbenicillin sodium, acetate Pirbuterol, pyrenperone, pirenzepine hydrochloride, pyretamide, pirf Enidone, pyridicillin sodium, pyridronate sodium, pyriprost, pyrito Lexim, Pirrimycin hydrochloride, Pirrindol, Pirmagrel, Pirmenol hydrochloride Pyrunabin, piroctone, pirodavir, pyrodomast, pyroglilide tartrate, pyrola Pyrozamide, piroxantrone hydrochloride, piroxicam, piroximon, pirpro Fen, Pyrquinozol, Pyrcidomin, Preniramine, Posterior pituitary (Pituitary, Poster) ior), pivampicillin hydrochloride, pivopril, pizotirine, placetin A, platinum compound, white Gold-triamine complex, plicamycin, promethane, povylcastoedamine, podophy Rox, urushi extract, porcini methylsulfate, polyglucum, sodium polyglutamate (Polygnate sodium), Polymyxin B sulfate, Polythiazide, Ponalrestat, Polf Sodium ionizer, porphyromycin, potassium chloride, potassium iodide, permanganate Potassium, povidone-iodine, praractol, pralidoxime chloride, pramiracetam hydrochloride Salt, pramoxin hydrochloride, planolium chloride, pravadrine maleate, pravastatin (Pravacol), prazepam, prazosin, prazosin hydrochloride, prednazate, pred Nicalbart, Prednimustine, Prednisolone, Prednisone, Prednivar, Co Pregnenolone Succiniate, Prenalterol Hydrochloride, Pridef Prilocalne hydrochloride, Prilosec, Primax Primidol phosphate, primidol, primidone, prinivir, prinomidotromethamine, pri Noxodane, Prizidilol hydrochloride, Proadifen hydrochloride, Probenecid, Proviclo Milcalcium, Probucol, Procainamide hydrochloride, Procain hydrochloride, Procal Basin hydrochloride, procaterol hydrochloride, prochlorperazine, procinonide, prochlorno Procyclidine hydrochloride, prodyl acid, prophadol hydrochloride Salt, progavid, progesterone, proglumide, human proinsulin, proline, pro Phosphate hydrochloride, promazine hydrochloride, promethazine hydrochloride, propafenone hydrochloride, pro Pagermanium, propanizide, propantheline bromide, propalacaine hydrochloride, proparacaine nitrate Patil, propentophilin, propenzolate hydrochloride, propicacin, propiommazine , propionic acid, L-propionylcarnitine, propylam, propylam + paracetamol , propiverine, propofol, propoxycaine hydrochloride, propoxyfen hydrochloride, Propranolol hydrochloride, propalside, propylbis-acridone, propylhexed Phosphorus, propyliodone, propylthiouracil, proquazone, prolenoate potassium , proloxane hydrochloride, proscylaridine, prostalen, prostratin, protamine Sulfates, protegrin, protirelin, protosufloxacin, protriptyline hydrochloride , proxazole, proxazole citrate, proxichromyl, proxolphan tartrate Salts, prulifloxacin, pseudoephedrine hydrochloride, puromycin, purul Pyrabrom, pyrantel pamoate, pyrazinamide, pyrazofrine, pyrazoloacid Pyridostigmine bromide, pyriramine maleate, pyrimethamine, pyrinoline, pyrithi On sodium, pyrithione zinc, pyrovalerone hydrochloride, pyroxamine maleate, pyro Caine, pyrrolephene hydrochloride, pyrrolnitrin, pyrvinium pamoate, quad mesylate Zosyn, Quazepam, Quazinon, Quazodine, Quazollast, Quetiapine, Kyflapo N, quinagolide, quinaldine blue, quinapril, quinaprilato, quinazosin hydrochloride, quinapril Nboron, quinctolate, quindecamine acetate, quindonium bromide, quine Loran hydrochloride, kinestrol, quinfamide, kingestanol acetate, kingestron Quinidine gluconate, quinielorane hydrochloride, quinine sulfur Salts, quinpyrrole hydrochloride, quinterenol sulfate, quinucrine bromide, quinupristin , kipazine maleate, rabeprazole sodium, racefenicol, racepinefri Raf antagonist, rafoxamide, laritrin, raloxifene, Lartitrexed, Ramatroban, Lamipril, Lamoplanin, Ramosetron, Raneric acid Ranimycin, ranitidine, lanolazine, Indian snakewood, lecanum, lecanum hydrochloride, Leclazepam, regavirumab, reglamotim, relaxin, reromycin, remasemide Hydrochloride, remifentanil hydrochloride, remiprostol, remoxiprid, repirinast, Repromycin, reproterol hydrochloride, reserpine, resinferatoxin toxin, resorcinol, demethylated reteriptin, reticulone, reviparin sodium Levidinon, Rhenium Re186 etidronic acid, Lyzoxin, Ribaminol, Ribavirin, Ribopurine, Ribozyme, Ricasetron, Lidogrel, Rifabutin, Rifamethan, Ri Famexil, Rifamide, Rifampin, Rifapentin, Rifaximin, RII Reti Rilopirox, Riluzole, Rimantadine, Limmazole hydrochloride, Rimexol Limoprogine, Liodipine, Lioprostil, Lipazepa Lipisartan, risedronate sodium, risedronate, lysocine, lysocylide salt Salts, rispenzepine, risperdal, risperidone, ritanserin, litipenem, ritonserin Dorin, Littlecast, Ritonavir, Rizatriptan benzoate, Locastine hydrochloride, Odor Rocuronium, rhodocaine, loflurane, logretimide, rohitzkin, rokitamycin Loletamicide, lorgamidin, roliciprine, rolipram, rolitetra Cyclin, lorozin, romazalit, romultide, ronidazole, ropinirole, rop Toin hydrochloride, ropivacaine, lopidine, lokinimex, rosalamycin, rosiglitazo Roxoxacin, rotoxamine, roxaitidine, roxarsone, rox Syndol, Roxithromycin, Rubiginone B1, Ruboxil, Rufloxacin, Rupati Rupatidine, rutamycin, luzadran, saberzole, safinol, safi Ronyl, cyntopein, salbutamol, R-sarcorex, saletamide maleate, sali Salicyl alcohol, salicylamide, meglumine salicylate, salicylic acid, salmeterol Salnacediin, salsalat, samezin, sanpatrilat, sansa Ikurin, Sanfetolinem, Sanguinalium chloride, Saperconazole, Supplisalta Sapropterin, saquinavir, salafloxacin hydrochloride, salalacin acetate, SarCNU , sarcophytol A, salglamostim, salmoxicillin, salpicillin, salpog Relat, Salprase, Saterinone, Sachigrel, Satsumomab Pentetide, Schick Test Control drugs: scopafungin, scopolamine hydrobromide, scrazaipine Hydrochloride, Sdi-1 mimetic, secalciferol, secobarbital, Seelzone Seglycide acetate, selegiline, selegiline hydrochloride, selenium sulfide, selenomethionine Se75 Cellhotel, sematilide, senturamycin, semothiazil, semustine, sensuol Ligonucleotides, sepazonium chloride, seperidol hydrochloride, seprilose, seproxene Chloride hydrochloride, ceractide acetate, cergolexol maleate, serine, cermetacin, vinegar Cermorelin acid, certaconazole, certindol, sertraline, setiptiline, certoline Toperone, sevilumab, sevoflurane, cezoramide, sibopyrdin, sibutramine hydrochloride Signal transduction inhibitors, silandrone, silipide, silteplase, silver nitrate, cymendan , simtrazene, simvastatin, cincalid, synefungin, cynitrodil, cinnabi Dol (sinnabidol), sipatrigine, sirolimus, shisomycin, citglucid, sizof Ilan, Sobuzoxane, Sodium Amylosulfate, Sodium Iodide I-123, Nitroprussate Sodium oxybate, sodium phenylacetate, sodium salicylate Sorubel, Solipertine Tartrate, Somalapol, Somantadine Hydrochloride Somatomedin B, Somatomedin C, Somatorem, Somatropin, Somenopol, Somidobob (somidobove), sonelmin, sorbin, sorivudine, sotalol, soterenol hydrochloride , sparfloxacin, sodium sparphosate, sparphosic acid, sparsomycin, s Parthein sulfate, spectinomycin hydrochloride, spicamycin D, spiperone, mesyl Spiradolin acid, Spiramycin, Spirapril hydrochloride, Spiraprilat, Spirogerma Spiromustine, spironolactone, spiroplatin, spiroxason Suprenopentin, Spongistatin 1, Suprodiamide, Squalamine, Starimycin stannous hydrochloride, stannous pyrophosphate, tin sulfur colloid, stanozolol, statron, sta Urosporine, stabudin, stefimycin, stenboron acetate, stepronin, iodine Stilbazine, styronium iodide, stipamide, stiripentol, stovazine Streptomycin sulfate, streptonicozide, streptonigrin, streptoz Syn, stromelysin inhibitor, strontium chloride Sr89, succinate, sucrose Simmer, succinylcholine chloride, sucralfate, sucrosophagopotassium, sudoxin Sicam, sufentanil, sufothidine, surazepam, sulbactam pivoxil, sulconate Zole nitrate, sulfabenz, sulfabenzamide, sulfacetamide, sulfacin Chin, sulfadiazine, sulfadoxine, sulfarene, sulfamerazine, sulf Ameth, sulfamethazine, sulfamethizol, sulfamethoxazole, sulfa Monomethoxyline, sulfamoxol, zinc sulfanilate, sulfanitran, sulf Asalazine, sulfasomisole, sulfazameth, sulfinalol hydrochloride, sulf Nosine, sulfinpyrazone, sulfisoxazole, sulfomyxin, sulfontero Sulfoxamine hydrochloride, sulfoxamine, sulinldac, sulmarin, sulnidazole, Suloctidyl, Sulofenul, Sulopenem, Suloxifen oxalate, Sulpiride, Sul Prostone, sultamicillin, sultiam, sultopride, sulkast, smalotene, s Matriptan, suncillin sodium, suprocron, suprofen , suradista, suramin, sulfomer, suricainide maleate, suritozo Sulfate, thronacrine maleate, squimelido sulfate, swinesonin, simacrim (sym akalim), simcrosene, Cimetine hydrochloride, synthetic glycosaminoglycan, taciamine hydrochloride, tacrine Hydrochloride, tacrolimus, talampicillin hydrochloride, taleranol, tarisomycin, talim Stine, Talmethacin, Talniflumate, Talopram hydrochloride, Tarosalat, Tametra Phosphate hydrochloride, tamoxifen, tampramine fumarate, tamsulosin hydrochloride, tandamin Hydrochloride, tandospirone, tapgen, taprosten, tasosartan, tauromus Chin, taxane, taxoid, tazadren succinate, tazanolast, tazarotene, tajif Tazobactam, Tazoferon, Tazolol hydrochloride, Tebuferon, Tebu N, bicisotectium (Tc)-99m, tecrozan, tecrogalan sodium, tecro Teecleukin, Teflurane, Tegaflu, Tegretol, Teicoplanin, Terenzepi Telrapyrium, telmestain, telmisartan, telomerase inhibitors, telok Santrone hydrochloride, terdipine hydrochloride, temafloxacin hydrochloride, tematropium methyl Sulfates, temazepam, temelastine, temocapril, temocillin, temoporfin, temo Zolomid, Tenidap, Teniposide, Tenosal, Tenoxicam, Tepilindol, Tepoki Sarin, teprotide, terazosin, terbinafine, terbutaline sulfate, terconazosin Lu, terfenadine, terflavoxate, terguride, teriparatide acetate, terlaxate Len, terlipressin, terodilin, teroxalen hydrochloride, teroxylon, tertatro Lu, Tesicum, Tesimide, Testolactone, Testosterone, Tetracaine, Tetrachlor Rhodecaoxide, tetracycline, tetrahydrozoline hydrochloride, tetramisol hydrochloride Tetrazolast meglumine, tetrazomine, tetrophosmin, tetroquinone, tetrox Soprim, Tetridamine, Talibrastin, Thalidomide, Theofibrate, Theofibrate Phosphorus, thiabendazole, thiamiprine, thiamphenicol, thiamylal, thiazes Thiamin hydrochloride, thiadinium chloride, ethylperazine, thimelon sodium, thimelon Sarl, thiocholalin, thiofedrine, thioguanine, thiomarinol , thiopental sodium, thioperamide, thioridazine, thiotepa, thiothixene, Tifenamil hydrochloride, tifenamil potassium, thyram, tozarinone, threonine, thoronine Thrombopoietin, thrombopoietin mimetic, thymalfacin, thymopoietin Receptor agonists, thymotrinan, thyromedan hydrochloride, thyroxine I-125, thyroxine I-1 31. Thiacrylast, Thiacrylast sodium, Thiagavin, Thiamenidine, Thianep Chin, tiapafant, thiapamil hydrochloride, tiaramide hydrochloride, thiazofloxacin N, tibenelast sodium, tiborone, tibulic acid, ticabesone propionate, ticarb Zin, ticalcyrincresil sodium, ticlatone, ticlopidine, ticlinafene, Thienoxolol, tifrac sodium, tigemonam dicolin, tigesol, tiretami Tyrinoprofen hydrochloride, tyrosine hydrochloride, tyrosolol, tyroprofen albamel, tyrolone hydrochloride Salt, disodium chydronic acid, chydronic acid, thimeflon, thymovesone acetate, timolol Tin ethyl ethiopropyl purine, tinnabinol, thymidazole, tinzaparin sodium Thioconazole, thiodazocin, thiodonium chloride, thioperidone hydrochloride, thiopinac Thiospirone hydrochloride, thiothidine, tiotropium bromide, thioxidazole, tipent Syn hydrochloride, cypredan, cyprenolol hydrochloride, cyprinastomeglumine, cypropid Tikinamide hydrochloride, tiquinamide hydrochloride, tirandaridine, tirapazamine, tirandaridine D, tyrofiban, tylopramide, titanocene dichloride, thixanox, thixoco pivalate Lutol, tizanidine hydrochloride, tobramycin, tokainide, tocanfil, tofenaci Tramolol, Trazamide, Trazoline hydrochloride, Tolbutamide, Tolcapone, Torsikrat, Torfamid, Torgabid, Lamotrigine, Trimidon, Trindart Tolmetine, tolnaphthate, tolpovidone I-131, tolpyramide, tolrestat, Tomerkast, Tomoxetine hydrochloride, Tonazosin mesylate, Topiramate, Topotecan, Topotecan hydrochloride, Topsentin, Topterone, Toxidine, Torasemide, Toremifene, Torsemid, Tosifen, Tosufloxacin, Pluripotent Stem Cell Factor, Tracasolate, Tra Fermin, Tralonide, Tramadol hydrochloride, Tramazoline hydrochloride, Trandolapril tranexamic acid, tranilast, transcainide, translation inhibitors, tranexamic acid, to Razodone hydrochloride, trazodone-HCl, trebenzomine hydrochloride, trefentanil hydrochloride, Leloxynate, Trepipam Maleate, Trestron Acetate, Tretinoin, Triacetate Triacetyluridine, triafungin, triamcinolone, triampidine sulfate Triamterene, triazolam, tribenoside, tricaprylin, tricetamide, tri Chlormethiazide, trichohyalin, trisirivine, tricitrate compounds, triclofe Nolpiperazine, Triclofos sodium, Triclonide, Trientine, Triphena Grel, Triflavin, Triflosin, Triflubazam, Triflumidate, Trifur Hydrochloride Loperazine, trifluperidol, triflupromazine, triflupromazine hydrochloride, Rifluridine, trihexyphenidyl hydrochloride, trilostane, trimazocin hydrochloride, tri Megestone, Trimeprazine tartrate, Trimethadione, Trimethaphan cansylate, Rimethobenzamide hydrochloride, trimethoprim, trimethodine, trimethrexate, tri Mipramine, Trimoprostil, Trimoxamine Hydrochloride, Triolein I-125, Triole In I-131, trioxyfen mesylate, tripamide, triperenamin hydrochloride, tripro Lysine hydrochloride, triptorelin, trisulfapyrimidine, troclocene potassium, tro Glitazone, trolamine, troleandmycin, trombodipine, tro Metamol, tropanserin hydrochloride, tropicamide, tropin ester, tropisetron Trospectomycin, trovafloxacin, trovildin, tryptophan, tuberculosis Clin, tubocurarine chloride, tubrozol hydrochloride, tucarcsol, turob Terol, tulosteride, cibamart, tyrogenin, sodium tyropanoate, tyrosine, Tyrosulisine, thylphostine, ubenimex, urdazepam, undecylenic acid, uracil Mustard, urapidil, urea, uredepa, uridine triphosphate, urofolitropin, u Rokinase, Ursodiol, Valacyclovir, Valine, Valnoctamide, Valproic acid Thorium, valproic acid, valsartan, bamicamid, vanadeine, vancom Icin, vaninolol, bapiprost hydrochloride, bapreotide, variolin B, vasopress Syn, vecuronium bromide, veraresol, vernacrine maleate, venlafaxine, Belladrine hydrochloride, veramine, verapamil hydrochloride, verzin, berilopam hydrochloride Salt, verulkast, berophilin, veroxan, verteporfin, vesnar Non, bexivinol, vidarabine, vigabatrin, biloxazine hydrochloride, vinblastic acid Vincristine sulfate, vinbulin citrate, vincophos, vinconate, vincristine sulfate, Vindesine, vindesine sulfate, vinepidine sulfate, binricinate sulfate, vinlein sulfate Rosine, vinorelbine, vinpocetine, vintoperol, vinxaltine Vinzolidine sulfate, biprostol, Virginiamycin, bili Viridoflavine, viroxime, vitaxin, borazosin, voriconazole, vo Rosol, voxergolide, warfarin sodium, xamoterol, xanomeline, Xanoxate sodium, xanthinol nicotinate, xemylofiban, xenalipi Xyloprofen, xenbucin, xyloba, xymoprofen, xipamide, xolphanol mesin Xylamide, xylamidine tosylate, xylazine hydrochloride, xylometazoline hydrochloride, xylometazoline S, Yanganbin, Zabishipril, Zacoprid, Zafirlukast, Zalcitabine, Zare Pron, Zarospirone, Zaltidine hydrochloride, Zaltoprofen, Zanamivir, Zanquilen Zanoterone, Zantac, Zarirlukast, Zatebrazine, Zatocetro N, Zatosetron maleate, Zenalestat, Zenazosin mesylate, Zeniplatin, Ze Lanol, Zidomethacin, Zidovudine, Diflosylon, Dilantel, Dirascorbe, Giro -ton, dimezine hydrochloride, zinc undecylenate, zindothrin, dinoconazole hydrochloride Zinostatin, Zinterol hydrochloride, Zinviroxime, Ziprasidone, Zobol t) Zofenopril calcium, zofenoprilat, zolamine hydrochloride, zolazepam hydrochloride Zoledronic acid, Zoreltine hydrochloride, Zolmitriptan, Zolpidem, Zomepyracnate Um, zometapine, zonicresol hydrochloride, zonisamide, zopiclone, zopolrestat It contains zolbamycin, zolubicin hydrochloride, zotepine, and zucapsaicin.

[0160] Another pharmaceutically active ingredient permitted for use herein is lumateperone, U.S. 97 45300, 9708322, 7183282, 7071186, 6552017, 8648077, 8598119, 9751883, 9371324, 9 315504, 9428506, 8993572, 8309722, 6713471, 8779139, 9168258, RE039680E1, 961606 Patent No. 1, 9586960, and U.S. Patent Application Publication Nos. 2017114037, 2017183350, 2015072964, 20 This information is disclosed in documents 04034015, 2017189398, 2016310502, and 2015080404, and all of its contents are as follows: It is incorporated into this specification as needed.

[0161] Furthermore, examples of antidiabetic active ingredients are not limited to those listed below, but include JTT-501 (PNU-182716) (Regritazal), AR-H039242, MCC-555 (Netoglitazon), AR-H049020 Tesagritazar) , CS-011(CI-1037), GW-409544×, KRP-297, RG-12525, BM-15.2054, CLX-0940, CLX-092 1, DRF-2189, GW-1929, GW-9820, LR-90, LY-510929, NIP-221, NIP-223, JTP-20993, LY 29311 Na, FK 614, BMS 298585, R 483, TAK 559, DRF 2725 (Lagaglitazar), L-68639 8, L-168049, L-805645, L-054852, Demethylasteriquinone) B1 (L-783281), L-363586, Includes KRP-297, P32 / 98, CRE-16336, and EML-16257.

[0162] The erectile dysfunction medications available in this specification include, but are not limited to, those that involve blood flow to the penis. Drugs to promote blood flow, and drugs that increase parasympathetic nervous system activity (cholinergic activity) and sympathetic nervous system activity. This includes drugs that act on autonomic nervous system activity, such as reducing sexual activity (adrenergic activity). The active ingredients that can be used to treat functional disorders are not limited, but alprostad Tadalafil, vardenafil, apomorphine, yohimbine hydrochloride, sildenafil The active ingredient is a citrate, and any combination thereof. In one embodiment, the active ingredient is a citrate. It's Darafil.

[0163] Active ingredients or therapeutic agents for the treatment of headaches and / or migraines are also available for use in this specification. Examples of special active ingredients are, but are not limited to, triptans, such as eletrip. Tan, naratriptan, rizatriptan (rizatriptan benzoate), sumatriptan, and zolmitriptan, etc. In one embodiment, the active ingredient is lyzatriptan. Furthermore, it may be optionally combined with NSAIDs.

[0164] In one embodiment, the pharmacoactive ingredient is epinephrine, a prodrug of epinephrine, and It may also be an analog, a derivative, or a salt.

[0165] (Epinephrine / dipivefrin dose profile) In example 1, a composition containing a prodrug such as an epinephrine prodrug is, for example, E Using a pipen, the biodelivery profile is similar to that of epinephrine administered by injection. It may have an il.

[0166] Epinephrine or its prodrugs are administered in doses ranging from approximately 0.01 mg to approximately 100 mg, for example, 0.1 mg In doses of 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. It can exist in amounts greater than 0.1 mg, 5 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg. , over 70mg, over 80mg, over 90mg, or less than 100mg, less than 90mg, less than 80mg, less than 70mg, less than 60mg , less than 50mg, less than 40mg, less than 30mg, less than 20mg, less than 10mg or less than 5mg, or any of the above. Includes any combination.

[0167] Dipivefrine is available in doses ranging from approximately 0.5 mg to approximately 100 mg, for example, 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg. It can be available in doses of mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. This applies to doses exceeding 1mg, 5mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, and 80mg. More than 90mg or less than 100mg, less than 90mg, less than 80mg, less than 70mg, less than 60mg, less than 50mg, less than 40mg , including less than 30 mg, less than 20 mg, less than 10 mg, or less than 5 mg, or any combination thereof. .

[0168] (Prodrug composition) In another example, a composition (e.g., containing epinephrine) is linked by bonding with hydrophilic sugars. A suitable, non-toxic, non-ionic alkyl glycoside having a hydrophobic alkyl group is provided below. It can be used in combination with a mucosal delivery promoter selected from the following: (a) an agglutination inhibitor; (b) an electrolytic agent. (c) Load modifiers; (d) pH adjusters; (e) Mucolytics or mucolytics; (f) Ciliary transport (g) A pharmacokinetic agent; (i) A membrane penetration enhancer selected from the following: (i) a surfactant; (ii) a bile salt; (ii) phosphorus Lipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) Enami (v) Nitric oxide donor compounds; (vi) Long-chain amphiphilic molecules; (vii) Hydrophobic permeation enhancers; (vii i) sodium or salicylic acid derivatives; (ix) glycerol acetoacetate ester; (x) cytoglycerol (xi) rhodextrin or β-cyclodextrin derivatives; (xii) medium-chain fatty acids; (xii) chelation (xiii) amino acids or salts thereof; (xiv) N-acetylamino acids or salts thereof; (xv) selected Degrading enzymes for damaged membrane components; (ix) Inhibitors of fatty acid synthesis; (x) Inhibitors of cholesterol synthesis; and (xi) those listed in (i) to (x) Any combination of membrane penetration enhancers; (h) modifiers of epithelial connective tissue function; (i) vasodilators; (j) Selective transport enhancer; or (k) the compound is effectively combined and associated with it, The stabilization of compounds for enhanced transmucosal delivery by being contained, encapsulated, or bound. Vehicles, carriers, mucosal adhesives, supports, or other materials that bring about transformation and stabilize delivery. This is a complex-forming species, where the compound and the above transmucosal delivery promoter are used in the target blood. This provides increased bioavailability of the compound in plasma. This formulation is similar to other epinephrine It may include an active pharmaceutical ingredient (API):enhancer ratio that is almost identical to that of Fulin.

[0169] Epinephrine, dipivephrine, or prodrugs AQEP-03, AQEP-04, AQEP-05, AQEP- 06, AQEP-07, AQEP-08, AQEP-09, AQEP-10, AQEP-11, AQEP-12, AQEP-13, AQEP-14 or When administered as a prodrug such as AQEP-15, it produces specific efficacy. One of these is, Dipivefrin and prodrugs AQEP-03, AQEP-04, AQEP-05, AQEP-06, AQEP-07, AQEP- 08, AQEP-09, AQEP-10, AQEP-11, AQEP-12, AQEP-13, AQEP-14 and AQEP-15 are lipophilic. Therefore, it is necessary to have higher transmucosal permeability. Dipivefrin and prodrugs AQEP-03, AQEP-04, AQEP-05, AQEP-06, AQEP-07, AQEP-08, AQEP-09, AQEP-10, AQEP-11 AQEP-12, AQEP-13, AQEP-14, and AQEP-15, respectively, benefit from stronger protein binding. Therefore, it has a longer plasma half-life. Dipivefrin allows for sustained blood levels, and α - Due to low interaction with receptors, undesirable or harmful vasoconstriction is minimized or eliminated. For example, prodrugs such as AQEP-09 are more epinephrine-like than dipivefrin. It exhibits similar binding and activation profiles, and high binding affinity to α- and β- receptors. Other prodrugs and combinations of prodrugs are similar to epinephrine. Or different binding affinity to α-receptors and β-receptors that preferentially target one or more receptors. It is also possible to indicate a tee.

[0170] [ka]

[0171] Dipivefrin or prodrug AQEP-03, AQEP-04, AQEP-05, AQEP-06, AQEP-07, AQEP- 08, AQEP-09, AQEP-10, AQEP-11, AQEP-12, AQEP-13, AQEP-14 or AQEP-15 individually or The combination may be delivered by sublingual film in a manner similar to epinephrine, and injection It may be delivered by other means, including.

[0172] The film and / or its components may be water-soluble, water-swellable, water-dispersible, or water-insoluble. The term "water-soluble" refers to a substance that is at least partially soluble in an aqueous solvent. This can be done, and in this case, the aqueous solvent includes water, but is not limited to water. (Term: "aqueous solvent") The term "solubility" does not necessarily mean that the substance is 100% soluble in an aqueous solvent. No. The term "water-insoluble" refers to a substance that does not dissolve in an aqueous solvent, and in this case the aqueous solvent is The solvent may include, but is not limited to, water. The solvent (preferably a polar solvent) may be included alone or in combination with water.

[0173] (Polymer matrix) This composition may include a polymer matrix. Any desired polymer matrix The drug can be used as long as it is orally soluble or disintegrable. This dosage form is easily removed. It must have sufficient bioadhesion properties and form a gel-like structure upon administration. These are not suitable for delivery of pharmaceutical active ingredients. However, all compositions, including immediate-release, delayed-release, controlled-release, and sustained-release types, are also intended to be effective. This includes the various embodiments shown in the diagram.

[0174] This pharmaceutical composition film is made of highly branched polymers with various structural architectures. It may contain dendritic polymers. Dendritic polymers include dendrimers and dendritic polymers. Mer (dendritic graft polymer), linear dendritic hybrid, multi-arm star polymer, Alternatively, it may contain a highly branched polymer.

[0175] Highly branched polymers are highly branched polymers that have imperfections in their structure. Yes, they exist. However, these can be synthesized in a single-step reaction, which is another dendritic structure. Because of its superior advantages, it is suitable for bulk production in large quantities. Apart from their spherical structure, their properties include abundant functional groups, intramolecular cavities, low viscosity, and high solubility. Yes, dendritic polymers have been used in several drug delivery applications. For example, in the citation... More specifically incorporated within this specification is "Dendrimers as drug carriers: Drug administration Application via Different Routes (Dendrimers as Drug Carriers: Applications in Different Routes) See "of Drug Administration," J Pharm Sci, VOL. 97, 2008, 123-143.

[0176] Dendritic polymers can have internal cavities capable of encapsulating drugs. High-density polymer chains The steric hindrance caused by this can prevent the crystallization of the drug. Therefore, branching The polymer offers the additional advantage of formulating crystalline drugs within the polymer matrix. It can be provided.

[0177] Suitable examples of dendritic polymers include poly(ether)-based dendrons, dendrimers, and Highly branched polymers, poly(ester)-based dendrons, dendrimers and highly branched polymers , poly(thioether)-based dendrons, dendrimers and highly branched polymers, poly(a (Icomethylamino acids)-based dendrons, dendrimers and highly branched polymers, poly(arylalkyl) (Ether-based) dendrons, dendrimers and highly branched polymers, poly(alkylene) (Min)-based dendrons, dendrimers and highly branched polymers, poly(amidoamine)-based Contains dendrons, dendrimers, or highly branched polymers.

[0178] Other examples of highly branched polymers include poly(amine), polycarbonate, and poly(etherketone). Polyurethane, polycarbosilane, polysiloxane, poly(esteramine), poly(s (Lufonamine), poly(urethane urea) or polyether polyol, for example, polyglyceride It includes n.

[0179] The film is a combination of at least one polymer and a solvent that optionally contains other components. It can be prepared using water, polar organic solvents, or other solvents, though not limited to these. For example methanol, ethanol, isopropanol, t-butyl alcohol, acetone, Cetonitrile, 2-butanone, 1,2-dimethoxyethane, or tetrahydrofuran, or the same Any combination of these is also acceptable. In some embodiments, the solvent is a nonpolar solvent such as methylene chloride. Organic solvents may also be used. The film is formed by a selected casting or film formation method and a controlled drying process. It can be manufactured by using a wet film matrix. For example, the film is made by using a wet film matrix. A controlled method of forming a viscoelastic structure by applying thermal and / or radiation energy. It may also be prepared through a drying process, which controls the uniformity of the film's contents. The controlled drying process uses air alone, heat alone, or heat and air together to dry the film. The upper side or the lower side of the film, or cast, film-formed, or extruded Contacting the substrate supporting the film, or simultaneously or at different points during the drying process. This may include bringing two or more surfaces into contact. Some of these processes This is described in more detail in U.S. Patent Nos. 8,765,167 and 8,652,378. These are incorporated herein by reference. Alternatively, the film is incorporated herein by reference. As stated in U.S. Patent Application Publication No. 2005 / 0037055A1, which is incorporated in the details: It may be manufactured by extrusion molding.

[0180] The polymer contained in the film is either water-soluble, water-swellable, water-insoluble, or water-soluble. A combination of one or more water-swellable and water-insoluble polymers may also be used. The polymer may be cellulose, It may contain cellulose derivatives or gums. Specific examples of usable water-soluble polymers are limited to... It is not a matter of, but polyethylene oxide, pullulan, hydroxypropyl methylcellulose hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl pylori Don, carboxymethylcellulose, polyvinyl alcohol, sodium alginate, po Ethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum Gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl Contains glycopolymers, starches, gelatin, and combinations thereof. Water-insoluble is available. Specific examples of polymers are not limited to ethylcellulose and hydroxypropylcellulose. ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose Includes talates and combinations thereof. For higher doses, compared to lower doses, It may be desirable to incorporate polymers that provide a high level of viscosity.

[0181] As used herein, the terms “water-soluble polymer” and its variants are defined as “at least partially.” To dissolve in water, preferably completely or largely in water, or to absorb water. This refers to polymers. Polymers that absorb water are often called water-swellable polymers. The materials usable in this invention are water-soluble at room temperature and other temperatures, for example, at temperatures above room temperature. These materials may also be water-swellable. Furthermore, these materials may be water-soluble or water-swellable at pressures lower than atmospheric pressure. It may also be a water-soluble polymer. In some embodiments, a film is formed from such a water-soluble polymer. It may be sufficiently water-soluble so that it can dissolve upon contact with bodily fluids.

[0182] Other polymers that can be incorporated into films include biodegradable polymers, polymers, and copolymers. This includes remers, block polymers, or combinations thereof. The term "biodegradable" refers to physical In contrast to materials that are easily broken down into pieces (i.e., bioerodable materials), chemical It is understood that it is intended to contain substances that decompose in a specific way. It is incorporated into the film. The polymer may also include a combination of biodegradable or bio-erosive materials. Known and usable polymers or polymer species that conform to the standard include: poly(glycolic acid) (PGA) Poly(lactic acid) (PLA), polydioxane, polyoxalate, poly(α-ester), polyacid-free Water, polyacetate, polycaprolactone, poly(orthoester), polyamino acid, Poly-aminocarbonate, polyurethane, polycarbonate, polyamide, poly(alkyl) This includes cyanoacrylates, as well as mixtures and copolymers thereof. Additional uses Possible polymers include stereopolymers of L- and D-lactic acid, and bis(p-carboxyphenoxy) Propanic acid and sebaciac acid copolymer, sebaciac acid copolymer, caprolactone copolymer Remer, poly(lactic acid) / poly(glycolic acid) / polyethylene glycol copolymer, polyure Copolymers of tan and (poly(lactic acid)), α-amino acid copolymers, α-amino acids and capro Copolymer of ammonium compounds, α-benzyl glutamate ester and polyethylene glycol Polymers, succinate esters and poly(glycol) copolymers, polyphosphazenes, It contains dihydroxyalkanoates or mixtures thereof. The polymer matrix is ​​1 It may contain two, three, four or more ingredients.

[0183] Various different polymers may be used, depending on the film's mucosal adhesion properties and the desired solvent properties. It is desirable to select a polymer that provides a suitable dissolution rate and / or decay rate. In particular, fil The time required to maintain contact between the mucous membrane and the mucous membrane is the time required for the pharmaceutically active ingredients contained in the composition. It depends on the type of drug. Some active pharmaceutical ingredients can be delivered through mucosal tissue in just a few minutes. While this may not be necessary, other active pharmaceutical ingredients may last for several hours, or even longer. This may take time. Therefore, in some embodiments, one or more of the aforementioned water-soluble polymers Mar is sometimes used to form a film. However, in other embodiments, water-soluble A water-swellable polymer and a water-insoluble and / or biodegradable polymer as described above. It may be desirable to use a combination of the following: water-swellable, water-insoluble and / or bioactive. By including one or more polymers that are soluble, a film formed solely of water-soluble polymers can be created. This allows us to provide a film with a slower dissolution or disintegration rate. This film adheres to mucosal tissue for longer periods, such as up to several hours, and this means This would be desirable for the delivery of certain active pharmaceutical ingredients.

[0184] (Film characteristics) Preferably, the individual film dosage forms of the pharmaceutical film have a suitable thickness and small size. It can have a size of approximately 0.0625 to 3 inches (1.5875 to 76.2 mm) x approximately 0.0625 to 3 inches It is between inches. The film size is also, in at least one aspect, greater than 0.0625 inches, 0. Over 5 inches (12.7 mm), over 1 inch (25.4 mm), over 2 inches (50.8 mm), approximately 3 inches (76.2 mm), and Over 3 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches, less than 0.0625 inches It can also be full. In another embodiment, more than 0.0625 inches, more than 0.5 inches, more than 1 inch, more than 2 inches , or more than 3 inches, approximately 3 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches , or less than 0.0625 inches. The aspect ratio, including thickness, length and width, is determined by the polymer The chemical and physical properties of Trix, active pharmaceutical ingredients, dosage forms, enhancers, and related other Based on the additives and the desired dimensions of the distribution unit, it can be optimized by those skilled in the art. Yes, it is possible. This film formulation, when placed in the user's buccal oral cavity or sublingual region, is effective. It must have good adhesion. Furthermore, this film formulation must disperse and dissolve. Ideally, the dispersion should occur within approximately 1 minute and the dissolution within approximately 3 minutes. In this film formulation, the incubation period is approximately 1 to 30 minutes, for example, approximately 1 to 20 minutes, or more than 1 minute, more than 5 minutes, 7 minutes. Over a minute, over 10 minutes, over 12 minutes, over 15 minutes, over 20 minutes, over 30 minutes, approximately 30 minutes, or less than 30 minutes, less than 20 minutes, 15 Disperse and dissolve in less than 1 minute, less than 12 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, or less than 1 minute. This may be possible. The sublingual dispersion time may be shorter than the intraoral buccal dispersion time.

[0185] For example, in some embodiments, the film contains polyethylene oxide alone or a It can be contained in combination with a dipolymer component. The second polymer is another water-soluble polymer. - Water-swellable polymers, water-insoluble polymers, biodegradable polymers, or any combination thereof This is also acceptable. Preferred water-soluble polymers include, but are not limited to, those presented above. It is not that it is. In some embodiments, the water-soluble polymer is a hydrophilic cellulose-based polymer. Mer, for example, hydroxypropylcellulose and / or hydroxypropylmethylcellulose It may include -, etc. In some embodiments, one or more water-swellable, water-insoluble and / or biodegradable substances. The polymer can also be included in the polyethylene oxide-based film. Any of the water-swellable, water-insoluble, or biodegradable polymers listed below can be used. The polymer component is present in an amount of approximately 0% to approximately 80% by weight, more specifically approximately 30% to approximately 7% It may be used in amounts of 0% by weight, and more specifically, about 40% to about 60% by weight, which is heavy In terms of quantity, over 5%, over 10%, over 15%, over 20%, over 30%, over 40%, over 50%, over 60%, and over 70%, Approximately 70%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, and This includes less than 5%.

[0186] (Stereo obstacles) Steric hindrance is the delay of chemical reactions due to their steric bulk. This is typically seen in enzymatic reactions, for example. It manifests in intermolecular reactions. Steric hindrance controls selectivity, such as delaying undesirable side reactions. Often developed for this purpose. In pharmacology, steric effects cause drugs to be targeted. The way and at what rate the drug interacts with body molecules is determined. Prodrug design is Each of the prodrug substituents and hydrolytic enzymes, esterases, amidases, etc. It is necessary to consider the steric hindrance arising from interactions with the enzyme. Additions such as those described below are necessary. The agent may also affect the activity and / or interaction with the enzyme. In one embodiment In other embodiments, one or more of these enzymes may be endogenous. Exogenous is also acceptable. Stereospecific nucleophilic attack on substituted carbon atoms is stereochemical. With a complete transformation, a simple and versatile method for constructing stereocenters next to heteroatoms. This is a good method. Tertiary groups adjacent to esters are, to an unexpected degree, compared to non-tertiary groups. It prevents hydrolysis.

[0187] (Additives) This film may contain additives. Examples of additives include preservatives and antibacterial agents. Excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, bulking agents, sweeteners Flavoring agents, aromas, release modifiers, adjuvants, plasticizers, salts, flow accelerators, mold release agents, Polyols, granulators, diluents, binders, buffers, absorbents, lubricants, adhesives, anti-adhesion agents, Acidulants, softeners, resins, lubricants, solvents, surfactants, emulsifiers, elastomers, anti-sticking agents This includes antistatic agents and mixtures thereof. These additives are pharmaceutically active ingredients (multiple may be included). It can also be added together with the active pharmaceutical ingredient. The term "stabilizer" as used herein refers to an active pharmaceutical ingredient. , prevents aggregation or other physical and chemical degradation of other excipients or combinations thereof. This refers to an excipient that can be removed or eliminated.

[0188] Stabilizers may also be antioxidants, metal ion chelating agents, pH modifying factors, emulsifiers, and / or interfaces. It can be classified as an activator or an ultraviolet (UV) stabilizer.

[0189] Antioxidants (i.e., substances that slow down, inhibit, interrupt and / or stop oxidation processes, and are suitable as pharmaceuticals) Compounds (or compositions) (or compositions) with properties include, in particular, the following substances: tocopherol and The ester, sesamol from sesame oil, coniferyl benzoic acid from benzoin resin, nordig Nordihydroguaietic resin and nordihydroguayaretinic acid (N DGA), gallic acid, gallic acid esters (especially methyl gallate, ethyl gallate, gallic acid) Propyl gallate, amyl gallate, butyl gallate, lauryl gallate), butylated hydro Xyanisole (BHA / BHT, also known as butyl-p-cresol); ascorbic acid and its salts and Esters (e.g., acorbyl palmitate), erythorbic acid cid) (isoascorbic acid) and its salts and esters, monothioglycerol, sodium Formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite Sodium sulfite, potassium metabisulfite, ethylenediaminetetraacetic acid (EDTA), ethylene Glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), butylated hydro Xytoluene (BHT) (including t-butylhydroxytoluene), cysteine, ferulic acid, corn - Contains hyalic acid, tannic acid, uric acid, and propionic acid. A typical antioxidant is Tocof Electrolytes, such as α-tocopherol and its esters, and butylated hydroxytoluene. and butylated hydroxyanisole. The term "tocopherol" is also tocopherol It also includes esters of α-tocopherol. The known tocopherol is α-tocopherol. "Copherol" contains esters of α-tocopherol (e.g., α-tocopherol acetate). nothing.

[0190] Metal ion chelating agent (i.e., another compound, e.g., active ingredient or another excipient, and host-gesu Any compound that can participate in complex formation (also called a chelating agent) is calcium chloride. , ethylenediaminetetraacetate calcium disodium, glucono delta-lactone, glucon Sodium phosphate, potassium gluconate, sodium tripolyphosphate, sodium hexametaphosphate This includes lium and combinations thereof. Metal ion chelating agents also include cyclic oligosaccharides, for example, cyanoacrylate. Clodextrin, cyclomannin (5 or more α-D-linked cyclomannin molecules linked at the 1,4 positions by α-bonds) (A rhinopyranose unit), cyclogalactin (a unit consisting of 5 or more β-linked units linked at positions 1 and 4 by β-bonds) -D-galactopyranose unit), cycloalthrin (5 units linked at positions 1 and 4 by α-bonds) This includes the α-D-altropyranose units mentioned above, as well as combinations thereof.

[0191] pH adjusters or stabilizers include acids (e.g., hydrochloric acid, hydrofluoric acid, tartaric acid, citric acid, lactic acid) Fumaric acid, phosphoric acid, ascorbic acid, acetic acid, succinic acid, propanoic acid, butyric acid, isobutyric acid, Pivalic acid, malic acid, tartaric acid, adipic acid and maleic acid), acidic amino acids (e.g., glucosulfate) (e.g., tamic acid, aspartic acid), inorganic salts (alkali metal salts, alkaline earth metal salts, ammonia) Acidic substances such as nium salts, and the above acidic substances and organic bases (for example, lysine, arginine, etc.) This includes salts of basic amino acids (such as meglumine), and their solvates (e.g., hydrates). Hmm. Other examples of pH adjusters include silicified microcrystalline cellulose and magnesium aluminometasilicate. Um, calcium salts of phosphate (for example, anhydrous or hydrated calcium hydrogen phosphate, Calcium, sodium, or potassium carbonates or bicarbonates, and calcium lactate (Lumin, or mixtures thereof), carboxymethylcellulose or cross-linked carboxymethylcellulose Sodium and / or calcium salts of croscarmellose (e.g., sodium croscarmellose) (and / or calcium salts), potassium chlorophyll, sodium alginate and / or calcium Cium, sodium doxate, magnesium stearate, calcium, aluminum Magnesium or zinc salts, magnesium palmitate, and magnesium oleate, fumaric acid This includes sodium stearyl and combinations thereof.

[0192] Examples of emulsifiers and / or surfactants include poloxamer or pluronic acid, polyethylene. Glycol, polyethylene glycol monostearate, polysorbate, lauryl sulfate Sodium, polyethoxylated and hydrogenated castor oil, alkyl polyoside (polyosi de), water-soluble protein graft polymerized to a hydrophobic main chain, lecithin, monostearate Glycerin, glyceryl monooleate, glyceryl monostearate / polyoxyethylene Lenstearate, ketostearyl alcohol / sodium lauryl sulfate, carbomer, Phospholipids, (C 10 ~C 20 ) Alkyl and alkylene carboxylates, alkyl ethers Bonate salts, aliphatic alcohol sulfates, aliphatic alcohol ether sulfates, alkylamides Sulfates and sulfonates, fatty acid alkylamide polyglycol ether sulfates, alka Sulfonates and hydroxyalkanesulfons, olefin sulfons, ethyl alcohol Thionic acid acyl esters, α-sulfo fatty acid esters, alkylbenzene sulfonates , alkylphenol glycol ether sulfonate, sulfosuccinate, sulfosuccinate monoesters and diesters of citric acid, aliphatic alcohol ether phosphates, proteins / Fatty acid condensation products, alkyl monoglyceride sulfates and sulfonates, alkyl glycerides Ether sulfonates, fatty acid methyl taurids, fatty acid sarcosinates, sulfolysines Oleates and acyl glutamates, quaternary ammonium salts (e.g., di-(C) 10 ~C 24 ) Al (C)dimethylammonium chloride or bromide), (C 10 -C 24 ) Alkyl-dimethylethyl Ammonium chloride or bromide, (C 10 -C 24 ) Alkyl-trimethylammonium chloride (C) or bromide (e.g., cetyltrimethylammonium chloride or bromide), (C 10 -C 24 )Alkyl-dimethylbenzylammonium chloride or bromide (for example, (C 12 -C 18 )a Lukyl-dimethylbenzylammonium chloride), N-(C 10 -C 18 ) Alkyl-pyridinium Lorid or bromide (e.g., N-(C) 12 -C 16 (Alkyl-pyridinium chloride or bromide) , N-(C 10 -C 18 ) Alkyl-isoquinolinium chloride, bromide, or monoalkyl sulfate , N-(C 12 -C 18 ) Alkyl-polyoylaminoformylmethylpyridinium chloride, N- (C12 -C 18 ) Alkyl-N-methylmorpholinium chloride, bromide, or monoalkyl sulf Eat, N-(C 12 -C 18 ) Alkyl-N-ethylmorpholinium chloride, bromide or monoal Killsulfate, (C 16 -C 18 Alkyl-pentaoxetylammonium chloride, diiso Butylphenoxyethoxyethyldimethylbenzylammonium chloride, N,N-diethyl Hydrochloric acid, acetic acid, lactic acid, and citric acid of aminoethylstearylamide and oleylamide. Salt with phosphoric acid, N-acylaminoethyl-N,N-diethyl-N-methylammonium chloride, b Romido or monoalkyl sulfate, and N-acylaminoethyl-N,N-diethyl-N-be Dinzylammonium chloride, bromide, or monoalkyl sulfate (as mentioned above) And, "acyl" (for example, represents stearyl or oleyl), as well as combinations thereof It is included.

[0193] Examples of ultraviolet (UV) stabilizers include UV absorbers (e.g., benzophenone), UV quenchers ( In other words, an arbitrary method that does not cause decomposition by UV energy, but instead dissipates that energy as heat. (compounds), scavengers (i.e., remove free radicals resulting from exposure to ultraviolet radiation) This includes any compound (and any combination thereof).

[0194] In other embodiments, the stabilizers are ascorbyl palmitate, ascorbic acid, and α-toco. Ferrol, butylated hydroxytoluene, butylated hydroxyanisole, cysteine HC1, citric acid, ethylenediaminetetraacetic acid (EDTA), methionine, sodium citrate, A Sodium scorbate, sodium thiosulfate, sodium metabisulfite, sodium bisulfite Thorium, propyl gallate, glutathione, thioglycerol, singlet oxygen quencher - Hydroxyl radical scavenger, hydroperoxide remover, reducing agent, metal cyanoacrylate Includes saturating agents, cleaning agents, chaotropes, and combinations thereof. "Singlet oxygen citric acid The term "char" is not limited to alkylimidazoles (e.g., histidine). L-camosine, histamine, imidazole 4-acetic acid), indole (for example, turkey Protophan and its derivatives, for example, N-acetyl-5-methoxytryptamine, N-acetyl Rotonin, 6-methoxy-1,2,3,4-tetrahydro-β-carbolin), sulfur-containing amino acids (e.g., Methionine, Ethionine, Gencolic acid, Lanthionine, N-Formylmethionine, Ferri Nin, S-allyl cysteine, S-aminoethyl-L-cysteine), phenolic compounds (for example) For example, tyrosine and its derivatives), aromatic acids (e.g., ascorbic acid, salicylic acid, and (These derivatives), azides (e.g., sodium azide), tocopherols and related vitamins It contains vitamin A derivatives, as well as carotene and related vitamin A derivatives. "Call scavengers" are not limited to azides and dimethyl sulfoxides. histidine, mannitol, sucrose, glucose, salicylic acids, and L-cysteine ​​are It is included. "Hydroperoxide removers" include, but are not limited to, catalase, Contains pyruvates, glutathione, and glutathione peroxidase. "Reducing agent" This includes, but is not limited to, cysteine ​​and mercaptoethylene. The term "genus chelating agent" is not limited to EDTA, EGTA, o-phenanthroline, and It contains citric acid. While not limited to "cleaning agents," it also contains SDS and lauroyl alcohol. It contains sodium sarcosinate. It is not limited to "chaotrope," however. This specification includes guanidine hydrochloride, isothiocyanate, urea, and formamide. As discussed above, the stabilizer can be present in amounts from 0.0001% to 50% by weight, These are in terms of weight: over 0.0001%, over 0.001%, over 0.01%, over 0.1%, over 1%, over 5%, over 10%, and over 20%. Greater than 30%, greater than 40%, greater than 50%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, 1 This includes less than %, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001%.

[0195] Suitable additives include, for example, gelatin, gelatin hydrolysate, recombinant gelatin, and plant-based gelatin. Proteins, such as sunflower protein, soy protein, cottonseed protein, peanut protein Proteins, grape seed protein, etc., whey protein, whey protein isolates, Blood proteins, egg proteins, acrylic proteins, polysaccharides, or carbohydrates, for example acacia gum, chitin, chitosan, xanthan gum, agar, ghat gum, chondroitin Sulfuric acid, dextran, carrageenan, karaya gum, hyaluronic acid, curdi an), alginate, tragacanth gum, pullulan, laminarin, kaya, zanthrox (Z anflo), Albizia gum, Guar gum, baker's yeast, locust bean gum, Glycan, starch, schizophyllan, amylase, lentinan, cellulose, crestin pectin, scleroglucan, larch gum, potato starch, pea starch Heta starch, starch acetate, starch phosphate, inulin and pectin, water-soluble polysaccharides, For example, alginates, carrageenan, guar gum, agar, xanthan gum, gellan gum , gum arabic and related gums (gatti gum, karaya gum, tragacanth gum), pec Water-soluble derivatives of cellulose, such as tin: alkylcellulose, hydroxyalkylcellulose S and hydroxyalkylalkylcellulose, for example, methylcellulose, hydroxymethylcellulose Hydroxycellulose, hydroxyethylcellulose, hydroxypropylcellulose, Hydro Xyxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutyl Methylcellulose, cellulose esters and hydroxyalkylcellulose esters, For example, cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose (HPMC); Boxyalkylcellulose, carboxyalkylalkylcellulose, carboxyalkyl Cellulose esters, such as carboxymethylcellulose and their alkali metal salts. ;Water-soluble synthetic polymers, such as polyacrylic acid and polyacrylic acid esters, polymethac Lylic acid and polymethacrylate esters, polyvinyl acetate, polyvinyl alcohol, Polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVA / vinyl acetate It may contain copolymers or polycrotonic acids; preferably, phthalic acid-treated gels. Tin, succinic acid-treated gelatin, cross-linked gelatin, shellac, water-soluble chemical derivatives of starch , for example, having a tertiary or quaternary amino group such as a diethylaminoethyl group, as needed Cationically modified acrylates and methacrylates that may be quaternized; or, It is another similar polymer.

[0196] The stabilizer may include nanoparticle stabilizers such as a dispersant layer that surrounds the surface of the nanoparticles. For example, see Langmuir's paper, 2007, (23)3, 1081-1090, December 20, 2006, doi.org / 10.10 See 21 / la062042s. The stabilizer is a stabilizer ligand, for example, chemically absorbed into nanoparticles. It contains a monomer having a functional group that can be attached to form a polymerizable monolayer. This is possible. For example, see the paper by Jadhav et al., https: / / doi.org / 10.1002 / ppsc.201400074. The stabilizer may include a surface stabilizer. For example, U.S. Patent No. 6428814 and See also Japanese Patent No. 4598399. The surface stabilizer is tyroxapole (US Patent No. 5, (Patents No. 429, 824), polyalkylene block copolymer (Patents No. 5,565, 188), sulfate group modification Nonionic block copolymer (U.S. 5,569,448), high molecular weight linear poly(ethylene o (Hydroxide) polymer (US Patent No. 5,580,579), butylene oxide-ethylene oxide block Gojicopolymer (U.S. Patent No. 5,587,143), Hydroxypropylcellulose (U.S. Patent No. 5,59 It may contain (Patent No. 1,456) and sugar-based surface stabilizers (U.S. Patent No. 5,622,938). The stabilizing agent may include a peptide stabilizer. For example, see International Publication WO2006097748A2. Please illuminate. Stabilizers include, for example, L-cysteine ​​hydrochloride, glycine hydrochloride, malic acid, etc. It can contain sodium bisulfite, citric acid, tartaric acid, and L-cystine dihydrochloride. See, for example, U.S. Patent No. 6,153,223. The stabilizer may contain a natural compound. This is possible. The stabilizer may include synthetic compounds. The stabilizer may be one or more of the above chemicals. It may contain blends of compounds or combinations. Stabilizers are used for the desired time. And, or until it reaches a specific target, tissue, or environment, it protects the metabolism of the prodrug. It can function in that way.

[0197] The additional components may be in the range of up to approximately 80% of the total weight of all composition components, preferably It can be in the range of approximately 0.005% to 50%, more preferably 1% to 20%, which is greater than 1%. More than %, More than 10%, More than 20%, More than 30%, More than 40%, More than 50%, More than 60%, More than 70%, About 80%, More than 80%, 80 Less than %, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, 5 Contains less than %, approximately 3%, or less than 1%. Other additives include anti-adhesion agents, fluidizing agents, and opaque agents, e.g. For example, magnesium, aluminum, silicon, titanium oxides, etc., and if possible, all of them. Based on the weight of the lumen component, the concentration range is approximately 0.005% to approximately 5% by weight, and preferably approximately 0. It can contain 0.02% to approximately 2% by weight, which is greater than 0.02%, greater than 0.2%, greater than 0.5%, greater than 1%, and greater than 1.5%. Over %, over 2%, over 4%, approximately 5%, over 5%, less than 4%, less than 2%, less than 1%, less than 0.5%, less than 0.2% Includes full percentages or less than 0.02%.

[0198] In one embodiment, the composition may include a plasticizer, which is a polyalkylene. Hoxides, for example, polyethylene glycol, polypropylene glycol, polyethylene-p Low molecular weight organic plasticizers such as polypropylene glycol, e.g., glycerol, glycerol mono Acetate, diacetate or triacetate, triacetin, polysorbate, Cetyl alcohol, propylene glycol, sugar alcohol, sorbitol, diethyl sulf Sodium succinate, triethyl citrate, tributyl citrate, plant extract, fatty acid It may contain sterols, fatty acids, oils, etc., and based on the weight of the composition, it can be approximately 0.1% to approximately 40% It is added at a concentration in the range of %, preferably in the range of approximately 0.5% to approximately 20%, which is greater than 0.5%. , over 1%, over 1.5%, over 2%, over 4%, over 5%, over 10%, over 15%, approximately 20%, over 20%, less than 20% This includes less than 15%, less than 10%, less than 5%, less than 4%, less than 2%, less than 1%, or less than 0.5%. Compounds that improve the texture properties of film materials, such as animal or vegetable fats. Preferably, these may be added in their hydrogenated forms. This composition is also a product technology. It may also contain compounds that improve stubbing properties. Other components may include film-forming compounds. It may contain binders that contribute to ease of use and overall quality. Non-limiting examples of binders include Ingredients: Flour, natural rubber, pregelatinized starch, gelatin, polyvinylpyrrolidone, methylcellulose carboxymethylcellulose sodium, ethylcellulose, polyacrylamide, Contains polyvinyloxoazolidone or polyvinyl alcohol. ru.

[0199] Further potential additives include substances that form encapsulation compounds with the active ingredient, and other substances that promote dissolution. The drug contains an active substance that is highly insoluble and / or highly unstable. These materials would be useful in improving the properties of hydrophobic internal cavities and hydrophilic materials. It is a donut-shaped molecule with a hydrophobic outer layer. Insoluble and / or unstable pharmaceutically active ingredients are hydrophobic. It fits into the cavity, thereby creating a water-soluble inclusion complex. Therefore, the inclusion complex The formation allows highly insoluble and / or unstable pharmaceutically active ingredients to be dissolved in water. A particularly desirable example of such a drug is cyclodextrin, which is derived from starch. It is a cyclic carbohydrate. However, other similar substances are also fully considered within the scope of this invention. That is the case.

[0200] Suitable colorants include food, pharmaceutical and cosmetic (FD&C) colorants, and pharmaceutical and cosmetic (D&C) colorants. This includes colorants, or colorants for topical medicines and cosmetics (Ext. D&C). These colorants are color These are the elements, their corresponding lakes, and certain natural and naturally derived colorants. The colorant is a pigment absorbed onto aluminum hydroxide. Other examples of colorants include the well-known A This includes zo dyes, organic or inorganic pigments, or colorants of natural origin. For example, oxides or Inorganic pigments such as iron or titanium are preferred, and their oxides are based on the total weight of the components. It is added at a concentration in the range of approximately 0.001 to approximately 10%, preferably approximately 0.5 to approximately 3%, which is 0.001% Greater than, greater than 0.01%, greater than 0.1%, greater than 0.5%, greater than 1%, greater than 2%, greater than 5%, approximately 10%, greater than 10%, less than 10%, 5 Includes less than %, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001%. nothing.

[0201] The flavor may be selected from liquids that emit natural and synthetic flavors. Examples of such chemicals include volatile oils, synthetic flavor oils, and flavored aromatics. Oils, liquids, oil-containing resins, or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof. This includes off-flavors. A non-restrictive list of representative examples includes mint oil, cocoa oil, and, for example, Citrus oils such as lemon, orange, lime, and grapefruit, as well as apple, pear, and mo Moss, grapes, strawberries, raspberries, cherries, plums, pineapples, and apricots Contains fruit essence or other fruit flavors. Other usable flavorings include , aldehydes and esters, such as benzaldehyde (cherry, almond), citra α-citral (lemon, lime), β-citral (lemon, lime) Im), decanal (orange, lemon), aldehyde C-8 (citrus fruit), aldehyde C-9 (citrus) Citrus fruits, aldehyde C-12, torraldehyde (cherries, almonds) , 2,6-dimethyloctanol (green fruit), or 2-dodecenal (citrus fruits, mandarin), so This includes combinations of these.

[0202] Sweeteners are listed below in an unrestricted list: sugars, glucose (corn syrup), dextrose Sugars, invert sugars, fructose, and combinations thereof; saccharin and its various salts, for example sodium salts; dipeptide-based sweeteners, such as aspartame, neotame, and adenocarcinoma. Bantaem; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevi a Rebaudiana (stevioside); chlorine derivatives of sucrose, e.g., sucralose; sugar alcohols For example, select from sorbitol, mannitol, xylitol, and similar substances. It can be done. Also, hydrolyzed hydrogenated starch and synthetic sweetener 3,6-dihydro-6-methyl 1-1-1,2,3-oxathiadin-4-one-2,2-dioxide, especially potassium salt (acesulfame-K), Also, their sodium and calcium salts, and natural strong sweeteners Examples include monk fruit (Luo Han Guo). Other sweeteners can also be used.

[0203] Antifoaming and / or defoaming agents can also be used in the film. These agents can be used in the film It helps remove air, such as trapped air, from the forming composition. Air can produce an uneven film. Simethicone is one particularly usable eraser. It is a foaming agent and / or a defoaming agent. However, the present invention is not limited thereto, and other suitable defoaming agents are also available. Foaming agents and / or defoaming agents can also be used. Simethicone and similar agents can be used to increase density. It can also be used for the purpose of filling voids, air, and moisture. This can facilitate the removal of similar undesirable components, thereby resulting in a finer texture. To provide a film, and therefore a more uniform film. A drug or component that achieves such a function. These are also called densification agents or density-enhancing agents. As mentioned above, the captured air or undesirable components may result in a non-uniform film. It has a sex.

[0204] As mentioned earlier, either of the following is common to U.S. Patent Nos. 7,425,292 and 8,765,167 Any other components may also be included in the film described herein.

[0205] This film composition further contains a buffer to control the pH of the film composition. This is desirable. Any desired level of buffer releases the pharmaceutically active ingredient from its composition. It is incorporated into the film composition to provide the desired pH level encountered during the process. This buffer controls the release of the pharmaceutically active ingredient from the film and / or its absorption into the body. It is preferable that it be provided in a sufficient amount. In some embodiments, the buffer is citric acid It may contain sodium, citric acid, bicarbonate tartrate, and combinations thereof.

[0206] The pharmaceutical films described herein may be formed by any desired process. The process is described in U.S. Patents No. 8,652,378, No. 7,425,292 and No. 7,357,891. These are incorporated herein by reference. In one embodiment, the film The dosage form composition is first prepared and formed by preparing a wet composition, which contains polymer carriers. It contains a rear matrix and a therapeutically effective amount of pharmaceutically active ingredient. This wet composition is cast The film is formed and then thoroughly dried to form a self-supporting film composition. The finished product is either cast into individual dosage forms, or cast into sheets, and then this sheet It may be cut into individual dosage forms.

[0207] This pharmaceutical composition can adhere to the surface of mucous membranes. The present invention relates to the mouth, vagina, organs, or other Body tissues, affected areas, etc., that have a moist surface, such as the surface of mucous membranes, and are susceptible to the effects of body fluids. It is particularly used for the local treatment of wounds. This composition delivers pharmaceuticals and to the mucosal surface. When applied and attached, it provides a protective layer and prevents the drug from reaching the treatment site, surrounding tissues, and other bodily fluids. To deliver. Simultaneous or subsequent film erosion in aqueous solutions or bodily fluids such as saliva. Considering the control of and the natural delay of film erosion at the treatment site, this composition is suitable for the treatment site. It provides a suitable residence time for effective drug delivery.

[0208] The residence time of this composition depends on the erosion rate of the aqueous disintegrating polymers used in the formulation and their It is determined by each concentration. The rate of erosion depends, for example, on components with different solubility properties, or chemically. Different polymers, for example, hydroxyethylcellulose and hydroxypropylcellulose By mixing them together; a mixture of low molecular weight and medium molecular weight hydroxyethylcellulose By using different molecular weight grades of the same polymer, etc., various lipophilic values ​​or water solubility can be achieved. By using excipients or plasticizers with high water-soluble properties (including essentially insoluble components); By using organic and inorganic salts; for partial crosslinking, crosslinking with glyoxal, etc. By using the agent with polymers such as hydroxyethylcellulose; or by making a film After manufacturing, it is possible to change the physical state of the film, including its degree of crystallinity or phase transition. This can be adjusted by irradiation or curing after processing. These strategies affect the film's penetration. It can be used alone or in combination to alter food dynamics. When applied, this pharmaceutical composition The film adheres to the mucous membrane surface and is retained in place. Water absorption softens this composition. This reduces the feeling of a foreign body. When this composition is present on the mucosal surface, drug delivery occurs. The residence time is determined by the desired timing of delivery of the selected drug and the desired lifespan of the carrier. Depending on the circumstances, it can be adjusted over a wide range. However, generally, residence time is adjusted between a few seconds and a few days. Preferably, the residence time of most pharmaceuticals is adjusted to approximately 5 seconds to approximately 24 hours. Preferably, the residence time is adjusted to approximately 5 seconds to approximately 30 minutes. In addition to providing drug delivery, once When the composition adheres to the mucous membrane surface, it also provides protection to the treatment site and acts as a disintegrating bandage. It works by slowing down erosion in order to reduce disintegration and dissolution. It is possible.

[0209] Excipients that are sensitive to enzymes such as amylase and are highly water-soluble, such as water-soluble organic compounds. The susceptibility dynamics of this composition can also be adjusted by adding salts and inorganic salts. Suitable excipients include sodium and potassium hydrochlorides, carbonates, bicarbonates, and citrates. Salts, trifluoroacetates, benzoates, phosphates, hydrofluoric acid, sulfates, or tartaric acid May contain salts. These excipients may also be used in this composition for other purposes. The amount added depends on how much the erosion dynamics are altered, as well as the amount of other components in the composition. It can vary depending on its properties.

[0210] Ion exchange resins, for example, and anion exchange resins, or buffers, are used in shaping the film. It can be used to adjust the behavior of the agent and its release from the film. Suitable io The exchange resin may be a gel, resin, or functionalized with anionic or cationic groups. Polymers, such as polyamines, polysulfonic acids, or polycarboxylic acids, may be included. Examples of suitable ion exchange resins include Duolite A143, Amberlite IRC 50, Indion 204, and Puro lite C102D, Kyron-T-104, Tulsion-355, Doshion P 544, Amberlight IR 120, Dowex Includes 50, Indion 244, Purolite C100HMR, Kryon-T-154, Dowex M-43, or Dowex G-55. It is possible.

[0211] The emulsifier typically used in the aforementioned water-based emulsion is preferably an insulator. When obtained in Ich, the ingredients are linoleic acid, palmitic acid, myristoleic acid, lauric acid, stearic acid A mixture of phosphoric acid, cetoleic acid, or oleic acid, and sodium hydroxide or potassium hydroxide. Selected from or sorbitol or anhydrous sorbitol laurate Palmitic acid ester, stearic acid ester, or oleic acid ester, mono Polyoxyl containing oleate, monostearate, monopalmitate, and monolaurate Chilean derivatives, aliphatic alcohols, alkylphenols, allyl ethers, alkyl ali Sorbitan ether, sorbitan monostearate, sorbitan monooleate and / or sorbitan ether It is either selected from vitamin monopalmitate.

[0212] The amount of active pharmaceutical ingredient used is determined by the desired therapeutic strength and the composition of the layer. Preferably, the pharmaceutical component is present in an amount of about 0.001% to about 99% of the composition weight, more preferably about 0.003% to about It constitutes 75%, and most preferably about 0.005% to about 50%, which is greater than 0.005%, greater than 0.05%, and 0. Over 5%, over 1%, over 5%, over 10%, over 15%, over 20%, over 30%, approximately 50%, over 50%, less than 50%, 3 Less than 0%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, less than 0.05%, or less than 0.005%. The amounts of other components may vary depending on the drug or other components. Typically, these components do not exceed 50% of the total weight of the composition, preferably not exceeding 30%. , and most preferably configured not to exceed 15%.

[0213] The thickness of the film may vary depending on the thickness of each layer and the number of layers. As mentioned above, Both the thickness and quantity can be adjusted to change the erosion dynamics. Preferably If the composition has only two layers, the thickness is 0.005 mm to 2 mm, preferably 0.01 mm to 1 mm, more preferably The range is approximately 0.1 to 0.5 mm, which includes sizes greater than 0.1 mm, greater than 0.2 mm, approximately 0.5 mm, greater than 0.5 mm, and 0.5 mm. Includes less than m, less than 0.2 mm, or less than 0.1 mm. The thickness of each layer is the total thickness of the layered composition. The value may vary by 10-90%, preferably by 30-60%, which is greater than 10% and greater than 20%. Over 30%, over 40%, over 50%, over 70%, over 90%, approximately 90%, less than 90%, less than 70%, less than 50%, 40 This includes less than %, less than 30%, less than 20%, or less than 10%. Therefore, the preferred thickness of each layer is 0. The size may vary between 0.1mm and 0.9mm, or between 0.03mm and 0.5mm.

[0214] As those skilled in the art will understand, when systemic delivery, such as transmucosal or transdermal delivery, is desirable, The site is where the film delivers the desired level of pharmaceuticals into the blood, lymph, or other bodily fluids. / or may include any area that can be maintained. Typically, such treatment area The areas include the mucous membranes of the mouth, esophagus, ears, eyes, anus, nose, or vagina, as well as the skin. When used as a body part, it is usually applied to areas such as the upper arm or thigh, where movement does not interfere with the film's adhesion. A relatively large area of ​​skin is preferred.

[0215] This pharmaceutical composition can also be used as a wound dressing. It is material and compatible. To provide a flexible barrier that is permeable to oxygen and water and can be removed by washing. Furthermore, the film not only protects the wound, but also promotes healing, sterilization, and scarification. To promote carization, relieve pain, or improve the overall symptoms of the affected person To that end, medicine can also be delivered. Some of the examples provided below are for skin or wounds. It is well suited for application to [unspecified area]. As those skilled in the art will understand, this formulation is suitable for long-term use in dry [unspecified area]. Special hydrophilic / hygroscopic excipients will help maintain good adhesion on dry skin. It will be necessary to incorporate the agent. Another advantage of the present invention when used in this form. If you do not want the film to be noticeable on the skin, the use of pigments or coloring agents is unnecessary. On the other hand, if you want to make the film stand out, you can use dyes or coloring substances. ru.

[0216] This pharmaceutical composition can adhere to mucosal tissue, which is naturally moist tissue, while the skin It can also be used on other surfaces such as skin or wounds. This medicinal film is applied to the skin before application. Even when the skin is moistened with a water-based fluid such as water, saliva, wound drainage, or sweat, It can adhere to the skin. This film can be used, for example, during rinsing, showering, bathing, or washing. Therefore, it can adhere to the skin until it is eroded by contact with water. Furthermore, the film can be easily peeled off and removed without causing significant damage to the tissue. [Examples]

[0217] (Examples) (Study experiment on intramuscular (IM) administration of dipivefrin / prodrug in miniature pigs) This research experiment involved L-dipivefrin and epinephrine in male Yucatan miniature pigs. Intramuscular (IM) administration of prodrugs (AQEP-01(A), AQEP-02(B), AQEP-03(C), and AQEP-04(D)) This was done to compare the subsequent pharmacokinetic profiles of epinephrine in Yucatan miniature pigs. The body weight of each animal (n=4 males / group) was measured and recorded. On the morning of the research experiment, the vascular accessories of each animal were measured. I checked if the VAP (Variable Action Program) was functioning correctly. I checked if the minib had a working VAP. The patient was removed from the home cage and placed in a sling-type restraint device. The patient was then rested overnight before dose administration. The animals were kept fasting during the PK blood collection period.

[0218] L-dipivefrin or other epinephrine prodrugs (AQEP-01(A), AQEP-02(B), AQEP-03) (C) and AQEP-04(D)) solutions (2 mg / animal) were administered via the IM route. All preparations were administered on the day of administration. The solution was freshly prepared and kept on wet ice until administration. The dose was injected into the hind limbs. Previously, I aspirated the plunger of the syringe and observed whether blood flowed into the syringe. When no liquid was observed, it was determined that the needle was properly positioned, and the test sample was administered.

[0219] Pharmacokinetic blood samples were collected at 0 (before administration), and 2, 5, 10, 12, 15, 17, 20, 25, and 3 after administration. At 0, 40, 60, 90, and 120 minutes, 3 hours, 4 hours, 6 hours, and 8 hours, via the vascular access port. The procedure was performed as follows: At each identified time point, 6 mL of whole blood was taken, with K2EDTA as an anticoagulant and a stabilizer. The sample was then collected in a blood collection tube containing sodium metabisulfite. The concentration was 8.9 mM, pH 3 (60 μL / 6 mL of whole blood in 890 mM stock solution). Immediately into the blood collection tube, Si gmaFast (600 μL of SigmaFast 1× solution per 6 mL of whole blood) was added as an enzyme inhibitor. After adding the AST solution, the blood collection tube was inverted several times for mixing. All blood samples The sample was centrifuged at 3000 RPM for 15 minutes at approximately 4°C within 30 minutes of collection. Plasma was obtained using this procedure. The samples were stored at approximately -70 degrees Celsius. Epinephrine was analyzed using LC-MS / MS.

[0220] (Example 1) Regarding Figures 1A and 1B, 24 mg of dipivefrin, a prodrug for epinephrine, is dissolved. Tested with a desaturated film (DSF), the time-course achievement of epinephrine plasma concentration (pg / ml) in humans. In relation to this, it was compared to EpiPen. Surprisingly, this research experiment showed that this prodrug... The same concentration as epinephrine was achieved in less than 0.6 hours, for example, 0.4 to 0.6 hours. This demonstrated that.

[0221] (Example 2) Regarding Figures 2A and 2B, these figures show dipivefrin-soluble film at doses of 24 mg to 30 mg. The results of comparing the prodrug dosage to 36 mg with that of EpiPen were then calculated. This shows that, as shown in the figure, increasing the dosage shifts the curve to the left, resulting in an increase in dosage. This achieves similar epinephrine plasma concentrations in a shorter time compared to lower doses.

[0222] (Example 3 - In vitro human whole blood hydrolysis assay) In vitro using human whole blood to develop an epinephrine prodrug with faster hydrolysis Epinephrine levels in plasma were measured for identification. Fresh, healthy human whole blood was collected using a blood collection tube. The sample was collected and pre-incubated at 37°C for 30 minutes. After incubation, under the presence of a stabilizer... Then, whole blood is used to obtain a final concentration of 1 μM dipivefrin or prodrug (AQEP-03, AQEP-04, AQEP-05, AQEP-06, AQEP-07, AQEP-08, AQEP-09, AQEP-10, AQEP-11, AQEP-12, and AQEP-13), Each time point was augmented separately. After addition, the sample was thoroughly mixed and incubated at 37°C for up to 6 hours. Incubation was performed at the appropriate time. After incubation, whole blood samples were taken at each time point. The plasma was quenched and separated by centrifugation. The plasma samples were analyzed for epinephrine concentration. The analysis was performed using established LC-MS / MS methods.

[0223] Regarding Figures 3A and 3B, the results show that the newly synthesized prodrug AQEP-10 produced significantly higher blood pressure. Serous epinephrine levels include those below 30 minutes, below 20 minutes, below 15 minutes, below 10 minutes, and below 5 minutes. This shows that it was achieved in a much shorter time. In this research experiment, the enzyme hydrolysis was stopped. Because there is a delay of about 3-5 minutes for mixing the components before adding the stabilizer, t=0 is not true zero. Please note that this is not the case.

[0224] Generally, prodrugs having an ester group include AQEP-05, AQEP-08, AQEP-09 and AQEP-10 and AQEP-11 showed faster hydrolysis in human whole blood compared to L-dipivefrin. The data shows that one or more of these prodrugs, as a combination of prodrugs, L-dipi This indicates that it can be used in place of or in addition to L-dipivefrin. Amazing. Increasing the number of carbon atoms did not affect the hydrolysis rate. Unexpectedly, carbon The prodrug AQEP-12, which has an ester group, is similar to AQEP-10, which has an ester group, in that it contains L-dipivef It showed faster hydrolysis in human whole blood compared to phosphorus. Unexpectedly, the ester group The prodrug AQEP-04 exhibits faster hydrolysis in human whole blood compared to L-dipivefrin. Decomposition was observed, but the same level of permeation was not achieved. AQEP, a prodrug containing a carbamate group. -06 or AQEP-07 did not show hydrolysis in the blood. This indicates that the carbamate compound did not undergo hydrolysis in the blood. This is consistent with literature indicating resistance to serous esterase. Finally, the prodrug AQEP-03 (di The group containing a methylamino group showed minimal hydrolysis, which gradually increased at later time points.

[0225] (Example 4) With respect to Figure 4, prodrugs AQEP-04 and AQEP-05 were tested in the same manner as in Example 31. Epinephrine levels in plasma were measured in vitro using human whole blood. Whole blood was collected from two individuals. The samples were collected from blood donors. The compound was incubated with a stabilizer at a concentration of 1 μM. After stopping the enzymatic reaction at a certain point, the plasma was separated. The sample was extracted and analyzed by LC-MS. The prodrugs AQEP-04 and AQEP-05 show faster conversion and more High levels of epinephrine were observed. This is because AQEP-04 or AQEP-05 is mixed with L-dipivefrin. When combined ("combo" drugs), they achieve a more rapid and sustained exposure to epinephrine in plasma. This demonstrates that it can achieve improved results compared to EpiPen.

[0226] (Example 5) With respect to Figure 5, the prodrugs AQEP-03, AQEP-06, and AQEP-07 are similarly prepared in the manner of Example 3. The experiment was conducted. Epinephrine levels in plasma were measured using human whole blood in vitro. Whole blood was collected from two donors. The compound was incubated with a stabilizer at a concentration of 1 μM. The enzyme reaction was stopped at different points in time, and the plasma was separated. The sample was extracted and analyzed by LC-MS. The analysis revealed that the prodrugs AQEP-03, AQEP-06, and AQEP-07 were compared to L-dipivefrin. It did not exhibit more rapid hydrolysis in human blood.

[0227] (Example 6 - Research experiment on intramuscular administration of prodrugs to miniature pigs) The applicant has developed a method for administering epinephrine that exhibits higher permeability and slower hydrolysis after intramuscular (IM) administration. The researchers attempted to identify the furinprodrug. This research experiment involved male Yucatan miniature pigs. In this context, L-dipivefrin and epinephrine prodrugs (AQEP-01(A), AQEP-02(B), AQEP- The pharmacokinetic profiles of epinephrine after intramuscular (IM) administration of 03(C) and AQEP-04(D)) were compared. This was done to measure the weight of Yucatan miniature pigs and the blood vessels of each animal on the morning of the research experiment. I checked whether the access port (VAP) was functioning correctly. The miniature pig was removed from its home cage and placed in a sling-type restraint device. The animals were kept fasted overnight and during the PK blood collection period.

[0228] L-dipivefrin or other epinephrine prodrugs (AQEP-01(A), AQEP-02(B), AQEP-03) (C) and AQEP-04(D)) solutions (2 mg / animal) were administered via the IM route. The dose was injected into the hind limbs. Injection was performed. Pharmacokinetic blood samples were collected at 0 (before administration), and 2, 5, 10, 12, 15, 17, and 20 after administration. At 25, 30, 40, 60, 90 and 120 minutes, 3 hours, 4 hours, 6 hours and 8 hours, vascular access point The procedure was performed via a transceiver. At each identified time point, 6 mL of whole blood was taken, along with an anticoagulant and stabilizer. The sample was collected in a blood collection tube. A protease inhibitor cocktail was added, and the blood collection tube was mixed several times. The samples were inverted. All blood samples were centrifuged, and the resulting plasma was analyzed for epinephrine. Analysis was performed using LC-MS / MS.

[0229] [Table 2]

[0230] The following transformations were observed. [Table 3]

[0231] Regarding Figures 6A and 6B, the figures show the normalization of L-dipivefrin to an epinephrine equivalent dose. It shows the average epinephrine plasma concentration. Prodrug AQEP-04 is a prodrug Compared to AQEP-01, AQEP-02, and AQEP-03, AQEP-04 had higher Cmax and AUC (AQEP-04 > AQEP-02 > AQEP-03 > AQEP-01). L-dipivefrin has a Cmax (1.94 ng / ml) and is superior to other epinephrine prodrugs. It showed an AUC of 256.8 ng / ml × min. Faster hydrolysis (Tmax = 5 min) up to 4 hours was sufficient. It was detected at plasma levels (0.5 ng / ml). AQEP-04 showed faster hydrolysis (Tmax=5 minutes). However, Cmax and AUC were lower compared to L-dipivefrin.

[0232] (Example 7-IV: Hydrolysis test after exposure) Regarding Figures 7A and 7B, the hydrolysis assay was performed using the prodrug L-dipivefrin and AQEP-03. The study used AQEP-05 as the test sample. Hydrolysis was analyzed after intravenous (IV) administration. All The groups were divided into the following time intervals: 0 (before administration), and 2, 5, 10, 12, 15, 17, 20, 25, 30, 40, 60, and 90 after administration. The tests were conducted for 120 minutes, as well as 3 hours, 4 hours, 6 hours, and 8 hours.

[0233] [Table 4]

[0234] The following pharmacokinetic (PK) parameters were observed. [Table 5]

[0235] Compared to L-dipivefrin, the rapid conversion of the prodrug AQEP-05 to epinephrine is IV Observed after administration. Approximately twofold increases in AUC and Cmax were observed. A similar Tmax (2 minutes) was observed. It was done.

[0236] (Example 8: Intramuscular (IM) and subcutaneous (SC) administration of L-dipivefrin) This research experiment involved administering L-dipivefrin intramuscularly (IM) and in male Yucatan miniature pigs. Administered subcutaneously (SC), the pharmacokinetic profile of epinephrine (EpiPen, 0.3 mg) This was done for comparison with the manufacturer, Mylan. In the research experiment, epinephrine exposure and dipive were used. The conversion of furin to epinephrine and its pharmacokinetic (PK) parameters were measured.

[0237] The weight of Yucatan miniature pigs was measured, and on the morning of the research experiment, the vascular access port (V) of each animal was measured. I checked if the AP was working properly. I brought a mini pig with a working VAP home. The animal was removed from the cage and placed in a sling-type restraint device. This was done overnight before dose administration and during PK blood collection. They kept the animals fasted the entire time.

[0238] L-dipivefrin solution was administered (0.6, 1, and 2 mg / animal) via the IM or SC route, but epinephrine The procedure was performed via the IM route. In the IM route, L-dipivefrin solution or an EpiPen was injected into the hind limb. In the case of the SC route, L-dipivefrin solution was administered to the animal's neck, just behind the right ear.

[0239] Pharmacokinetic blood samples were collected at 0 (before administration), and 2, 5, 10, 12, 15, 17, 20, 25, and 3 after administration. At 0, 40, 60, 90, and 120 minutes, 3 hours, 4 hours, 6 hours, and 8 hours, via the vascular access port. The procedure was performed as follows: At each identified time point, 6 mL of whole blood was collected in a blood collection tube containing an anticoagulant and stabilizer. The sample was collected. A protease inhibitor cocktail was added, and the blood collection tube was inverted several times for mixing. All blood samples were centrifuged, and the resulting plasma was treated with dipivefrin and epinephrine. T...

Claims

1. The process involves administering a composition containing a prodrug and a permeation enhancer from a matrix. A method for treating a medical condition in humans; The permeation enhancer facilitates the permeation of the prodrug through mucosal tissue, Achieving effective plasma concentrations of the pharmaceutically active form of the prodrug within the human subject in less than an hour, Treatment method.

2. The aforementioned matrix is ​​a ratio of 1000:1 to 1:1000 for the weight of the permeation enhancer relative to the prodrug. The method according to claim 1, having a ratio.

3. Claim 1: The weight ratio of the permeation enhancer to the prodrug is 100:1 to 1:

100. Methods used.

4. The weight ratio of the permeation enhancer to the prodrug is 50:1 to 1:50, according to claim 1. Method of description.

5. The weight ratio of the permeation enhancer to the prodrug is 50:1 to 1:1, as described in claim 1. Method of loading.

6. The weight ratio of the permeation enhancer to the prodrug is 50:1 to 10:1, according to claim 1. Method of description.

7. The weight ratio of the permeation enhancer to the prodrug is 10:1 to 1:10, according to claim 1. Method of description.

8. The method according to claim 1, further comprising administering a pharmaceutically active ingredient with the prodrug.

9. A method for treating a medical condition in humans; Administering a composition containing a prodrug from a matrix; The prodrug is delivered through mucosal tissue, and the prodrug in the human subject is absorbed in less than one hour. The therapeutic method comprising achieving an effective plasma concentration of the pharmaceutically active form of the drug.

10. The method according to claim 1, wherein the prodrug comprises 0.01 to 90% by weight of the matrix.

11. The method according to claim 1, wherein the prodrug comprises 0.1 to 50% by weight of the matrix.

12. The method according to claim 1, wherein the permeation enhancer comprises 1 to 50% by weight of the matrix.

13. The method according to claim 1, wherein the permeation enhancer comprises 5 to 25% by weight of the matrix.

14. The method according to claim 1, wherein the pharmaceutically active form of the prodrug has a Tmax of less than 240 minutes. 。

15. The method according to claim 1, wherein the prodrug has a Tmax of less than 120 minutes.

16. The method according to claim 1, wherein the prodrug has a Tmax of less than 60 minutes.

17. The method according to claim 1, wherein the prodrug has a Cmax of 0.1 pg / ml to 50,000 pg / ml.

18. The method according to claim 1, wherein the prodrug has a particle size not exceeding 100 microns.

19. The prodrug and the permeation enhancer penetrate the mucosal tissue simultaneously, as described in claim 1. Method of loading.

20. The prodrug is an ester of the pharmaceutically active form of the prodrug, as described in claim 1. Method of loading.

21. The prodrug comprises an alkyl ester of the pharmaceutically active form of the prodrug, claim The method described in item 1.

22. The prodrug comprises a butyl ester of the pharmaceutically active form of the prodrug, claim The method described in 1.

23. The prodrug comprises an isopropyl ester of the pharmaceutically active form of the prodrug. The method according to claim 1.

24. The prodrug comprises an ethyl ester of the pharmaceutically active form of the prodrug, claim The method described in 1.

25. The method according to claim 1, wherein the prodrug comprises an ester of epinephrine.

26. At least half of the administered prodrug is converted in less than 240 minutes, as described in claim 1. Method of loading.

27. At least half of the administered prodrug is converted in less than 120 minutes, as described in claim 1. Method of loading.

28. At least half of the administered prodrug is converted in less than 60 minutes, as described in claim 1. Method of loading.

29. The aforementioned prodrug is converted to an active compound with an active compound concentration of 20 pg / ml to approximately 40 ng / ml. The method according to claim 1, which occurs in less than 0 minutes.

30. The matrix may be in the form of a chewable or gelatin-based dosage form, an inhalation form, a capsule, Freeze-dried solid dose units, mist, powder, spray, liquid, gum, gel, cream The method according to claim 1, which is applied as a film or a tablet.

31. The matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 90 minutes, as described in claim 1. method.

32. The matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 60 minutes, as described in claim 1. method.

33. The matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 15 minutes, as described in claim 1. method.

34. The administration of the prodrug stimulates one or more adrenergic receptors, as per claim 1. Law.

35. The administration of the prodrug does not activate the α1 adrenergic receptor, as described in claim 1. method.

36. The method according to claim 1, wherein the administration of the prodrug minimizes the side effect of epigastric pain.

37. The method according to claim 1, wherein the aforementioned medical condition falls within the range of anaphylaxis.

38. The method according to claim 1, wherein the aforementioned medical condition is an allergic reaction.

39. The method according to claim 1, wherein the aforementioned medical condition is a cardiac abnormality.

40. The method according to claim 1, wherein the aforementioned medical condition is an abnormality of the lungs.

41. The method according to claim 1, wherein the permeation enhancer comprises a phenylpropanoid.

42. The phenylpropanoid is eugenol or eugenol acetate, as described in claim 1. Method of loading.

43. The phenylpropanoid is cinnamic acid, cinnamic acid ester, cinnamaldehyde or phenylpropanoid. The method according to claim 1, wherein the material is derosilicic acid.

44. The method according to claim 1, wherein the phenylpropanoid is cavicol.

45. The method according to claim 1, wherein the phenylpropanoid is safrole.

46. The method according to claim 1, wherein the permeation enhancer comprises an essential oil extract of the clove plant.

47. The method according to claim 1, wherein the permeation enhancer is a compound.

48. The method according to claim 1, wherein the permeation enhancer is a biosynthetic product.

49. The method according to claim 1, wherein the permeation enhancer is a natural product.

50. The method according to claim 1, wherein the permeation enhancer contains 150-95% eugenol.

51. Claim 1, the permeation enhancer comprises a terpenoid, terpene, or sesquiterpene. Methods used.

52. The method according to claim 1, wherein the permeation enhancer comprises benzyl alcohol.

53. The method according to claim 1, wherein the permeation enhancer comprises farnesol.

54. The method according to claim 1, wherein the permeation enhancer comprises a self-emulsifying excipient.

55. The method according to claim 1, wherein the matrix comprises a mucosal-adhering water-soluble polymer.

56. The method according to claim 1, wherein the permeation enhancer contains linoleic acid.

57. The composition containing a prodrug comprises one or more prodrugs, each of which prodrugs The method according to claim 1, wherein the derivative is a pharmacoactive ingredient.

58. The method according to claim 1, wherein one of the prodrugs is dipifebrin.

59. The first prodrug is the primary ester of epinephrine, and the second prodrug is G is the second ester of epinephrine, and the first ester of epinephrine and the epinephrine The method according to claim 54, wherein the secondary ester of phosphorus is different.

60. The aforementioned prodrug is a compound of formula (I); 【Chemistry 1】 (In the formula, each R 1a , R 1b , R 2 and R 3 These are independently H, C1-C16 acyl, alkyl aminocarbon Alkyloxycarbonyl, phenacyl, sulfate or phosphate may also be, or, R 1 , R 2 and R 3 Unless one of is H, R 1a and R 1b are both, R 1a and R 2 Both, R 1a and R 3 Both, R 1b and R 2 Both, R 1b and R 3 Both, or R 2 and R 3 Both have a cyclic structure containing a dicarbonyl, disulfate, or diphosphate component. The method according to claim 1, wherein the salt is a pharmaceutically acceptable salt thereof (forming a ) or a pharmaceutically acceptable salt thereof.

61. R 2 and R 3 H is H, and each R 1a and R 1b These are independently ethanol, n-propanoyl, and isopyl. Ropanoyl, n-butanoyl, isobutanoyl, sec-butanoyl, tert-butanoyl, n-pe Isopentanoyl, sec-pentanoyl, tert-pentanoyl, or neopentanoyl The method according to claim 60, wherein Tanoyl.

62. The process involves administering a prodrug from a matrix, wherein the prodrug is converted to 20 p A treatment method for a medical condition that delivers an active compound concentration of g / ml to approximately 40 ng / ml in less than 240 minutes.

63. The aforementioned prodrug is converted to an active compound concentration of 200 pg / ml to approximately 1200 pg / ml in less than 120 minutes. The method according to claim 62, provided as follows.

64. The aforementioned prodrug is converted to an active compound concentration of 200 pg / ml to approximately 1200 pg / ml in less than 100 minutes. The method according to claim 62, provided as follows.

65. The aforementioned prodrug is converted to an active compound concentration of 200 pg / ml to approximately 600 pg / ml in less than 60 minutes. The method according to claim 62, provided.

66. The aforementioned prodrug is converted to an active compound concentration of 200 pg / ml to approximately 600 pg / ml in less than 45 minutes. The method according to claim 62, provided.

67. The aforementioned prodrug is converted to an active compound concentration of 200 pg / ml to approximately 600 ng / ml in less than 30 minutes. The method according to claim 62, provided.

68. The prodrug is converted to produce a sustained concentration of 200 pg / ml to about 600 pg / ml, claim. The method described in 62.

69. The method according to claim 62, further comprising administering the pharmaceutically active ingredient with the prodrug.

70. The method according to claim 62, wherein less than 100% of the prodrug is converted.

71. The method according to claim 62, wherein 100% of the prodrug is converted.

72. The procedure involves administering a prodrug, which is converted to a dose of 20 pg / ml to approximately 40 ng / ml. A treatment method for a medical condition in which a concentration of the active compound in ml occurs within 240 minutes.

73. The method according to claim 72, wherein less than 100% of the prodrug is converted.

74. The method according to claim 72, wherein 100% of the prodrug is converted.

75. The aforementioned prodrug delivers a therapeutic level of epinephrine exceeding 100 pg / ml for at least 15 minutes. The method according to claim 59, which occurs during the period.

76. The aforementioned prodrug delivers a therapeutic level of epinephrine exceeding 100 pg / ml for at least 30 minutes. The method according to claim 59, which occurs during the period.

77. The aforementioned prodrug delivers a therapeutic level of epinephrine exceeding 100 pg / ml for at least one hour. The method according to claim 59, which occurs during the period.

78. The aforementioned prodrug delivers a therapeutic level of epinephrine exceeding 100 pg / ml for at least 4 hours. The method according to claim 59, which occurs during the period.

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