Multimodal composition and therapeutic method

Abstract

This provides a method for administering diazepam in a multimodal delivery profile. [Solution] A method is provided for administering diazepam in a multimodal delivery profile, which includes delivering diazepam from a matrix and facilitating the permeation of at least some of the diazepam through mucosal tissue.

Description

[Technical Field]

[0001] (Claiming priority) This application claims priority to U.S. Provisional Application No. 62 / 935,460, filed on November 14, 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) A seizure is a sudden, uncontrolled electrical disturbance in the brain. It affects behavior and actions. , or may cause changes in emotions and levels of consciousness. Two or more seizures or recurrent seizures. When seizure tendencies occur, the person is often diagnosed with epilepsy. Epilepsy is a condition in the brain. Sudden, frequent episodes of sensory disturbances, loss of consciousness, or seizures associated with abnormal electrical activity. It is a neurological disorder characterized by [symptoms]. Benzodiazepines often cause seizures, It is used to treat conditions such as anxiety disorders, insomnia, alcohol withdrawal disorders, and amnesia. These can be used as muscle relaxants. They are sometimes administered before anesthesia, such as before surgery. Some examples of benzodiazepines include alprazolam (Xanax) and lorazepam (Athi). (Van), chlordiazepoxide (Librium), and diazepam (Valium) Benzodiazepines can be used to treat CNS (central nervous system) disorders. [Overview of the project]

[0004] (overview) Broadly speaking, the method of administering diazepam in a multimodal delivery profile is matrix The delivery of diazepam from the sac, and the passage of at least some of the diazepam through the mucosal tissue. This may include facilitating permeation. In one embodiment, multimodal The profile may also be a bimodal delivery profile.

[0005] In one embodiment, the method further delivers a permeable enhancer from the matrix. It can include this. In one embodiment, at least about 5-50% of diazepam is administered via the oral transmucosal route. In one embodiment, at least about 5% of diazepam is administered via the gastrointestinal route. ru.

[0006] In one embodiment, diazepam is administered as a prophylactic treatment. In one embodiment, diazepam can be administered as an emergency treatment drug. In one embodiment, diazepam can be administered to treat CNS disorders.

[0007] In one embodiment, diazepam can be administered to treat seizures. In one embodiment, diazepam can be administered to treat generalized seizures. In one embodiment, diazepam can be administered to treat focal seizures. Therefore, diazepam can be administered to treat focused, unconscious seizures.

[0008] In one embodiment, diazepam can be administered to treat seizures of focal loss of consciousness. In one embodiment, diazepam can be administered to treat bilateral tonic seizures. In one embodiment, diazepam can be administered to treat absence seizures. In one embodiment, diazepam can be administered to treat atypical absence seizures.

[0009] In one embodiment, diazepam can be administered to treat tonic-clonic seizures. In one embodiment, diazepam can be administered to treat cataplexy. In one embodiment, diazepam can be administered to treat clonic seizures. In one embodiment, diazepam can be administered to treat tonic seizures.

[0010] In one embodiment, diazepam can be administered to treat myoclonic seizures. In one embodiment, diazepam can be administered to treat laughter and crying fits. In one embodiment, diazepam can be administered to treat febrile seizures.

[0011] In one embodiment, diazepam can be administered to treat non-epileptic seizures. In one embodiment, diazepam can be administered to treat refractory seizures. In one embodiment, diazepam can be administered while the patient is eating food.

[0012] In one embodiment, the method of administering diazepam is one in which the subject is in a state of food intake and is safe and effective. To achieve the desired quantity, the dosage is increased to counteract the food effect, thereby compensating for the food effect. This includes adjusting the dose of diazepam to correct the condition. In one embodiment, diazepam is administered to a fasted patient.

[0013] In one embodiment, approximately 2.5 to 30 mg of diazepam is delivered. In one embodiment, approximately 2.5 mg of diazepam is delivered as a single dose. In one embodiment, approximately 5 mg of diazepam is delivered as a single dose. In one embodiment, approximately 7.5 mg of diazepam is delivered as a single dose.

[0014] In one embodiment, approximately 10 mg of diazepam is delivered as a single dose. In one embodiment, approximately 12.5 mg of diazepam is delivered as a single dose. In one embodiment, approximately 15 mg of diazepam is delivered as a single dose. In one embodiment, approximately 17.5 mg of diazepam is delivered as a single dose.

[0015] In one embodiment, approximately 20 mg of diazepam is delivered as a single dose. In one embodiment, approximately 25 mg of diazepam is delivered as a single dose. In one embodiment, approximately 30 mg of diazepam is delivered as a single dose. In one embodiment, the dose of diazepam is administered according to a body weight-based regimen.

[0016] In one embodiment, the matrix is ​​a mucosal-adhering matrix. In one embodiment, diazepam is provided in the form of a chewable tablet, gelatin, or freeze-dried tablet. Or inhalation-based dosage forms, sprays, gums, gels, creams, films, capsules. , or administered as tablets.

[0017] In one embodiment, the matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 30 minutes. . In one embodiment, the matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 15 minutes. . In one embodiment, the matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 10 minutes. . In one embodiment, the matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 5 minutes. .

[0018] In one embodiment, the permeation enhancer includes a terpenoid. In one embodiment, the permeation enhancer contains an aliphatic alcohol. In one embodiment, the permeation enhancer contains an aromatic alcohol. In one embodiment, the permeation enhancer contains benzyl alcohol.

[0019] In one embodiment, the permeation enhancer includes a phenylpropanoid. In one embodiment, the mucosal adhesive matrix includes a water-soluble polymer. In one embodiment, the permeation enhancer contains linoleic acid.

[0020] In general, the treatment method for the condition involves administering 2.5-30 mg of diazepam from an oral matrix once an hour. Administer diazepam in a multimodal profile, including delivery within a period of less than two hours. This includes the following.

[0021] In one embodiment, the treatment method for the aforementioned condition involves administering 2.5 to 30 mg of diazepam via bimodalp This includes administering it via rofil. In one embodiment, the treatment method for the aforementioned medical condition involves administering 2.5 to 30 mg of diazepam, at least for a period of time. This includes delivery via mucosal and gastrointestinal routes.

[0022] In one embodiment, the method for treating the disease involves delivering 0.1 to 0.4 mg / kg of diazepam. This includes. In one embodiment, the method for treating the disease involves delivering 0.1 to 0.3 mg / kg of diazepam. This includes.

[0023] In general, the treatment method for the condition involves delivering diazepam in a multimodal profile. This includes delivering diazepam and a permeation enhancer from the matrix, thereby allowing the diazepam to Delivered with an effective linear AUC and up to approximately 10 ml of C max This includes achieving the treatment of the disease. Diazepam has a multimodal profile, which is a bimodal profile. This may include delivering diazepam and a permeation enhancer from the matrix. Cut.

[0024] Treatment for this condition involves delivering the drug at least via the transmucosal route and the gastrointestinal route. This includes administering diazepam. Diazepam has an effective linear AUC and a maximum of approximately 1 C up to 0 ml max It can be delivered to achieve this.

[0025] Other aspects, embodiments, and features will be apparent from the following description, drawings, and claims. It is likely. [Brief explanation of the drawing]

[0026] (Brief explanation of the drawing) [Figure 1] Figure 1A shows the dose-proportional pharmacokinetics of diazepam buccal film (DBF) in healthy adult males, where plasma diazepam concentrations were measured in a single-dose, randomized, open-label crossover study of 5 mg, 10 mg, and 15 mg diazepam buccal film (DBF) over three periods in 30 fasted healthy adult male volunteers. Figure 1B shows the same study as Figure 1A, where plasma diazepam concentrations were measured over time. Figure 1C shows a comparison of diazepam buccal film versus diazepam rectal gel, expressed as Cmax relative to nominal dose.

[0027] [Figure 2] Figure 2 shows dose-proportional studies conducted over the 5 mg, 10 mg, and 15 mg ranges of diazepam buccal film. [Figure 3] Figure 3 shows a key study comparing one DBF dose (15 mg) with three rectal gel doses (5 mg, 12.5 mg, and 20 mg). [Figure 4]Figure 4A shows a study in which AUC was measured relative to the dose of Diastat®. Figure 4B shows a study in which AUC (dose-normalized) was measured relative to the dose of Diastat®.

[0028] [Figure 5] Figure 5 shows the food effect tests conducted under food intake and fasting conditions. [Figure 6] Figure 6 shows the mean plasma diazepam concentrations in a food efficacy study comparing subjects in a fasted, upright, fasted, high-fat diet, and moderate-fat diet postures.

[0029] [Figure 7] Figure 7 shows the geometric mean diazepam plasma concentrations after administering body weight-dependent doses of DBF and DRG to epileptic adults (N=28) following a moderate-fat diet. Geometric mean plasma concentrations were obtained from 28 subjects with effective profiles for both DBF and DRG. Error bars represent geometric standard errors. The inset shows the geometric mean Cmax of DBF and DRG along with their geometric standard deviations. [Figure 8] Figure 8 shows the Cmax (geometric mean) for the weight-grouped groups (N=28). [Modes for carrying out the invention]

[0030] (Detailed explanation) Cluster seizures occur in many epilepsy patients despite treatment with antiepileptic drugs. It occurs. Available treatment options remain limited. Diazepam and midazolam. Benzodiazepines, including [specific benzodiazepine], are the mainstay of emergency treatment for acute recurrent seizures. Parenteral ( If intravenous or intramuscular administration is not feasible, a non-extraintestinal dosage form is used. Suitable non-extraintestinal dosage forms include ease of use, accuracy of administration, potential for inflammation (irritation), and patient compatibility. Benzodiazepines have limitations in terms of caregiver acceptance, rate of action, and portability. It may cause adverse effects and may be taken in excessive amounts, intentionally or accidentally. Therefore And improved medication administration and control, medication compliance, rate of action, accountability and ease of use The medication regimens that enable this offer solutions to important but still unresolved challenges. It is likely.

[0031] Conventionally, diazepam gel formulations intended for rectal administration (e.g., Diastat (registered trademark)) Rectal gel has been administered to certain epilepsy patients. This drug has been shown to reduce the duration of increased seizure behavior. This medication is administered to patients who need to use diazepam as needed to control the symptoms. Common side effects include drowsiness, sleepiness, or hypnosis. Other side effects include dizziness and headache. Pain, pain, abdominal pain, irritability, vasodilation, diarrhea, ataxia or impaired coordination, euphoria, asthma This includes rhinitis (allergic or cold-like nasal inflammation) and rash. Diazepam and AR Other products currently available for the treatment of S and acute seizures have significant limitations. Intestinal administration is difficult to implement and may cause confusion for patients and caregivers, as well as social and legal issues. Its use may be limited by certain restrictions. Furthermore, intranasal administration is susceptible to sloppy medication administration and Due to nasal inflammation, it is often unacceptable to patients and negatively impacts medication compliance. It may have an effect. Benzodiazepines such as lorazepam, diazepam, and clonazepam. Most oral tablets need to be swallowed with water, and this requires the patient to be aware of and careful. This is only feasible if... Some sublingual or buccal dosage forms also have properties that suit the pharmaceutical composition. Depending on the circumstances, patient cooperation may be required. Oral dispersible tablet form of lorazepam (Temesta Expansion) idet (registered trademark) is used sublingually to treat acute seizures in children, but lorazepam and Other available oral dosage forms may not act as rapidly as rectal diazepam.

[0032] If an epileptic patient experiences a worrying seizure exacerbation outside of a medical facility, they should inform their caregiver or bystander. They will benefit from rapid treatment, and even from self-administered treatment. Such an exacerbation of a seizure is a standalone breakthrough seizure (more severe than the patient's usual seizures or The continuum ranges from prolonged seizures to acute recurrent seizures (ARS), and the most severe form is a continuum. It is classified as a status epilepticus. ARS is also commonly called a cluster seizure or a series of seizures. A series of seizures that are usually short (or shorter than usual) in intervals between seizures, and are grouped together consecutively. This represents... More generally, ARS can be considered a change in the frequency of seizures that require treatment. Patients experiencing this have drug-refractory epilepsy and have experienced spontaneous seizures on a relapse basis. To test. Once ARS is identified, symptoms include post-seizure psychotic disorders, injuries from falls or burns, and frequent emergency situations. Social and pharmacoeconomic negative consequences of missing departmental visits, hospitalizations, or school / work days. Concerns about the risks associated with seizures, including Hibiki, and importantly, constant neurological Concerns are growing about status epilepticus, which can lead to injury or death. Parenteral (static) Intravascular or intramuscular administration is particularly beneficial for emergency treatment of status epilepticus, especially in the treatment of seizures. It is difficult. When parenteral therapy cannot be administered, or when parenteral therapy is not practical for the patient due to the frequency of use. If such episodes occur, a non-parental formulation is used as an alternative. The goal of this therapy is to prevent seizure recurrence, interrupt the progression of a series of seizures, or interrupt an ongoing seizure. It would be to put an end to it.

[0033] Drug delivery through the oral mucosa is an alternative to systemic drug delivery, including injection, nasal, rectal, and It offers several advantages compared to both enteral administration methods. The oral mucosa is highly vascularized. Therefore, drugs absorbed through the oral mucosa bypass first-pass metabolism in the gastrointestinal tract and liver. It circulates and enters the systemic circulation directly. For some medications, this is more comfortable than the intravenous route. It acts rapidly via a convenient delivery route. Absorption via the oral mucosa is 100%. Absorption can be obtained. In some embodiments, absorption via the oral mucosa may be less than 100%. For example, In this embodiment, absorption via the oral mucosa may be less than approximately 90%. It may be less than approximately 80%. It could be less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%. In one embodiment, absorption via the oral mucosa is approximately 10%, 20%, 30%, and 40%. It could exceed 50%, 60%, 70%, 80%, or even 90%.

[0034] Diazepam buccal film (DBF) is compact, easy to carry, and easy to administer. A novel method for incorporating diazepam into a soluble polymer matrix using a method designed to enable this process. It is a formulation that has a pharmacokinetic profile similar to diazepam administered rectally. However, this is done via multimodal delivery. Multimodal delivery means that the active ingredient is delivered via multiple pathways. For example, this refers to delivery via the transmucosal route and the gastrointestinal route. DBF refers to delivery via the oral mucosa on the inside of the cheek. It is applied to a membrane, a film adheres to it, and is hydrated, releasing diazepam, which then enters the oral cavity. It is absorbed through the buccal mucosa, and some can also be absorbed enterally after being swallowed. In several studies, when DBF was applied during the interictal or peripheral seizure period (within 5 minutes of a seizure), it was effective in adults. The study showed no significant difference in bioavailability among epilepsy patients. DBF was measured immediately after a seizure. It can be successfully deployed even without patient cooperation and is usually used without problems. In fact, it is used in adult epilepsy. In a cross-comparison study with diazepam rectal gel (Diastat®) in patients, DBF was It functioned similarly to intestinal gel, but with less variation in peak exposure. DBF is used as an extra-hospital treatment for seizure exacerbations. It is a convenient alternative treatment. DBF is also useful in treating acute emergency seizures. Emergency seizures For children, adolescents, and adults with epilepsy who are experiencing this condition, especially out-of-hospital patients, it is safe and It is known to be highly tolerable. DBF is ultimately well-placed in 99.6% of use cases. Furthermore, it was easy to administer without difficulty, even when administered by patients or caregivers.

[0035] Diazepam can be administered via a monomodal delivery profile. Other embodiments Therefore, diazepam can also be administered using a multimodal delivery profile. Azepam can be administered using a bimodal delivery profile.

[0036] Absorption of diazepam through the mucous membrane is determined by (i) the release rate from the film and (ii) the surface of the film. (iii) accumulation, film residence time, and (iv) molecules permeating across the oral mucosa to reach the vascular system. It is determined by several factors, including the ability to reach the target. Incorporate the penetration enhancer into the formulation. Despite the significant improvement in transmission rate resulting from this, only a portion of diazepam is delivered transmucosally. The remaining diazepam is either washed away or swallowed by the flow of saliva and digested. It is excreted into the tube and absorbed into the body. By combining these two absorption routes, DBF can provide diazepam blood levels faster than can be achieved by oral administration alone, but due to its high oral bioavailability, full doses are provided for all applications. However, the ingested portion of diazepam is also exposed to variations in absorption rate due to the well-known food effect. When delivered orally, diazepam is usually rapidly and completely absorbed by the gastrointestinal tract. For example, the onset of absorption can be as rapid as within about 15 minutes, and the T can also be observed within the range of about 1 hour to 1.5 hours . However, after ingestion of a medium-fat meal, the onset of absorption can be delayed up to about 45 minutes

[0037] , and the T is extended to about 2 to 3 hours. Along with the delay in absorption, as absorption occurs over a longer period of time max , a decrease in C occurs. The C is reported to decrease by about 28% after ingestion of a medium-fat meal max . As absorption is delayed and occurs over a longer period of time , a decrease in C max occurs. The C max is reported to decrease by about 28% after ingestion of a medium-fat meal .

[0038] The recommended DBF doses for each weight class specified on the DRG label were selected to provide a sufficiently high dose to ensure that the predicted median C of diazepam that occurs after ingestion of a medium-fat meal is similar to the median C max after administration of the dose described on the label of the Diastat rectal gel, and (2) to provide a dose such that the predicted median C of diazepam obtained in the fasting state does not exceed the median C max ]>that was observed in the first-phase trial of DBF and for which safety was demonstrated. The predicted median C max of diazepam when the proposed regimen is administered in the fasting state is such that it does not exceed the median C max that was observed in the first-phase trial of DBF and for which safety was demonstrated. When the proposed regimen is administered in the fasting state, the predicted median C max of diazepam is In a Phase 1 trial conducted by Company B, 104 healthy volunteers were administered DBF 15 mg in a fasted state. C observed in individuals (adult males and females) max It was demonstrated that the values ​​did not significantly exceed the median. In these 104 healthy subjects (127 DBF doses), C max The median value was 467 ng / mL. Under the conditions of a fatty diet, the proposed DBF medication regimen is labeled with diastat rectal gel (DRG). Expected C after administration of the corresponding dose specified max Similar to C max This generates... High-dose and low-dose formulations were tested in pilot clinical trials for DRG at intensities of 5 mg and 20 mg. The results showed excellent agreement between 5 mg DBF and 5 mg DRG, and between 20 mg DBF and 5 mg The dose-proportionality between DBF was also supported. This was between the 5 mg DRG and the 20 mg DRG shown in Figure 1C. This is in contrast to the lack of a proportional relationship. 20 mg of DBF is expected to achieve approximately 367 ng / ml. Although measured, the levels unexpectedly exceeded 600 ng / ml, or 180% of the target C. max It exceeded expectations.

[0039] Unexpectedly, DBF can reach therapeutic levels within one hour. Under certain conditions, DBF can reach the therapeutic range within 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes. Under certain conditions, DBF can reach the therapeutic range in 5 minutes or more. Under specific conditions, DBF exceeds 10 minutes. The therapeutic range can be reached for more than 15 minutes, more than 30 minutes, or more than 45 minutes. In the therapeutic range of DBF, 1 00 ng / ml or more, 90 ng / ml or more, 80 ng / ml or more, 70 ng / ml or more, 60 ng / ml or more, 50 ng / ml or more Above, blood DBF concentrations of 40 ng / ml or higher, 30 ng / ml or higher, 20 ng / ml or higher, or 10 ng / ml or higher are considered indicative of a high risk of developing Observable. In one embodiment, the therapeutic range for DBF is ≤10 ng / ml, ≤20 ng / ml, ≤30 ng / ml l or less, 40 ng / ml or less, 50 ng / ml or less, 60 ng / ml or less, 70 ng / ml or less, 80 ng / ml or less, 90 This can result in and allow observation of blood DBF concentrations of ng / ml or less, or 100 ng / ml or less.

[0040] Furthermore, unexpectedly, 17.5 mg of DBF provides the same bioavailability as DRG. Unexpectedly, 17.5 mg of DBF yielded the same C1c as 20 mg of DRG when consumed with a moderate-fat diet. max Provide It was revealed that this would happen.

[0041] DBF differed from DRG in the following respects: (1) DBF showed higher bioavailability than DRG. 2) The PK behavior of DBF was linear. Specifically, in the case of DBF, C max Both AUC and dose-to-dose ratio For example, it increased. In contrast, the PK behavior of DRG was not linear. Specifically, in the case of DRG, C max While the increase in AUC was less than dose-proportional, it increased with dose. (3) DBF showed a dietary effect (C after consuming a high-fat diet). max The average decreased by approximately 45%. And after consuming a moderate-fat diet, the average decreased by approximately 33%, but there was no change in AUC. In contrast, Since DRGs are administered via the rectal route, they are not considered to be affected by food. Compared to the diastat gel, transmucosal film or transbuccal film This can reduce variability between different targets.

[0042] The applicant uses population PK modeling to correct for the difference in PK between DBF and DRG. The medication regimen was selected as shown in the table below.

[0043] [Table 1]

[0044] Simply put, it corresponds to each weight class specified on the label of the Diastat rectal gel. The recommended DBF dose is (1) diazepam C produced after consuming a moderate-fat meal. max The predicted median is, C after administration of the labeled dose of Astatin rectal gel max It is certain that it is similar to the median. (2) Provides a sufficiently high dose and diazepam C obtained in a fasted state. max Prediction center The value was observed in a Phase 1 healthy volunteer trial of DBF, demonstrating safety. max Above median We selected a dose that would not otherwise be available. A simulation based on population PK modeling. The proposed medication regimen, under the conditions of a moderate-fat diet, involves diastat rectal gel. Predicted C after administration of the labeled dose max Similar to C max Generate for each weight class This demonstrated that they had done so.

[0045] In another example, the medication regimen may be as shown in the table below. [Table 2] TIFF2026076173000004.tif187170TIFF2026076173000005.tif186170

[0046] Population pharmacokinetic modeling involves DBF and diastats under fasting and food intake conditions. This was used to model the pharmacokinetic profile of the rectal gel. This shows an acceptable profile in a fasting state, after consuming a moderate-fat diet, or after consuming a high-fat diet. This profile can distinguish between male and female targets. Sexual targets may have low plasma concentrations. Treatment for the condition involves 0.1-0.4 mg / kg of diphtheria. This involves delivering azepam, for example, 0.1 to 0.3 mg / kg of diazepam.

[0047] In some embodiments, the dose is for a subject of a certain weight class, for example, a fasting state. The dose may be lower than the equivalent dose of diastat. In other embodiments, the dose may be, for example, An equivalent dose of diastat for a certain weight class of subject in a food intake state is less than It's okay if it's expensive.

[0048] Regarding Figures 1A and 1B (same study), plasma diazepam concentrations were measured using a single dose, randomization, and non- A blinded, 3-period cross-matching study was conducted using 5 mg, 10 mg, and 15 mg diazepam buccal film (DBF). The measurement was performed on 30 healthy adult male volunteers in a fasted state. Data points represent mean ± SD maximum plasma volume. Concentration (C max ) and the region below the concentration-time curve extrapolated from zero time to infinite time (AUC 0-inf ) The most fitting straight line shows that both values ​​increase linearly with dose.

[0049] Regarding Figure 1A, DBF doses of 5 mg to 15 mg showed rapid absorption and linear dose-proportional pharmacokinetics. In contrast, diazepam rectal gel was C max It exhibits sublinear dose-proportional pharmacokinetics. Recent animal model studies have shown that plasma diazepam concentrations in the 70 ng / ml range are associated with seizure thresholds. It has been shown to be related to the rise. For example, the whole thing is incorporated by quotation Dhir A Rogawski MA's paper, "Minimum steady state of diazepam causing seizure threshold elevation in rats" Determination of minimal steady-state plasma level of diaze pam causing seizure threshold elevation in rats)” Epilepsia. May 2018; 59(5):935 -944. doi: 10.1111 / epi.14069. Electronically published April 6, 2018, PubMed PMID: 29682729; PubM Please refer to ed Central PMCID: PMC5934328. 15 minutes after application to the oral buccal mucosa, 15 m The mean plasma concentration after administering the g DBF dose exceeds this level (70 ng / ml).

[0050] Regarding Figure 1B, the applicant states that exposure to diazepam during the interictal and pericillinary periods is equivalent to exposure to diazepam immediately after an epidemic. Even when administered to the oral buccal mucosa during a later period, the appropriate performance of DBF was demonstrated, and there was no significant difference. This was discovered. The subjects were aged 18-55 years, weighed 83.5±11.4 kg, and had a BMI of 26.7±2.2 kg / m². 2 (Mean ± SD) 30 In healthy adult males, DBF containing 5 mg, 10 mg, or 15 mg of diazepam was administered as a single dose. In a crossover trial conducted in an open-label manner over three periods, with participants in a randomized order, 21 participants were crossovered between each treatment period. The study was conducted with a drug-free period of several days in between. Regarding Figure 1A, each subject received at least one dose of DBF. The data points represent 25-30, which is the mean ± SEM value of plasma concentration measurements taken 4 hours after drug administration. Error bars are not shown if they are smaller than the size of the symbol.

[0051] Linear interpolation C of 12.5 mg DBF dose in fasted healthy volunteers max The values ​​are shown in Figure 1A. Based on the data, the value is 417 ng / mL, and the geometric mean C obtained from studies in individuals with epilepsy. max The actual value is larger than the stated value. Diazepam is N-demethylated by CYP3A4 and CYP2C19. Therefore, the clearance of these isozymes is increased by their derivatives. For example, The entire work is incorporated by citation from the literature of Riss J, Cloyd J, Gates J, and Collins S. "Benzodiazepines for epilepsy: pharmacology and pharmacokinetics" 2008 Aug;118(2):69-86. doi: 1 0.1111 / j.1600-0404.2008.01004.x. Electronically published March 31, 2008 Review. PubMed PMID: 183 See 84456. Lower C than predicted in the epilepsy population. max The values ​​are, in part, In many cases, this may be caused by an incidental induction of CYP activity due to the anticonvulsant medication being taken. AUC that matches the lead 0-inf There was also a decrease in drug absorption rates because the subjects were not fasting. Additional, yet-to-be-identified, factors such as the effects of certain foods may also be contributing to the average prevalence of epilepsy. Average C max It will likely play a role in preventing the value from decreasing.

[0052] Food effects observed after DBF administration were described for orally administered diazepam. It is clearer than the other. This is because the dose portion is absorbed through the oral buccal mucosa and absorbed orally. It is assumed that this is the result of the portion that is affected. This portion of the dose is not affected by food, therefore Under the condition of physical ingestion, only a portion of the absorption profile travels for a longer period. max P Rophile (in a fasted state, both absorption pathways are combined) unexpectedly decreases. However, the reason is not only that the portion absorbed orally is reduced by the presence of food, This is because the oral profile is separated from the intraoral buccal profile.

[0053] (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. This can be improved. A suitable example of a permeation enhancer is, for example, U.S. Patent Application 15 / 5. This is shown in U.S. Patent No. 87,364 and U.S. Patent Application No. 15 / 791,249, both of which are cited in their entirety. It's built in.

[0054] In one 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 substances, when combined with mucosal delivery enhancers, serve as: (a) aggregation inhibitors; (b) charge modifiers; and (c) pH adjusters. (d) Drugs; (e) Enzyme inhibitors; (f) Mucolytics or mucolytics; (g) Ciliostats (ciliostat) IC agent); (g) Membrane penetration enhancer selected from the following: (i) Surfactant; (ii) 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) Low molecular weight hydrophobic permeation enhancers -; (viii) sodium or salicylic acid derivatives; (ix) glycerol acetoacetate ester; ( (x) Cyclodextrin or β-cyclodextrin derivatives; (xi) Medium-chain fatty acids; (xii) Sharpness (xiii) amino acids or salts thereof; (xiv) N-acetylamino acids or salts thereof; (xv) (ix) Degradative enzymes against selected membrane components; (x) Inhibitors of fatty acid synthesis; (x) Cholesterol compounds Inhibitors of the formation of (xi)(i)~(x) Any combination of membrane penetration enhancers listed in (xi)(i)~(x); (h) Epithelial (i) modifiers of binding physiological functions; (j) vasodilators; (k) selective transport promoters; and (k) the compound thereof Effectively combined, associated, contained, encapsulated, or bound together with, Vehicles that stabilize 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-mentioned Combining this compound with a mucosal delivery enhancer increases the bioavailability of the compound in the target blood plasma. It is provided. The infiltration enhancer is described in the literature of J. Nicolazzo et al., J. of Controlled Disorders. This is described in ase, 105(2005) 1-15, which is incorporated herein by reference. ru.

[0055] (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 endobuccal 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 is biological for some compounds. This could be the main reason for its poor usability. In addition, the mucous membrane covering the oral cavity is easily accessible. This means that the dosage form can be applied to the site where it is needed, and in emergency situations, Ensure that it can be easily removed. However, like the skin, the buccal mucosa inside the oral cavity is a biologically different tissue. It acts as a barrier to the absorption of substances, which prevents compounds from passing through this tissue. It is possible to have little to no oral irritation. This is an important factor when using it. Therefore, the identification of safe and effective penetration enhancers is crucial. This has become a major goal in the pursuit of improved drug delivery through the oral mucosa.

[0056] A chemical permeability enhancer controls the permeation rate of drugs administered co-administered or sequentially through biological membranes. It is a substance that controls [something]. Extensive studies have shown that osmotic enhancers are effective in enteral and transdermal [stimulation]. The focus is on gaining a better understanding of how to change the transparency. However, the mechanisms involved in enhancing penetration in the oral cavity (buccal side) and sublingually are largely unknown. not present.

[0057] The oral cavity buccal mucosa is located on the inner wall of the cheek, as well as in the area between the gums and the upper and lower lips. , and 100cm 2 It has an average surface area of ​​[value missing]. The surface of the buccal mucosa inside the oral cavity is made of stratified squamous epithelium. This is due to the gently undulating basement membrane (a continuous layer of extracellular material with a thickness of approximately 1-2 μm), It is separated from the underlying connective tissue (lamina propria and submucosa). This stratified squamous epithelium is differentiated. It consists of cell layers, and as they transition from the basal region to the surface region, their size changes. The shape and contents change, and cells detach from the surface region. Approximately 40-50 cell layers are present. As a result, the thickness of the buccal mucosa inside the oral cavity is 500-600 μm.

[0058] Structurally, the sublingual mucosa is similar to the buccal mucosa inside the oral cavity, but the thickness of this epithelium is 100-200 μm. This membrane, too, is not keratinized and is relatively thin, making it more permeable than the buccal mucosa inside the oral cavity. It has been shown to be transient. Blood flow to the sublingual mucosa is slower than to the buccal mucosa inside the oral cavity. 1.0ml / min -1 / cm -2 It is in the order of magnitude. However, the flow of saliva to the sublingual region is greater than that of the buccal mucosa inside the oral cavity. Because it is large, there is a risk that the medication will be swallowed before it can be quickly diluted and penetrate the sublingual mucosa. This creates a problem.

[0059] 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. In the oral buccal mucosa, where greater permeability occurs, the thickness increases and tight junctions are also lacking. , it has lower permeability than intestinal tissue.

[0060] 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.

[0061] 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 due to the chemical properties of the lipids present within.

[0062] (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.

[0063] 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 requires a chemical permeation enhancer, a further permeable prodrug, and a physical method. Various methods, including the use of [specific method], can be utilized to overcome the barrier properties of the oral buccal mucosa. can.

[0064] 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.

[0065] (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 oral mucosa. Aromatic and aliphatic alcohols, e.g. For example, benzyl alcohol is a mouthpiece for various compounds both in vitro and in vivo. It can increase permeability through the lumen mucosa. The data obtained from these research experiments showed increased permeability. The strong effect strongly suggests that it is due to the action of surfactants on the intercellular lipids of the mucous membrane. The permeable enhancer can be administered via oral mucosa, for example, the buccal side of the oral cavity or sublingually. The permeation enhancer may be a synthetic compound. In one embodiment, the permeation enhancer is biosynthetic It may also be a compound. In one embodiment, the permeation enhancer may be a natural compound. In the application method, the permeation enhancer is a combination of compounds selected from one or more of these compound species. It can include...

[0066] 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.

[0067] 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. Furthermore, the enhancing effect of Azone (registered trademark) on the permeability of compounds through the oral mucosa is also observed. 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.

[0068] 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, 47( This is described in 498-506 (2014), and this reference is incorporated herein by reference. OTDD continues to attract the attention of academic and industrial scientists. (Skin and nasal delivery routes) Despite the limited characterization of the permeation pathways within the oral cavity compared to other methods, ionization Recent advances in our understanding regarding the permeability of molecules through the buccal epithelium of the oral cavity Furthermore, the emergence of new analytical techniques for studying and experimenting with the oral cavity, and the intraoral buccal and sublingual areas. The outlook is bright, given the progress in the development of in silico models that predict transparency.

[0069] For a wider range of drugs to be delivered through the buccal mucosa of the oral cavity, this tissue barrier is necessary. Reversible methods that reduce the likelihood should be used. The necessity of this is evident in the buccal mucosa of the oral cavity. To promote research and experimentation with permeability enhancers that can safely modify the permeability constraints. Intraoral buccal side The penetration is due to bile salts, surfactants, fatty acids and their derivatives, chelating agents, and cyclo Various types of transmucosal and transdermal penetration enhancers, such as dextrin and chitosan. It has been shown that its use may improve the condition. Used to enhance drug permeability. Of these chemical substances, bile salts are the most common.

[0070] 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 permeation through the intraoral buccal pathway: possibilities and limitations (Drug permeation) 'eation enhancement via buccal route: possibilities and limitations)', Journal o This is discussed in Controlled Release 72 (2001) 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 animal 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. Other studies have shown that it promotes absorption through the intestinal mucosa and cultured Caco-2 cells. It shows an enhancing effect on the penetration of compounds.

[0071] 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 produced 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, or 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.

[0072] Some natural products of plant origin are known to have vasodilatory effects. There are several mechanisms or patterns by which the products of vasodilation can cause vasodilation. (Review) The following is incorporated herein by reference: JR McNeill and TM Jurgens See the following reference, Can. J. Physiol. Pharmacol. 84:803-821(2006). Specifically, The vasodilatory effect of igenol has been reported in many animal studies. For example, The following are incorporated herein by reference: Lahlou, S. et al., J. Cardiovasc. P. harmacol. 43:250-57 (2004), Damiani, CEN et al., Vascular Pharmacol. 40:59-66 (2003), Nishijima, H. et al., Japanese J. Pharmacol. 79:327-334 (1998), and Hume See WR's reference, J. Dent Res. 62(9):1013-15(1983). Calcium channels Blockage is the cause of vasodilation induced by plant essential oils, or their main component, eugenol. It has been suggested that Interaminense is incorporated herein by reference. See the literature by LRL et al., Fundamental & Clin. Pharmacol. 21: 497-506 (2007).

[0073] 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 Rustan AC and Dre von, CA, "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). There exists a place where the first double bond is found between the third and fourth carbon atoms from the ω carbon. These are collectively called ω-3 fatty acids. The first double bond is between the sixth and seventh carbon atoms. In this case, these are called omega-6 fatty acids. PUFAs are formed by the addition and desaturation of carbon atoms (hydrogen). (Removal) leads to further metabolism in the body. Linoleic acid, an omega-6 fatty acid, is further metabolized into gamma-linolenic acid. Dihomo-γ-linolenic acid, arachidonic acid, adrenaline, tetracosatetraenoic acid, tetraco α-linolenic acid, an omega-3 fatty acid, is metabolized to sapentaenoic acid and docosapentaenoic acid. Octadecatetraenoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosa Pentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and docosahexaenoic acid It is metabolized into acid (DHA).

[0074] 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 and hyperinflation of coronary artery smooth muscle cells in pigs As polarization is induced and the degree of cis-unsaturation of fatty acids increases, higher efficacy is achieved. It has been reported that this has been done. This is incorporated herein by reference by Pomposiello, S. See the literature by I. et al., Hypertension 31:615-20 (1998). Interestingly, Rhinore The pulmonary vascular response to arachidonic acid, a metabolite of uric acid, depends on the dose, animal species, and arachidonic acid. Depending on the mode of administration and the tone of pulmonary circulation, it will be either vasoconstrictive or vasodilatory. For example, arachidonic acid is involved in cyclooxygenase-dependent and cyclooxygenase-independent lung It has been reported to cause vasodilation. Each is incorporated herein by reference. This is based on the literature by Feddersen, CO et al., J. Appl. Physiol. 68(5):1799-808(1990); and, The literature by Spannhake, E.W. et al., J. Appl. Physiol. 44:397-495 (1978) and the text by Wicks, TC et al. See the reference, Circ. Res. 38:167-71 (1976).

[0075] Many research experiments have shown that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be taken orally. The effects on vascular reactivity after administration in an ingestible form have been reported. Research experiments have shown that EPA-DHA or EPA alone can cause norepinephrine vasoconstriction in the forearm microcirculation. We discovered that the effect was suppressed or the vasodilatory response to acetylcholine was enhanced. The following are incorporated herein by reference: Chin, JPF et al., Hypertension 2 See 1:22-8 (1993), and the literature by Tagawa, H. et al., and J Cardiovasc Pharmacol 33:633-40 (1999). Please be informed. Another study showed that both EPA and DHA increase systemic arterial compliance. It was found that this tends to cause and reduce pulse pressure and total vascular resistance. The following references are incorporated herein: Nestel, P. et al., Am J. Clin. Nutr. 76:326-30( See 2002. On the other hand, one research experiment showed that DHA, not EPA, was effective in treating hyperlipidemia. In the microcirculation of the forearm of overweight men, the vasodilatory mechanism was enhanced and the systolic response was attenuated. This was discovered. The following is incorporated herein by reference: the literature by Mori, TA et al., Circulat See Ion 102:1264-69(2000). Another research experiment discovered the vasodilatory effect of DHA on the rhythmic contraction of isolated human coronary arteries in vitro. See the literature of Wu, K.-T. et al., Chinese J. Physiol. 50(4):164-70(2007), which is incorporated herein by reference.

[0076] (Order of permeation enhancer(s) and active pharmaceutical ingredient(s)) The arrangement, order, or sequence of the permeation enhancer(s) and active pharmaceutical ingredient(s) (API) delivered to the desired mucosal surface can be varied to deliver the desired pharmacokinetic profile. For example, the permeation enhancer(s) can be applied first, either by film, swab, spray, gel, rinse, or by the first layer of the film, and then the API can be applied by a single film, swab, or by the second layer of the film. This order can be reversed or modified, for example, by first applying the API by film, swab, or by the first layer of the film, and then applying the permeation enhancer(s) by film, swab, spray, gel, rinse, or by the second layer of the film. In another embodiment, the permeation enhancer(s) can be applied by film and the drug by another film. For example, depending on the desired pharmacokinetic profile, a permeation enhancer film can be placed under the film containing the API, or under the film containing the permeation enhancer(s). A film containing API(s) may be placed.

[0077] For example, an absorption enhancer(s) may be used, as a pretreatment, alone or in combination with at least one API to precondition the mucosa for further absorption of the API(s). Following this treatment, another treatment with a neat absorption enhancer(s) may be continued, followed by application of the at least one API to the mucosa. This pretreatment may be applied as another treatment (film, gel, solution, swab, etc.) or as one layer within a multilayer film structure of one or more layers. Similarly, this pretreatment may be included within a separate domain of a single film designed to dissolve and release to the mucosa, followed by release of a second domain, which may or may not contain an absorption enhancer(s) or API(s). Thereafter, the active ingredient may be delivered from the second treatment, alone or in combination with an additional absorption enhancer(s). There may be a third treatment or domain delivering additional absorption enhancer(s) and / or at least one API(s) or prodrug(s), either in different ratios from each other or different ratios from the total load of other treatments. This enables obtaining a desired pharmacokinetic profile. In this way, the product may have one or more domains containing absorption enhancer(s) and API(s) that can vary the order of application, composition, concentration, or total load to the mucosa, leading to the desired absorption amount and / or absorption rate to achieve the intended pharmacokinetic profile and / or pharmacodynamic effect. There may be a third treatment or domain delivering additional absorption enhancer(s) and / or at least one API(s) or prodrug(s), either in different ratios from each other or different ratios from the total load of other treatments. This enables obtaining a desired pharmacokinetic profile. In this way, the product may have one or more domains containing absorption enhancer(s) and API(s) that can vary the order of application, composition, concentration, or total load to the mucosa, leading to the desired absorption amount and / or absorption rate to achieve the intended pharmacokinetic profile and / or pharmacodynamic effect. absorption amount and / or absorption rate to achieve the intended pharmacokinetic profile and / or pharmacodynamic effect. domains containing absorption enhancer(s) and API(s) that can vary the order of application, composition, concentration, or total load to the mucosa, leading to the desired absorption amount and / or absorption rate to achieve the intended pharmacokinetic profile and / or pharmacodynamic effect.

[0078] This film format may be designed so that there is no distinct side, or The film has at least one side of a multilayer film where multiple ends are shared It is a terminal end (having a shared boundary or limit or joining there) You can also serve it facing the direction.

[0079] This pharmaceutical composition may be chewable, gelatin, or freeze-dried or inhaled. In base dosage forms, sprays, gums, gels, creams, tablets, capsules, liquids, or films. This is also acceptable. For example, this composition may contain a texture such as microneedles or fine protrusions on its surface. It is possible to do so. Recently, the use of micron-scale needles in increasing skin permeability has been found to be beneficial for polymers. It was shown to significantly increase transdermal delivery, particularly of [the drug]. Most drug delivery research experiments have shown that We place importance on solid-type microneedles, which are effective against a wide range of molecules and nanoparticles. It has been shown to increase skin permeability in vitro. In in vivo research experiments, Ori Delivery of nucleotides, reduction of blood glucose levels by insulin, and immunity from DNA vaccines. The induction of responses has been clarified. For these research experiments, needle arrays puncture the skin. It is used to increase transport by diffusion or iontophoresis, or Icloneedle is used as a drug carrier to release drugs into the skin from the surface coating. Hollow microneedles have also been developed to deliver small amounts of insulin to diabetic rats. This was shown. For the actual application of microneedles, the microneedle fracture strength The ratio of the force to the skin insertion strength (i.e., the safety margin) is greater for needles with a small tip radius and a large wall thickness. It was found to be optimal. Microneedles inserted into the skin of human subjects are painless. It was reported that there are microneedles. In summary, these results suggest that microneedles have an applicable range. This suggests that it could be a promising technology for delivering therapeutic compounds into the skin. - Mike Using tools from the electronics industry, microneedles are available in various sizes and shapes. They are made from various materials. Microneedles are, for example, encapsulated in a minimally invasive manner. A fine polymer needle may be used to deliver the drug, but other suitable materials can also be used. .

[0080] 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.

[0081] The term "film" can include films and sheets of any shape, including rectangular, square, or other desired shapes. The film can be of any desired thickness and size. In a preferred embodiment, the film can have a thickness and size such that it can be administered to a user, for example, placed in the user's oral cavity. The film can have a relatively thin thickness of about 0.0025 mm to about 0.250 mm, or the film can have a somewhat thicker thickness of about 0.250 mm to about 1.0 mm. In some films, the thickness can be even greater, i.e., greater than about 1.0 mm, or thinner, i.e., less than about 0.0025 mm. The film can be single-layer or multilayer, including laminated films or multiple cast films. The permeation enhancer and the pharmaceutically active ingredient can be combined within a single layer, each contained in separate layers, or each contained in separate regions of the same dosage form. In certain embodiments, the pharmaceutically active ingredient contained within the polymer matrix can be dispersed within the matrix. In certain embodiments, the permeation enhancer contained within the polymer matrix can be dispersed within the matrix. Oral soluble films can be classified into three main categories: immediate solubility, moderate solubility, and slow solubility. Oral soluble films can also include any combination of the above categories. Immediate solubility films can dissolve in the mouth in about 1 second to about 30 seconds, including greater than 1 second, greater than 5 seconds, greater than 10 seconds, greater than 20 seconds, or less than 30 seconds. Moderate solubility films can dissolve in the mouth in about 1 to about 30 minutes, including greater than 1 minute, greater than 5 minutes, greater than 10 minutes, greater than 20 minutes, or less than 30 minutes, and slow solubility

[0082] [[ID=2b]] ​​​​​​​​​​ The film can dissolve in the mouth over a period of more than 30 minutes. Generally speaking, fast-dissolving films are more common. Lum is a low molecular weight hydrophilic polymer (for example, a polymer with a molecular weight of approximately 1,000 to 9,000 daltons). It may contain (or consist of) a polymer (or a polymer having a molecular weight of up to 200,000 daltons). In contrast, slow-dissolving films generally use high molecular weight polymers (e.g., with molecular weights of several million). (Includes having). Moderately soluble films are between immediately soluble films and slowly soluble films. It will likely tend to fall within that range.

[0083] 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 is not a matter of sex. Such moderately soluble films dissolve quickly enough, most preferably 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 This can provide an acceptable level of mucosal adhesion that prevents the material from easily peeling off. This ensures that the active pharmaceutical ingredient is delivered to the user.

[0084] 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.

[0085] 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 epi Comparison with that of nephrine (Site of ocular hydrolysis of a prodrug, dipivefrin, and a comparison of its ocular metabolism with that of the parent compound, epinephri See "ne)"Invest., Ophthalmol. Vis. Sci. July 1980. Prodrugs are, Benzodiazepine prodrugs such as abizafone, which is a prodrug of azepam, are also acceptable. Another prodrug from the chemical series of benzodiazepines that falls within the scope of this invention is, It is ethyl loflazepate. All chemical derivatives, analogs, or protozoa of benzodiazepines. All drugs are considered to fall within the scope of this invention.

[0086] 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 Control drugs, drugs for managing hypocalcemia, drugs for managing hypocholesterolemia, blood glucose lowering drugs, lipid lowering drugs, Antihypertensive drugs, ion exchange resins, contrast agents, immunotherapy drugs, immunomodulatory drugs, immunostimulants, immunotherapy drugs Inhibitors, keratolytics, laxatives, LHRH agonists, mood regulators, motion sickness medications, mucolytics Antidotes, muscle relaxants, pupil dilators, nasal congestion decongestants, neuromuscular blockers, neuroprotective agents, NMDA antagonists Non-hormonal sterol derivatives, osteoporosis treatment drugs, uterine contraction drugs, parasympathetic nerve blockers, Parasympathetic agonist mimetic drugs, plasminogen activators, platelet-activating factor antagonists Stroke, platelet aggregation inhibitors, prostaglandins, psychotropic drugs, antipsychotics, radiopharmaceuticals, respiratory Inhalant therapy drugs, scabies insecticides, sclerosing agents, sedatives, sedative-hypnotics, selective adenocarcinoma Nosine A1 antagonist, serotonin antagonist, serotonin inhibitor, serotonin receptor Antagonists, smoking cessation medications, steroids, stimulants, sympathetic nerve blockers, terin (ter ine) Thyroid relaxants, thyroid hormones, thyroid inhibitors, thyroid mimetic drugs, tranquilizers Iza, tremor treatment drug, amyotrophic lateral sclerosis drug, cerebral ischemia drug, Paget's disease drug, unstable angina pectoris Drugs, vasoconstrictors, vasodilators, weight management drugs, wound healing drugs, xanthine oxidase inhibitors , as well as combinations thereof.

[0087] Examples of suitable active ingredients used herein include antacids, H2 antagonists, and analgesics. This includes, for example, the administration of antacids, which contains calcium carbonate alone or magnesium hydroxide. It may also be prepared by using it in combination with um and / or aluminum hydroxide. Furthermore, Antacids may be used in combination with H2 antagonists.

[0088] 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) Silapap Children's (registered trademark), Tylenol (registered trademark), Tylenol Children's (registered trademark) (Registered Trademark), Tylenol Extra Strength (Registered Trademark), Tylenol Infants' Original (Registered Trademark), Tylenol Infants'(R), Tylenol Arthritis(R), T-Painol(R), QP ap(registered trademark), Cetafen(registered trademark), Dolono(registered trademark), Tycolene(registered trademark), APAP(registered trademark) Available on the market as a trademark and Aminofen (registered trademark), and optionally contains caffeine. These may include combinations thereof. Other pain relievers that can be used in the present invention include meperidine. Hydrochloride (available on the market as Demerol®), capsaicin (Qutenza® and Available on the market as morphine sulfate and naltrexone hydrochloride (as Embeda®). (Available on the market), hydromorphone hydrochloride (available on the market as Dilaud®), Lopoxyfen napsylate and acetaminophen (marketed as Darvocet-N®) Available), fentanyl (Duragesic®, Onsolis®, and Fentora®) (Available on the market as a trademark), sodium hyaluronate (Euflexxa (registered trademark) is available on the market (Available on the market), adalimumab (available on the market as Humira®), sumatriptan succinate Nate (available on the market as Imitrex®), fentanyl for iontophoresis (Io Available on the market as nsys(registered trademark), Orphenadol (Norgesic(registered trademark)) (Available on the market as) Magnesium salicylate tetrahydrate (Available on the market as Novasal®) (Available on the market), oxymorphone hydrochloride (available on the market as Opana ER®), Metca Rubamol (available on the market as Robaxin®), Carisoprodol (Soma®) (Available on the market as) Tramadol hydrochloride (Ultracet® and Ultram®) (Available on the market as), morphine sulfate (available on the market as MS Contin®), methax Salon (available on the market as Skelaxin(registered trademark)), oxycodone hydrochloride (OxyContin(registered trademark) Available on the market as a trademark, acetaminophen / oxycodone hydrochloride (Percocet (Registered Trademark) Available on the market as (trademark), oxycodone / aspirin (available on the market as Percodan (registered trademark)). (Possible), Hydrocodone bitartrate / acetaminophen (marketed as Vicodin®) (Available for purchase), hydrocodone bitartrate / ibuprofen (marketed as Vicoprofen®) Available on the market), nepafenac (available on the market as Nevanac®), and pregabalin (L It may also include (available on the market as yrica®, a registered trademark).

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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 Ca H -Antagonists, for example, nifedipine (Procardia (Registered Trademark) This may also include (Mark) and (Available on the market as Adalat®).

[0093] 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 C1 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).

[0094] 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 (commercially known as Ocuflox®, Floxin®), telosulfone Mycin (available on the market as Ketek®), lomefloxacin hydrochloride (Maxaquin® (Available on the market as a registered trademark), minocycline hydrochloride (available on the market as Minocin (registered trademark)) Possible), fosfomycin tromethamine (available on the market as Monurol®), penicillin ¹-Potassium (Penicillin VK®, available on the market as Veetids®), Tri Metoprim (available on the market as Primsol®), ciprofloxacin hydrochloride (Proqui n XR (registered trademark) is available on the market), rifampin, isoniazid and pyrazinamide (Ri Available on the market as fater (registered trademark), cefditoren (available on the market as Spectracef (registered trademark)) (Available on the market), cefixime (available on the market as Suprax®), tetracycline (Ac (Available on the market as hromycin V (registered trademark) and Sumycin (registered trademark)), tobramycin (Tob Available on the market as rex (registered trademark), rifaximin (available on the market as Xifaxan (registered trademark)) Possible), Azithromycin (available on the market as Zithromax®), Azithromycin Suspension (available on the market as Zmax®), linezolid (available on the market as Zyvox®) (Available for purchase), benzoyl peroxide and clindamycin (marketed as BenzaClin®). (Possible), erythromycin and benzoyl peroxide (available on the market as Benzamycin®) (Potentially), dexamethasone (available on the market as Ozurdex®), ciprofloxacin and Dexamethasone (available on the market as Ciprodex®), polymyxin B sulfate / neoma Isine sulfate / hydrocortisone (available on the market as Cortisporin®), Coristi Cortisone sulfate / Neomycin sulfate / Hydrocortisone acetate / Tonzonium bromide (Cortis Available on the market as porin-TC Otic (registered trademark), cephalexin hydrochloride (Keflex (registered trademark) (Available on the market as) cefdinir (available on the market as Omnicef®), and gachi Contains floxacin (available on the market as Zymar®).

[0095] 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 a trademark), 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.

[0096] 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®).

[0097] 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).

[0098] 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.

[0099] 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.

[0100] 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 / dichlorphenazone / Acetaminophen (available on the market as Midrin®), dihydroergotamine Silates (available on the market as Migranal®), Eletriptan hydrobromide (Relpa (Available on the market as x (registered trademark), and zolmitriptan (available on the market as Zomig (registered trademark)) Available); influenza treatment drugs, e.g., Haemophilus b conjugate vaccine; tetanus toxoid Conjugates (available on the market as Hiberix®); as well as cardiac therapeutics, such as quinidine sulfur Salts, isosorbide dinitrate / hydralazine hydrochloride (available on the market as BiDil®), Digoxin (available on the market as Lanoxin®), flecainide acetate (Tambocor( Available on the market as a registered trademark, mexiletine hydrochloride (available on the market as Mexitil (registered trademark)) (possible), disopyramide phosphate (available on the market as Norpace®), procaine phosphate Procanbid hydrochloride (available on the market as Procanbid®), and propafenone (Rythmol®) This may include (available on the market as a trademark).

[0101] 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®). (Potential), 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), Isradipin (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®).

[0102] 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.

[0103] 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 cyclobenz. Purine hydrochloride (available on the market as Flexeril®), tizanidine (Zanaflex®) (Available on the market as) and hyoscyamine sulfate (Available on the market as Levsin®) It can include...

[0104] 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).

[0105] The film disclosed herein further contains information on antipsychotic drugs, such as alprazolam (Niravam®), Available as Xanax (registered trademark), clozopin (Clozaril (registered trademark)) (Available as), haloperidol (available as Haldol®), fluoxetine hydrochloride Salt (available as Prozac®), sertraline hydrochloride (available as Zoloft®) (Available), asenapine (available on the market as Saphris®), iloperidone (Fanapt®) Available on the market as a registered trademark, and paroxtine hydrochloride (Paxil (registered trademark) and (Available as), aripiprazole (available on the market as Abilify®), guanfang Syn (available on the market as Intuniv (registered trademark)), amphetamine and methamphetamine (Ad Available on the market as derall (registered trademark) and Desoxyn (registered trademark), clomipramine hydrochloride (A Available on the market as nafranil (registered trademark), buspirone hydrochloride (available on the market as BuSpar (registered trademark)) (Available on the market), citalopram hydrobromide (available on the market as Celexa®), duro Xetine hydrochloride (available on the market as Cymbalta®), methylphenidate (Ritalin (Available on the market as Daytrana®), divalproex sodium (valproic acid) Depakote (registered trademark), available on the market, dextroamphetamine sulfate (Dexedrine ( Available on the market as (registered trademark), venlafaxine hydrochloride (marketed as Effexor (registered trademark)). Available), selegiline (available on the market as Emsam®), carbamazepine (Equetro (Available on the market as registered trademark), lithium carbonate (Available on the market as Eskalith (registered trademark) ), fluvoxamine maleate / dexmethylphenidate hydrochloride (Focalin® and (Available on the market as), ziprasidone hydrochloride (available on the market as Geodon®), Meth Ergoloid ruate (available on the market as Hydergine®), escitalopram shu Salt (available on the market as Lexapro®), chlordiazepoxide (Librium (registered trademark) Available on the market as a trademark, morindone hydrochloride (available on the market as Moban (registered trademark)), Phenerzine sulfate (available on the market as Nardil®), thiothixene (Navane®) Available on the market as a trademark, desipramine hydrochloride (available on the market as Norpramin (registered trademark)) (Potential), benzodiazepines (e.g., those available as oxazepam®), Nord Liptiline hydrochloride (available on the market as Pamelor®), tranylcypromine sulfate ( Available on the market as Parnate (registered trademark), prochlorperazine, mirtazapine (Remeron ( (Available on the market as a registered trademark), risperidone (available on the market as Risperdal (registered trademark)) Possible), quetiapine fumarate (available on the market as Seroquel®), doxepin Hydrochloride (available on the market as Sinequan®), atomoxetine hydrochloride (Strattera®) (Available on the market as a registered trademark), Trimipramine maleate (Surmontil (registered trademark) Available on the market), olanzapine / fluoxetine hydrochloride (available on the market as Symbyax®). Possible), imipramine hydrochloride (available on the market as Tofranil®), protriptyline Bupropion hydrochloride (available on the market as Vivactil®), Bupropion hydrochloride (Wellbutrin®) (Available on the market as Wellbutrin SR (registered trademark) and Wellbutrin XR (registered trademark)) This may also include olanzapine (available on the market as Zyprexa®).

[0106] 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.

[0107] 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 (Ambien®, Ambien CR®, Edluar®) (Available on the market), lorazepam (available on the market as Atiban®), flurazepam salt Salt (available on the market as Dalmane®), triazolam (as Halcion®) (Available on the market), clonazepam (available on the market as Klonopin®), barbiturate Examples include phenobarbital (registered trademark), modafinil (registered trademark as Provigil), and others. (Available on the market), Temazepam (Available on the market as Restoril (registered trademark)), Rameltheon (Roze Available on the market as rem (registered trademark), dipotassium chlorazepate (Tranxene (registered trademark)) (Available on the market), diazepam (available on the market as Baylium (registered trademark)), quazepam ( Available on the market as Doral (registered trademark), and estazolam (available on the market as ProSom (registered trademark)). (Available) Includes smoking cessation medications, such as varenicline (available on the market as Chantix®). (Potentially, nicotine, for example, Nicotrol®, and bupropion hydrochloride (Zyban®) Available on the market as; as well as steroids, such as alclomethasone dipropionate steroids. Tel (available on the market as Aclovate®), betamethasone dipropionate (D Available on the market as iprolene (registered trademark), mometasone furoate (Elocon (Available on the market as a registered trademark), fluticasone (Flonase (registered trademark), Flovent (registered trademark) (Available on the market as Flovent Diskus® and Flovent Rotadisk®), full Ocinonide (available on the market as Lidex®), mometasone furoate Lu monohydrate (available on the market as Nasonex(registered trademark)), deoxymethasone (Topicort(registered trademark) Available on the market as a registered trademark, clotrimazole / betamethasone dipropionate ( Available on the market as Lotrisone (registered trademark), prednisolone acetate (Pred Forte (registered trademark)) ), Prednisone (registered trademark), Budesonide Pulmicort (registered trademark), Rhinocort Aqua (registered trademark) (Available on the market as a registered trademark), prednisolone phosphate sodium (Pediapred (Registered Trademark) Available on the market as (Tradesilon®), desonide (available on the market as Tridesilon®), and p It can contain halobetazole lopionate (available on the market as Ultravate®). ru.

[0108] The film of the present invention is further useful for active ingredients, thyroid disease treatments, and hormones, as described below. TC and TD (available on the market as Armour Thyroid®); treatment for potassium deficiency, e.g. Potassium chloride (available on the market as Micro-K®); triglyceride regulators, for example ω-3 fatty acid ethyl ester (available on the market as Omacor®); urinary tract medication, for example Phenazopyridine hydrochloride (available on the market as Pyridium®) and methenamine, Chilen blue / Phenyl salicylate / Benzoic acid / Atropine sulfate / Hyoscyamine (Urised Available on the market as a registered trademark); Vitamin supplements for pregnant women (Advanced Natalcare®, Mate Available on the market as RNA®, Natalins®, and Prenate Advance®; Weight control drugs, such as orlistat (available on the market as Xenical®) and It may contain butramine hydrochloride (available on the market as Meridia®).

[0109] 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.

[0110] 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 subsilysilate, calcium carbonate, calcium phosphate, citrate ions (acid or salt), Minoacetic acid, magnesium aluminate sulfate hydrate, Magaldorate, aluminosilicate Magnesium, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide Magnesium, magnesium trisilicate, milk solids, monobasic or dibasic aluminum phosphate Calcium carbonate, tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate It contains thorium, magnesium aluminosilicate, tartaric acid, and salts.

[0111] 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.

[0112] Examples of specific active ingredients include, but are not limited to, the following: 16-α-fluorotransferase 16-α-Gitoxin, 16-Epiestriol, 17-α-Dihydro Echirenin, 17-α-estradiol, 17-β-estradiol, 17-hydroxyprogesterone Steroid, l-α-hydroxyvitamin D2, 1-dodecpyrrolidinone ,20-Epi-1,25-Dihydroxyvitamin D3, 22-Oxacalcitriol, 2CVV, 2'-nor-cG MP, 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, can Lennon, capecitabine, sodium capobenate, capobenic acid, capreomycin sulfate, Capromab, capsaicin, captopril, caprid, chalasemide, carbachol, cal Badox, carbamazepine, carbamide peroxide, carbantel lauryl sulfate, carbaspirin Calcium phosphate, carbazelan, carbazomycin C, carbenicillin potassium, carbe Noxolone sodium, carbethimer, carbetocin, carbidopa, carbidopa-levodo Pa, Carbinoxamine maleate, Carbifen hydrochloride, Carbochloral, Carboshi Stein, Carbol-Fuchsin, Carboplatin, Carboprost, Carbovir, Car Boxamide-aminotriazole, carboxyamide triazole, carboxymethylated β-1,3-glucan, carbuterol hydrochloride, CaRest M3, carfentanyl citrate, potassium Soprodol, Carmantadine, Carmustine, CARN 700, Camidazole, Caloxazone Carperitide, carfenadine maleate, carprofen, calsatrin succinate, Cartazolate, carteolol, carteolol hydrochloride, cartilage-derived inhibitors, carbicin Hydrochloride, carmonam sodium, carvedilol, carbotrolin, carbotrolin hydrochloride Salt, kazelesin, casein kinase inhibitor (ICOS), castanospermine, caulmonam (caurumonam), sevaracetam, cecropin B, sedefingol, cefaclor, cef Droxyl, Cephamandor, Cephaparol, Cephatidine, Cephazaflourna Thorium, cefazolin, cefbuperazone, cefcapene pivoxil, cefdaroxine tosylate Sympentexyl, cefdinir, cefditoren pivoxil, cefepime, cefetameth, Cefetechol, Cefixime, Cefluplenum, Cefinenoxime hydrochloride Salt, cefinetazole, cefminlox, cefozidime, Fonisid sodium, cefoperazone sodium, ceforamide, cefo Celis, cefotaxime sodium, cefotetan, cefotiam, cefoxitin, ce Fozoplan, cefpimisole, cefpyramide, cefpirome, cefpodoxime proxetin Cefprodil, ceffloxazine, cefsurodin, ceftazidime, cefteram, cefti Butene, ceftizoxime sodium, ceftriaxone, cefuroxime, cerastrol Celicarim, Celiprolol, Cepacidiine A, Cephacetril Sodium Cephalexin, Cephaloglysin, Cephaloridine, Cephalothin sodium, Ce Fapirin sodium, cefradin, cericlamin, cerivastatin, seronapril, Lutoparin sodium, ceruretide, cetaben sodium, cetalkonium chloride, cetamo Cetizyl hydrochloride, cethiezil, cetirizine, cetofenicol, cetraxate hydrochloride, Trollelix, cetylpyridinium chloride, kenodiolus, clofedianol hydrochloride, clofedianol Larbetaine, Chlorambucil, Chloramphenicol, Chlordantoin, Chlordi Azepoxide, chlorhexidine gluconate, chlorin, chlormadinone acetate Chloroorientisin A, chloroprocaine hydrochloride, chlorpropamide, chloroquine, Chloroquinoxaline sulfonamide, chlorothiazide, chlorotrianicene, chloroxyl Chloroxylenol, chlorphenesin carbamate, chlorpheniramine malein Salts, chlorpromazine, chlorpropamide, chlorprothixene, chlortetratetrabisulfate Cyclin, chlorthalidone, chlorzoxazone, cholestyramine resin, chromoral hydrochloride Salt, cibenzoline, cicaprost, cyclafrine hydrochloride, cyclazine dol, ciclesoni D, cicletanin, cyclopirox, cycloprofen, cycloprolol, cidofovir , sidoxepin hydrochloride, cyfenlin, ciglitazone, siladopa hydrochloride, silancetron , cilastatin sodium, cilazapril, cilnidipine, silobamine mesylate, silob Radin, silofungin, cilostazol, simaterol, cimetidine, simeropio bromide Mu, Cinalcast, Sinanserin hydrochloride, Cinepazet maleate, Synflumid, Shinge Stol, Sinitaprid, Cinnamedrine, Cinnarizine, Synolazepam, Synoxacin Simperen, Synlomid, Syntazone, Syntriamide, Sioteronel, Sipamfil , cyprefadol succinate, cyprosinonide, cyprofibrate, ciprofloxa Syn, cyprosten, silamadol, cilolemycin, cisapride, cisatran besylate Rium, cisconazole, cisplatin, cis-porphyrin, cystinexin, citalop Lamb, citrenamide, citicoline, citreamycin α, cladribine, clamoxyquin hydrochloride Salt, clarithromycin, claucenmamide, potassium clavulanate, clazolam, cla Zolimine, Clevopride, Clemastine, Clentheme maleate, Clidinium bromide , clinafloxacin, clindamycin, cryoquinol, clioxamide e) Criprofen, clobazam, clobetasol propionate, clobetazone butyrate, vinegar Crocoltrone acid, clodanoren, clodazone hydrochloride, clodronate, clofazimine, Clofibrate, Clofilium phosphate, Chlogestone acetate, Chromacran phosphate, Vinegar Clomegestone acid, Clometerone, Clomethiazole, Clomiphene analog, Clominol Rex, clomiphene, clomipramine hydrochloride, clonazepam, clonidine, clonitra Clonixeryl, Clonixin, Clopamide, Clopentixol, Cloperidone Hydrochloride, clopidogrel, clopimodide, clopipazan mesylate, clopirac, clopre Donol, cloprostenol sodium, chlorazepate dipotassium, chloretate, Lorexolone, chloroperone hydrochloride, chlorprenaline hydrochloride, chlorthrone, chlorte Lumin hydrochloride, Closantel, Clocilamine acetate, Clothiapine, Clothiapine maleate Thixamide, Cloticasone propionate, Clotrimazole, Cloxacillin benzathine Cloxiquin, clozapine, cocaine, coccidioidin, codeine, cotoxime, co Ruchine, Colestimide, Colestipol Hydrochloride, Colestron, Colforcin, Palmi Colphosseryl tinate, sodium colistimate, colistin sulfate, colismycete Combretastatin A, Corismycin B, Corterol Mesylate, Combretastatin A4, Combretastatin Tin analogs, compressatin, conogenin, conorfone hydrochloride, contignasterol Contratrostatin, Colmetasone acetate, Corticorelin ovine triflutate Corticotropin, cortisone acetate, cortibazole, cortodoxone, kosalan, ko Statride, Cosyntropin, Cotinine, Coumadin, Coumamycin, Crambesidine 81 6. Krillvastatin, Cristinator, Clomitril sodium, Cromolyn sodium Mu, Crotamiton, Cryptophycin 8, Cucumarioside, Cuprimyxin, Crasin A, Curdlan sulfate, curiosin, cyclacillin, cyclazosin, cyclazosin (c yclazosin), cyclic HPMPC, cyclindol, cycliramine maleate, cyclidine, cycl Robendazole, cyclobenzaprine, cyclobut A, cyclobut G, cyclocapron, pa Cycloguanyl moate, cycloheximide, cyclopentaanthraquinone, cyclopentia Zid, cyclopentolate hydrochloride, cyclophenazine hydrochloride, cyclophosphamide, cyclo Loplatam, cyclopropane, cycloserine, cyclocin, cyclosporine, cyclothi Alizin, cyclothiazide, cyclothiazomycin, cyheptamide, cypemycin (cypem YCIN), cypenamine hydrochloride, ciprazepam, cyproheptadine hydrochloride, cyprolidol salt Salts, cyproterone, cycloximide, cysteamine, cysteine ​​hydrochloride, cystine, cy Tarabine, cytarabine hydrochloride, cytarabine octophosphate, cytochalasin B, cell lysate Resolution factors, cytostatin, dacarbazine, dacliximab, dactimycin, Dactinomycin, daidzein, daledarin tosylate, dalfopristin, dalteparin Sodium, daltroban, dalvastatin, danaparoid, danazol, dantrolene dapagliflozin, daphlenodorin A, dapiprazole, dapitant , dapoxetine hydrochloride, dapsone, daptomycin, dalglitazone sodium, darif Enasyn, Darulusin A, Darodipine, Dalcidomin, Daunorubicin hydrochloride, Malein Dazadrol acid, dazepinyl hydrochloride, dazmegrel, dazopride fumarate, dazoxyben Hydrochloride, debrisoquin sulfate, decitabine, deferipron, deflazacort, dehydro Cholic acid, dehydrodidemnin B, dehydroepiandrosterone, delapril, delap Lyl hydrochloride, delavirdine mesylate, delexamin, delfaprazine, dermadin acetate Dermopinol, delphinidin, demepotassium bromide, demeclocycline, demesa Ikurin, Demoxepam, Denofungin, Deoxypyridinoline, Depacote, Deprodone Deprostil, depsidomycin, delamcyclan, dermatan sulfate, desciclovir Decinolone acetonide, desflurane, desipramine hydrochloride, decilzine, desranosyl Deslorerin, desmopressin, desogestrel, desonide, desoxymethasone, de Suoxoamiodarone, deoxycorticosterone acetate, detadimium bitartrate, Deterenol hydrochloride, detirelix acetate, debazepide, dexamethasone, dexamisol Dexchlorpheniramine maleate, Dexchlorpheniramine maleate, Dex Clamol hydrochloride, dexetimide, dexfenfluramine hydrochloride, dexphosphamide (dexifosfamide), deximafene, dexivacaine, dexketoprofen, dexro Xiglumide, dexmedetomidine, dexormaplatin, dexoxadrol hydrochloride, Dexpanthenol, Dexpemedrac, Dexpropranolol hydrochloride, Dexrazox Sun, Dexotalol, Dextrin Disulfate, Dextroamphetamine, Dext Lomethorphan, dextrorphan hydrochloride, dextrothyroxine sodium, dex Verapamil, Dezaguanine, Dezinamide, Dezosine, Diacetol Hydrochloride, Cyclamin Diamocaine acid, diapamide, meglumine diatrizoate, diatrizoate, diaperidine, Diazepam, diaziquan, diazoxide, dibenzepine hydrochloride, dibenzothiophene, Dibucaine, dichliorvos, dichlorphenazone, dichlorphenami D, disylenone, diclofenac sodium, dicloxacillin, dicranine, dikumarol Dicyclomine hydrochloride, didanosine, didemnin B, Zidox, Dienestro L, dienogest, diethylcarbamazine citrate, diethyl homospermine, diethyl Norspermine, diethylpropion hydrochloride, diethylstilbestrol, diphenoxyethanol Simid hydrochloride, difenoxine, diflorazone diacetate, difloxacin hydrochloride, diflua Diflumidone hydrochloride, diflucortolone, diflumidone sodium, diflunisal, diflupred Nat, diphthalone, digitalis, digitoxin, digoxin, dihexyberine hydrochloride, Dihydrolexidine, dihydro-5-azacitidine, dihydrocodeine bitartrate, mesyl Dihydroergotamine acid, dihydroestosterone, dihydrostreptomycin sulfate , dihydrotachisterol, 9-dihydrotaxol, dilantine, dilevalol hydrochloride, Diltiazem hydrochloride, dimefadan, dimephrine hydrochloride, dimenhydrinate, dimerca Prol, Dimethadione, Dimethindene Maleate, Dimethisterone, Dimethylprosta Grandin Al, Dimethyl Sulfoxide, Dimethyl Homospermine, Dimiracetam, Dimox Samine hydrochloride, dinoprost, dioxadrol hydrochloride, dioxamyl Syn, diphenhydramine citrate, diphenidol, diphenoxylate hydrochloride, dif Enylspiromustine, dipivefin hydrochloride, dipivefrin, diprienci Pron (dipliencypron) e) Zipraphenone, dipropylnorspermine, dipyridamole, dipyrithione, dipy Ron, zilithromycin, discodermolide, disobutamide, disofenine, disophi Lamid, disoxalil, disulfiram, ditexene, divalproex sodium, ma Disosilpine leate, dobutamine, docarpamine, dosevenone, docetaxel, docona Zole, docosanol, dofetilide, drasetron, ebastine, ebiratide, ebro Tizidine, ebselen, ecabapid, ecabet, ecadotril, ecdysterone, exetin N, exostatin, iodide ecothiophate, eclanamine maleate, eclazolate Ecomustine, Econazole, Ectainacidine 722, Edaravone, Edatrexate ederfosine, ediphorone acetate, edbacomab, edoxdin, edrecolomab, chloride Edrophonium, edroxyprogesteone acetate, ephe Gatran, eflornithine, efonidipine, egualcen, erantrin, e Leatonin, Elemen, Eletriptan, Ergodipine, Eribrozil, E Lusamitolucin, eltenae, elcaine, emalkalim, emeda Stine, emetine hydrochloride, emiglitate, emylium tosylate, emiteflu, emocta Kin, empagliflozin, enadrine hydrochloride, enalapril, enalaprilat, enal Kiren, Enazadrem, Ensiplat, Endralazine Mesylate, Endrithone, En Flurane, englitazone, enilconazole, enisoprost, enrimomab, enro Platin, Enofalast, Enolicum sodium, Enoxacin, Enoxacin, Enox Xaparin sodium, enoxaparin sodium, enoxymon, empyroline phosphate Emprophylline, Empromart, Entacapone, Enterostatin, Enviraden Enviroxime, ephedrine, epicillin, epimestrol, epinephrine, pho Epinephryl borate, epipropidine, epirizole, epirubicin, Epitetracycline hydrochloride, epithiazide, epoetin α, epoetin β, epoplos Tenol, epoprostenol sodium, epoxymexlenone, epristeride, Prosartan, Eptastigmine, Equirenin, Equilin, Elbrozole, Eldoste In, ergoloid mesylate, ergonovine maleate, ergotamine tartrate, erce Ntilide, Elsofermin, Erythritol, Erythrityl tetranitrate, Erythromycin esmolol hydrochloride, esorubicin hydrochloride, esproquine hydrochloride, estazolam, es Estraziol, estramustine, estramustine analog, estradiol bromide Estriol, estroflate, estrogen agonist, estrogen Streptagonist, estrogen, conjugated estrogen, esterified estrone, estropi Pate, Espron, Etaphedrine hydrochloride, Etanidazole, Ethanterol, Etalo Ten, ethazolate hydrochloride, eterovalvulb, etasidine, sodium ethacrylate, eth Cryophosphate, ethambutol hydrochloride, etamiban, ethanolamine oleate, s- Florbinol (Ethehlorvynol), ether, ethinylestradiol, ethiodide Ethionamide, Ethinamide, Ethonamide nitrate, Etopropazine hydrochloride, Ethosuximide, Etho In, etoxazene hydrochloride, etibenzutropine, ethyl chloride, dibnate ethyl, eti Luestrenol, Ethindiol, Ethinerone, Ethinodiol diacetate, Ethibendazo Etidocaine, Etidronate disodium, Etidronic acid, Etiphenine, Ethin Tidine hydrochloride, etizolam, etodolac, etofenamate, etformin hydrochloride, eto Midart, etonogestrel, etoperidone hydrochloride, etoposide, etopurine, etoxa Drol hydrochloride, etozolin, etravamine, etretinate, etryptamine acetate, yu - Catropine hydrochloride, eugenol, euprosin hydrochloride, ebeminocycline, exam Tadzim, Examorelin, Exaprolol hydrochloride, Exemestane, Fadrozol, Feriefungin, famciclovir, famotidine, fanprizine, fantofalo Phantridone hydrochloride, faropenem, facidotril, fasudil, fazarabine , Fedotodin, Felbamart, Felbinac, Felodipine, Felypressin, Fe Nalamide, phenamol, fenbendazole, fenbufen, phencibutyrol, Fenclofenac, Fenclonin, Fenchlorac, Fendosar, Fenestre Lu, phenetine hydrochloride, fenfluramine hydrochloride, fengabine, phenimide, pheni Solex, fenmethozol hydrochloride, fenmethramide, phenobam, phenoctymic acid Fenofibrate, phenoldopam, fenoprofen, fenoterol, fe Npipalone, fenprinast hydrochloride, fenprostalen, fenkizone, fenreti Nido, fenspirid, fentanyl citrate, fentiazac, fenticlor, f Enchiconazole, phenilipol hydrochloride, feprazino, felpiphosate sodium Um, ferristen, ferrixan, ferrous sulfate (dried), fermoxides, Fermoxil, fethoxylate hydrochloride, fexofenadine, fezolamine fumarate , Fiacitabine, Fiallysine, Fibrinogen I-125, Filgrastim, Fili Pin, finasteride, flavodilol maleate, flavopyridol, flavoxate Hydrochloride, flazalone, flecainide, flerobuterol, fleroxacin, fresinoxa Frobufen, Frocatefen Nin, flomoxef, flordipine, florfenicol, florifenin, flosatid Lu, Furosekinan, Floxacillin, Furoxuridine, Fluasterone, Fluazacillin Fluvanillate hydrochloride, flubendazole, flucindol, fluchloronide, flu Conazole, flucytosine, fludaranine, fludarabine phosphate, fludazonium chloride, Fludeoxyglucose F-18, Fludrex, Fludrocortisone acetate, Flufenamic acid Fluphenisal, Flumazenil, Flumesinol, Flumequin, Flumeridone, Flu Metasone, flumetramide, flumezapine, fluminorex, flumizole, flumoxo Nido, flunarizine, flunidazole, flunisolide, flunitrazepam, flunixine , fluocalcitriol, fluocinolone acetonide, fluocinonide, fluocorti Fluorobutyl, Fluorocortone, Fluorescein, Fluorodaunornicin nicin hydrochloride, fluorodopa F-18, fluorometholone, fluorouracil, fluotrace Hydrochloride, fluoxetine, fluoxymesterone, fluparoxane, fluperamide, vinegar Fluperolone acid, fluphenazine decanoate, flupirtin, fluprednisolone, flup Loquazon, Fluprostenol sodium, Fluquazon, Fluradrine hydrochloride, Flu Landrenolide, flurazepam hydrochloride, flurbiprofen, fluretofen, fluris Romycin, flurocitabine, flurofamide, flurogestone acetate, flurotil, flu Loxen, fluspiperone, fluspiren, 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 Dimegiumine, gadoteric acid, gadoteride Galantamine, Galantamine, Galantamine hydrochloride, Galantamine Lamintriethiozide, gallium nitrate, gallopamil, gallocitabine, gunfexin, ga Morenic acid, ganciclovir, ganirelix, gelatinase inhibitors, gemcadiol, gem Cytabine, Gemprost, Gemfibrozil, Gentamicin sulfate, Gentian Bio Lett, Gepilone, Gestaclon, Gestodene, Gestonolone caproate, Gestrinone Gevotrolin hydrochloride, gilysopam, graspimod, glaucocalyxin A, gremance Phosphorus, gliamilide, glybornuride, sodium glycetanyl, glyflumid, glyme Pyramide, glipizide, gloximonam, glucagon, glutapyrone, glutathione inhibitors , glutethimide, glybride, glycopine, glycopril, glycopyrrolate, glychexyl Samide, Glimidine sodium, Glyoctamide, Glyparamid, Gold Au-198, Gonadoct Linine (gonadoctrinins), gonadorelin, gonadotropin, goserelin, gramicidin Granisetron, grepafloxacin, griseofulvin, guaiapat, guatiline, Guanabenz, guanabenz acetate, guanadrel sulfate, guancidin, guanethidine Sulfates, guanfacine hydrochloride, guanisoquine sulfate, guanochlor sulfate, guanochlor Zinc hydrochloride, guanoxabenz, guanoxane sulfate, guanoxyfen sulfate, guspe Limus trihydrochloride, halazepam, halcinonide, halichondrin B, halobetamine propionate Zol, halofantrin, halofantrin hydrochloride, halofenate, halofdinone odor Hydrogenated salts, halomones, halopemide, haloperidol, halopredone, haloprogesterone Haloprozin, Halothan, Haloquinol, Hamycin, Human (Han) Menopausal Gonadotropin Pin, Hatoma Sewing Machine, Hatoma Begin A, Hatoma Begin B, Hatoma Begin C, Hatoma Begin D, heparin sodium, hepsulfame, heregulin, hetacillin, heterobromide nium, hexachlorophene: hydrogen peroxide, hexafluorenium bromide, hexamethylene Bisacetamide, hexedine, hexobenzine, hexoprenaline sulfate, hexylure Zolcinol, histamine phosphate, histidine, histoplasmin, histrelin, ho Matropin hydrobromide, foxidyl hydrochloride, human chorionic gonadotropin, hycanthone, hi Dralazine hydrochloride, hydralazine polystyrene, hydrochlorothiazide, hydrocod Hydrocortisone, hydroflumethiazide, hydromorphone hydrochloride, Hydroxyamphetamine hydrobromide, hydroxychloroquine sulfate, hydroxyamphetamine Namet, hydroxyprogesterone caproate, hydroxyurea, hydroxyzine hydrochloride Salt, hymechromone, hyoscyamine, hypericin, ivafloxacin, ibandronate, Ibogaine, Ivopamin, Ibudilast, Ibufenac, Ibuprofen, Ibu fumarate Chilid, Icatibant acetate, Ichthammol, Icotidine, Idarubicin, Idoxyfe Idoxuridine, Idramanthon, Remefloxacin, Lesopitol Iesopitron, Ifetroban, Ifosfamide, Ilepeimide, Ilima Quinone (illimaquinone), irmofosine, ilomastat, ilonidap, iloperidone, Iloprost, Imafen hydrochloride, Imazodane hydrochloride, Imidapril, Imidazenin Midazoacridone, Imidecyliodine, Imidocarb hydrochloride, Imidolin hydrochloride, Imid Urea, imiloxane hydrochloride, imipenem, imipramine hydrochloride, imiquimod, immunostimulant Butid, impromidine hydrochloride, indacrinone, indapamide, indecinide hydrochloride Inderoxaji Indigotine hydrochloride, indigotine disulfate sodium, indinavir, indocyanine green, Indorapril hydrochloride, Indolidan, Indomethacin, Indomethacin sodium, Indomethacin Doprofen, indramin, indolenate hydrochloride, indoxol, indoliline salt Salts, inocoteron, inogatoran, inorimomab, inositol nicotinate, insulin N, interferon, interleukin, intrazole, intriptyline hydrochloride, Iobenguan, Iobenzam acid, Iobitridol, Iocalmic acid meglumine, Ioc Lum acid, iodamide, iodine, iodipamide meglumine, iodixano Iodamiloride, Iodoantipyrine I-131, Ioditol Cholesterol I-131, Iodine Dodoxorubicin, Iodohippurate sodium I-131, Iodopiracet I-125, Iodoquinol Lu, iodoxamic acid meglumine, iodoxamic acid, ioglycic acid, hydrochloric acid Iofetamine I-123, Iofrator, Ioglucol, Ioglucomid, Ioglica Muic acid, yoglamide, iohexol, iomeprole, iometine I-125, iopamide Iopanoic acid, iopentolic acid, iofendilate, ioprosemic acid, iopromyl Iopronic acid, iopidol, iopidone, iopyrrol, iocefam Acids, ioceric acid, ioslamide meglumine, iosmethic acid, iotasul, iotetolic acid, Sodium iotalamate, iotalamic acid, iotriside, iotrolan, iotroxic acid Iotyrosine I-131, Ioversol, Ioxagiate sodium, Io Meglumine xaglucate, ioxaglucate, ioxiran, ioxotrizoic acid, ipazylide Ipenoxazone, ipidacrine, calcium ipodate, 4-ipomeanol, ipra bromide Tropium, ipriflavone, iprindol, iprofenin, ipronidazole, i Proplatin, iproxamine hydrochloride, ipsapirone, irbesartan, irinotecan, Illoxacin, Iroplact, Ilsogladine, Iltemazole, Isalus Thein, isamoxol, isvogrel, isepamycin, isobengazole ole), isobutamen, isocarboxazide, isoconazole, isoetalin, isoflo Xitepine, isoflupredone acetate, isoflurane, isoflurofate, isohomohali Chondrin (isohomohalicondrin) B, isoleucine, isomazole hydrochloride, isomiramine Hydrochloride, isoniazid, isopropamide iodide, isopropyl alcohol, isopropyl Unoprostone, isoproterenol hydrochloride, isosorbide, isosorbide mononitrate, iso Thiquimid, isotretinoin, isoxepac, isoxicam, isoxuprine hydrochloride, i Sladipine, Itamelin, Itasetron, Itazigrel, Itopride, Itraconazole Ivermectin, Jaspraquinolide, Josamycin, Kahalalide F, Calafungin Kanamycin sulfate, ketamine hydrochloride, ketanserin, ketazocine, ketazolam, keto Xar, ketipramine fumarate, ketoconazole, ketoprofen, ketorphano Lu, Ketrolac, Ketotifen fumarate, Kitasamycin, Labetalol hydrochloride, Laci Dipine, Lasidipine, Lactitol, Lactibicin, Lacosamide, Laennec, Lafuchi Zin, lamelalin-N-triacetate, lamifibane, lamivudine, lamotrigine, lano Conazole, Lanoxine, Lamperison, Lanreotide, Lansoprazole, Latanopro Sto, lateritin, laurocapram, lauryl bromide isoquinoline, lavoltidine succinate Lazabemide, resimipide, raynamycin, remildipine, reminoprazole, Renel Sept, Renikinsin, Lenograstim, Lenperone, Lentinan sulfate, Leptin, Leptin Tolstatin, relcanidipine, relgotril, rerisetron, retimid hydrochloride, Letra Zuril, letrozole, leucine, leucomycin, leuprolide acetate, leuprolide +Estrogen +Progesterone, Leuprorelin, Levanfetamine succinate, Levanfetamine Sole, levodobutamine lactobionic acid, Leveromakalim, Levetirace Tam, Leveycloserine, Levobetaxolol, Levobunolol, Le Bobpivacaine, levocabastine, levocarnitine, levodopa, levodropropidine, Bofloxacin, levoflartadone, levoleucovorin calcium, levometadil acetate, Levometadil acetate hydrochloride, levomoprolol, levonantradol hydrochloride, levonordef Phosphorus, levonorgestrel, levopropoxyfen napsylate, levopropyl silicone Lilium, levolmeroxifen, levorphanol tartrate, levocimendan, levosul Pyrido, levothyroxine sodium, leboxadrol hydrochloride, lexipaphant, lexi Cisromycin, Rialozol, Ribenzapril, Ridamidine hydrochloride, Lidocaine, Lido Fenin, lidoflazin, rifadin, rifibrate, rifibrol, linalotene Lincomycin, linear polyamine analogs, linoglylide, linopyridine, linotro Ban, Lincidomin, Lincitrypto, Lintoprid, Liothyronine I-125, Liothyronine Sodium, Riotrix, Rilexapride, Lisinopril, Lisoclinamide 7, Lixazinone sulfate, lobaplatin, lobenzalit sodium, lobucavir, roderaben , rhodoxamide, lofemizole hydrochloride, lofentanil oxalate, lofe Pramine hydrochloride, lofexidine hydrochloride, rombrisin, lomefloxacin, lomerizine , lometraline hydrochloride, lometrexol, lomofungin, romoxicam, lomustine, Lonaparen, lonazolac, lonidamin, loperamide hydrochloride, loracalbef, loradumine Hydrochloride, loratadine, lorazepam, lorvamart, lorcainide hydrochloride, lorecresol Loreinadol, lorglumide, lormetazepam, lornoxicam, lor Noxicam, Lortalamine, Lorzafone, Losartan, Rosigamon, Rosoxantrone, Rosladine hydrochloride, loteprednol, lovastatin, rovirid, roxapine, loxor Bin, ruberzol, rucanton hydrochloride, ruphylonil, lurosetron mesylate, lulutote Can, luteinizing hormone, lurasidone, lutetium, luterelin acetate, rudindol, li Apolate sodium, lycetamin, ridicamycin, ridimycin, linestrenol Repressin, lysine, lysophyllin, lysostafin, soluble peptide, Maduramai Syn, mafenide, magainin 2-amide, magnesium salicylate, magnesium sulfate, Magnolol, Mytansine, Maletamer, Malotochromene, Malotojaponin, Malochi Laat, Marochilate, Mangahodipil, Manidipine, Maniwamycin A, Mannitol Mannostatin A, Manumycin E, Manumycin F, Mapinastine, Maprotiline, Ma Remastered, Martek 8708, Martek 92211, Masoprocol, Masupin, Massetrid Matrilicin inhibitors, Mytansin, Mazapertine succinate mazindol, mebendazole, mebeberine hydrochloride, mebrophenin, mebutamate, Mecamillamine hydrochloride, mechloretamine hydrochloride, meclocycline, sodium meclofenamate Rium, Mecrocalon, Mechlorison dibutyrate, Medazepam hydrochloride, Medrinone, Med Logeston, medroxalol, medroxyprogesterone, medrison, meridin (M eelizine hydrochloride, mefenamic acid, mefenidyl, mefenorex hydrochloride, mefexamide Mefloquine hydrochloride, mefluside, megalomycin potassium phosphate, megestin acetate Trol, Meglumine, Meglutol, Melengestrol acetate, Melitracene hydrochloride, Melphalan, Memotin hydrochloride, Menavitan hydrochloride, Menoctone, Menogalil, Menotro Pin, meobenzine sulfate, mepaltricin, mepenzolate bromide, meperidine hydrochloride, me Phentermine sulfate, mephenyloin, mefobarbital, mepivaca Inohydrochloride, meprobamate, meptadinol hydrochloride, mekidox, melain sodium Mercuron, mercaptopurine, merck phenol chloride, mercury sulfate, melisoprose Hg-197, meropenem, mesalamine, mesecrazone, mesolidazine, mesterone, mesalamine Tranole, Mespurine hydrochloride, Metarol hydrochloride, Metaproterenol Polystylec S, metalaminol bitartrate, metaxalon, meteneprost, meterelin, methor Min, methacholine chloride, metacycline, methadone hydrochloride, methazyl acetate, methazyl methadone Methamphetamine hydrochloride, metacalon, metazolamide, methidilazine, methenamine, Metenolone acetate, metetoin, methicillin sodium, methimazole, methioninase, Methionine, methisazone, methixene hydrochloride, methocarbamol, methhexita sodium Rium, metforin, methotrexate, methotrimeprazine, methoxatone (methoxa tone), methoxyflurane, methosuximide, meticlothiazide, methyl palmoxylate Methylatropine nitrate, methylbenzethonium chloride, methyldopa, methyldopa hydrochloride, Chilen blue, methylergonovine maleate, R-α-methylhistamine, methyl iodine Synmonophosphate, methylphenidate hydrochloride, methylprednisolone, methyltes Tosterone, methinodiol diacetate, methyserzide, methyserzide maleate, methiami D, Methiapine, Methioprim, Methipamide, Metipranolol, Metizoline hydrochloride, Vinegar Methcefamide acid, metoclopramide, methocrine iodide, metogest, metrazone, Topimazine, Metoprine, Metoprolol, Methoxine, Metrifonate, Metrizamide Sodium metrizoate, metronidazole, metsuredepa, metyrapone, methyrosine, Xiletine hydrochloride, potassium mexrenoate, mezlocillin, mufonelic acid ), Mianserin hydrochloride, Mibeflazil, Mibeflazil dihydrochloride, Miboleron, Mikelamy N B, miconazole, microcholine A, midaflul, midazolam hydrochloride, midodrine, mif epristone, mihobart, miglitol, mirasemide, miramelin, mildronate, Mylenperon, myripertine, myrnacipran, myrlinone, myrtefosine, mimban salt Salts, minaprin, minaxolone, minoclomil, minocycline, minoxidil, myo Flazin hydrochloride, myokamycin, mipragoside, milfentanil, mirimostim, mi Linkamycin hydrochloride, myrisetron maleate, mirtazapine, mismatch double-stranded RNA Misonidazole, misoprostol, mitindomide, mitocalcin, mitocromin, mi Togiline, Mitoguazone, Mitractol, Mitomarcin, Mitomycin, Mitonaf Do, Mitospel, Mitotan, Mitoxantrone, Mibacrylium chloride, Mivazerol, Miki Sanpril, Mixidine, Mizolastine, Mizoribine, Moclobemide, Modafinil, Sulfur Modalin acid, modicainide, moexipril, mophalotene, mofegiline hydrochloride, mof Ezorak, Morglamostim, Morinazon, Morindone hydrochloride, Morcidomin, Mometazon Monatepyr maleate, monensin, monoctanoin, montelukast sodium, Montilelin, Mopidamol, Moracidine, Morantel Tartrate, Moricidine, Morniful Mart, morphine sulfate, sodium molinate, mosapramine, mosapride, motilide, Motoretinide, Moxalactam disodium, Moxazosin, Moxylaprin, Moxni Dazole, moxonidine, mumps skin test antigen, mustard anticancer drug, muzolim N, Micaperoxide B, Mycophenolic acid, Miriapolon, Nabazenil, Navilon, Na Vitan hydrochloride, Naboctart hydrochloride, Nabumetone, N-acetyldinaline, Nadide, Nadi Floxacin, Nadolol, Nadropalin Calcium, Nafadotolid, Nafamostat Nafarelin, Nafcillin sodium, Nafenopine, Nafimidone hydrochloride, Naflo Colt, Nahomine malate, Nafoxidine hydrochloride, Naflonyl oxalate, Naphthifine salt Salts, naphtopidil, Nagrivan, Nagrestip, Nalbufine hydrochloride, Naldemedine, Nalidic Sodium phosphate, nalidixic acid, nalmefene, nalmexone hydrochloride, naloxone + penetrant Tazosin, naltrexone, napoxylate, fenpropionate nandrolone, nanto Radol hydrochloride, napactadine hydrochloride, napadisyl acids, napamezole hydrochloride, napabi Napaviin, naphazoline hydrochloride, naphterpine, naproxen, naproxol, Psagatran, naranol hydrochloride, naracin, naratriptan, naltograstim, NASA Luprase, Natamycin, Nateplase, Naxagolide hydrochloride, Nebibolol, Nebula Mycin, Nedaplatin, Nedocromil, Nefazodone hydrochloride, Neflumodide hydrochloride, Ne Hopam hydrochloride, nerezaprine maleate, nemazoline hydrochloride, nemorubicin, palmitin Neomycin acid, neostigmine bromide, neridronic acid, netylmycin sulfate, neutral endothelial acid Peptidase, Neutramycin, Nevirapine, Nexeridine hydrochloride, Niacin, Nib Roxan, nicardipine hydrochloride, nicergoline, niclosamide, nicorandil, nicotinide Alcohol, nifedipine, nifirmerone, niflulidide, niflade Niflardezone, Niflatel, Nifltron, Nifludazil, Niflmid, Niflup Linoleic acid, nifluquinazole, nifluthiazole, nitamide, nilvadipine, nimazon Nimodipine, niperotidine, niborin, niridazole, nisamycin, mesylate varnish Buterol, Nisin, Nisobamat, Nisoldipine, Nisoxetine, Nisterim Acetate, Nitalson, nitazoxamide, nitecapone, nitrafdam hydrochloride, nitrafdam Lamin hydrochloride, nitramisol hydrochloride, nitrazepam, nitrendipine, nitrocycline Nitrodan, Nitrofurantoin, Nitrofurazone, Nitroglycerin, Nitromel Sole, nitromide, nitromiphene citrate, nitrous oxide, nitrogen oxide antioxidant, nitrite Nitrallyn, Nivazole, Nibimedone sodium, Nizatidine, Novelastine Nocodazole, Nogaramycin, Norinium bromide, Nomifensin maleate, Noracin Mesadol hydrochloride, norboreton, norepinephrine bitartrate, norethindrone, Norethinodrel, norfloxacin, norflurane, norgestimate, norgestimate T, norgestrel, nortriptyline hydrochloride, noscapine, novobiocin sodium, N-substituted benzimide, nufenoxol, nilestriol, nystatin, O6 benz Luguanine, ovidoxime chloride, ocaperidone, ocfentanil hydrochloride, osinapron Octanoic acid, octazamide, octenidine hydrochloride, octodrine, octreotide, li Octriptyline phosphate, ofloxacin, Oformine, oxenone, oran Zapine, oligonucleotides, olopatadine, olprinone, olsalazine, olsalazi Sodium, olbanil, omeprazole, onapristone, ondansetron, on Tazolast, oocyte maturation inhibitors, opipramol hydrochloride, oracin, orconazol nitrate Orgotine, Orlistat, Ormaplatin, Olmetprim, Ornidazole Orpanoxin, Orphenadine, Osateron, Otenzepad, Oxacin Sodium phosphate, oxagrelate, oxaliplatin, oxamarin hydrochloride, oxam Sole, oxamnichine, oxandrolone, oxantel pamoate, oxaprotiline salt Salts, oxaprozin, oxalvazole, oxatomide, oxaunomycin, ox Zepam, oxcarbazepine, oxendrone, oxethazaine, oxetron fumarate Oxfendazole, oxphenicin, oxybendazole, oxiconazole, Oxidopamine, oxidronic acid, oxyfungin hydrochloride, oxilorphan, oximo Nam, Oxymonam sodium, Oxyperomide, Oxyracetam, Oxylamide, Oxy Cislan, oxmethidine hydrochloride, oxodipine, fenpropionate oxogestone, Oxolinic acid, oxprenolol hydrochloride, oxtriffine, oxybutynin chloride, Oxychlorocene, oxycodone, oxymetazoline hydrochloride, oxymetholone, oxymo Lufone hydrochloride, oxypertin, oxyfenbutazone, oxyprinol, oxyte Tracycline, oxytocin, ozagrel, ozolinone, paclitaxel, parauami Palimycin, palinavir, palmitoyl lyzoxin, sodium palmoxylate Pamequesid, Pamatorol sulfate, Pamicogrel, Disodium pamidronate, Pami Panadipronate, Panamesin, Panoxytriol, Pancoprid, Panchlorobromide Nium, Panipenem, Pannoline, Panomiphene, Pantethine, Pantoprazole, Papa Verine hydrochloride, parabactin, parachlorophenol, paraaldehyde, parametazone acetate Paraniline hydrochloride, parabenzolate bromide, pararosaniline pamoate, parabendazolate Palconazole hydrochloride, Paregoric, Paleptide sulfate, Pargiline hydrochloride, Pal Naparin sodium, paramomycin sulfate, paroxetine, parthenolide, patricin , paulomycin, pazeriptin, padinacron, pazoxide, pazufloxacin, peph Roxacin, pegaspargase, pegolgotine, perancerin hydrochloride, perdesine, pe Liomycin, Perretin, Perlinone hydrochloride, Pemedrac, Pemerido nitrate, Pemiro Pemolin, Penamecillin, Penbutrol sulfate, Penciclovir, Penflulid Penicillin G benzathine, Penicillin G potassium, Penicillin G procaine, Penicillin Phosphorus G sodium, penicillin V, penicillin V benzathine, penicillin V hydravamin, penicillin Nishirin V potassium, pentabamate, pentaerythritol tetranitrate, pentafuside (pent afuside, pentamidine, pentamorphone, pentamustine, pentapiperium methylsulfate Pentazocine, pentetate, pentiapine maleate, pentigetide, pentisomycete Penthizidone sodium, pentobarbital, pentomon, pentopril, pento Sun, Pentostatin, Pentoxifylline, Pentrinitrol, Pentrozole (pen trozole), pepromycin sulfate, pepstatin, perflubron, perphofamide (per fofamide, perphosphamide, pergolide, perhexylline maleate, perirylal Cole, perindopril, perindoprilat, perlapine, permethrin, perospirone Perphenazine, phenasemide, phenaridine, phenazinomycin, phenazopyridine Fenbutazone hydrochloride, fenbutazone sodium glycerate, fencarbamide, fencyclide Fendimethrazine hydrochloride, fendimethrazine tartrate, phenelzine sulfate, fendimethrazine hydrochloride Phenobarbital, phenoxybenzamine hydrochloride, fenprocum, fenceli Phensuccinal, Phenximide, Phentermine, Pentet Lumin hydrochloride, phentolamine mesylate, phentoxifylline Phenyl aminosalicylate, phenyl acetate, phenylalanine, phenylalanyl ketocopherol Nazol, phenylbutazone, phenylephrine hydrochloride, phenylpropanolamine hydrochloride Phenylpropanolamine polystyrene, pheniramidol hydrochloride, pheniloin (phenyloin), phosphatase inhibitors, physostigmine, picenadol, picibanil picotrin diolamine, picrolibu, picmeterol, pidotimod, pifam ine), pilocarpine, pilsicainide, pimagedin, pimetine hydrochloride, pimiprost, Pimobendan, pimozide, pinacidyl, pinadrine, pindolol, pinenol l) Pinocebrin, pinoxepine hydrochloride, pioglitazone, pipemperone, Pipazetate, pipecuronium bromide, piperacetazine, piperacillin sodium, Murray Piperamide acetate, piperazine, pipobromane, piposulfan, pipothiazine palmitate Pipoxolane hydrochloride, Piprozoline, Pikindone hydrochloride, Pikidyl hydrochloride, Piraceta Pyramidamine hydrochloride, pirarubicin, pyrazmonam sodium, pyrazolac, pirubin Nishirin sodium, pyrbuterol acetate, pyrenperone, pirenzepine hydrochloride, Pyreta Pyretamide, pirfenidone, pyridicillin sodium, pyridronate sodium Pyriprost, pyritrexime, pirrimycin hydrochloride, pyrrindol, pirmag Rel, pirmenol hydrochloride, pirunabin, piroctone, pirodavir, pirodomast, piro Glylid tartrate, pyrolate, pyrorazamide, piroxantrone hydrochloride, piroxicam Pyroximon, Pilprofen, Pilquinozol, Pilcidomin, Preniramine, Ptosis Posterior lobe (pituitary), pivampicillin hydrochloride, pivopril, pizoticin, pla Cetin A, platinum compounds, platinum-triamine complexes, plicamycin, promethane, povilka Stoedamine, Podophyllox, Urushi extract, Polzin methylsulfate, Polyglucum, Polygnate sodium, polymyxin B sulfate, polythiazide, Narrestat, porfimer sodium, porphyromycin, potassium chloride, iodide Potassium, potassium permanganate, povidone-iodine, pralitol, pralidoxy chloride Pramiracetam hydrochloride, Pramoxin hydrochloride, Planolium chloride, Praba maleate Drin, pravastatin (pravacol), prazepam, prazosin, prazosin hydrochloride, Prednazate, Prednicalvert, Prednimustine, Prednisolone, Prednizo Prednival, Pregnenolone Succiniate, Prenalte Rol hydrochloride, Pridefin hydrochloride, Priferon, Prilocalne hydrochloride, Prilosec, Primaquine phosphate, Primidrol, Primidone, Prinivir, Prino Midotromethamine, Prinoxodane, Prizidilol hydrochloride, Proadifen hydrochloride, Robenecid, Proviclomil calcium, Probucol, Procainamide hydrochloride, Pro Caine hydrochloride, procarbazine hydrochloride, procaterol hydrochloride, prochlorperazine, pr Rocinonide, Proclonol, Procyclizine hydrochloride, Prozirizine hydrochloride, Prodol Acid, Profadol hydrochloride, Progavid, Progesterone, Proglumide, Human Proine Sulin, proline, prolinetan hydrochloride, promazine hydrochloride, promethazine hydrochloride, pro Pafenone hydrochloride, propagermanium, propanizide, propantheline bromide, propara Caine hydrochloride, propatil nitrate, propentophilin, propenzolate hydrochloride, prop Casin, propiomazine, propionic acid, L-propionylcarnitine, propylam, pro Pyram + paracetamol, propiverine, propofol, propoxycaine hydrochloride, Lopoxifen hydrochloride, propranolol hydrochloride, propalside, propylbis-acrylate Don, propylhexedrin, propyliodone, propylthiouracil, proquazone, Prolenoart potassium, proloxane hydrochloride, proscillaridine, prostalen, pro Stratin, protamine sulfate, protegurin, protirelin, protosufloxacin, Protriptyline hydrochloride, Proxazole, Proxazole citrate, Proxichromil , proxolphan tartrate, prulifloxacin, pseudoephedrine hydrochloride, purulifloxacin Roromycin, purpurin, pyrabrom, pyrantel pamoate, pyrazinamide, pyrazof Phosphorus, pyrazoloacridine, pyridostigmine bromide, pyriramine maleate, pyrimethamine Pyrinolin, pyrithione sodium, pyrithione zinc, pyrovalerone hydrochloride, Murray Pyroxamine phosphate, pirocaine, pyrrolephene hydrochloride, pyrrolnitrin, pyrbiate Nium, quadazosine mesylate, quazepam, quadinone, quazodin, quazolast, Quetiapine, quiflapon, quinagolide, quinaldine blue, quinapril, quinapril , quinazosine hydrochloride, quinboron, quinctolate, quindecamine acetate, Kindniwol bromide Mu, quinerolan hydrochloride, kinestrol, quinfamide, kingestanol acetate, kinge Stron, quinidine gluconate, quinielorane hydrochloride, quinoline Nine sulfate, quinpyrrole hydrochloride, quinterenol sulfate, quinucrine bromide, quinup Listin, kypazine maleate, rabeprazole sodium, racefenicol, race Pinephrine, Raf antagonist, rafoxamide, laritrin, raloxy Fen, Larcitrexed, Ramatroban, Ramipril, Lamoplanin, Ramosetron, Raneric acid, ranimycin, ranitidine, lanolazine, Indian snakewood, lecainum, leca hydrochloride Inam, leclazepam, regavirumab, reglamostim, relaxin, reromycin, le Masemide hydrochloride, remifentanil hydrochloride, remiprostol, remoxiprid, repiri Nast, Repromycin, Reproterol hydrochloride, Reserpine, Resinferatoxin (r Esinferatoxin, resorcinol, demethylated reteliptin, reticulone, reviparin Thorium, Levidinone, Rhenium Re-186 etidronic acid, Ryzoxin, Ribaminol, Riba Biline, Ribopurine, Ribozyme, Ricasetron, Lidogrel, Rifabutin, Rifamet Tan, rifamexil, rifamid, rifampin, rifapentin, rifaximin, RII retinamide, rilopirox, riluzole, rimantadine, limukasol hydrochloride, ri Mexolone, Limiterol hydrobromide, Rimoprogin, Riodipine, Rioprostil, Lipazepam, lipisartan, risedronate sodium, risedronate, lysocine, lyso Tirid hydrochloride, rispenzepine, risperdal, risperidone, ritanserin, lichipene Mu, ritodrine, litocust, ritonavir, rizatriptan benzoate, locastine salt Salts, rocuronium bromide, rhodocaine, loflurane, logretimide, rohitzkin, rokita Mycin, loretamicide, lorgamidin, loriciprine, loripram, ro Retetracycline, lorodine, lomazalit, lomultide, lonidazole, ropinillol Ropitoin hydrochloride, ropivacaine, lopidine, lokinimex, rosalamycin, rosin Glitazone, loxoxacin, rotoxamine, roxaitidine, roxalso Roxindol, Roxithromycin, Rubiginone B1, Ruboxil, Rufloxacin Rupatidine, rutamycin, luzadran, saberzole, safinol Safinol, Cyntopine, Salbutamol, R-Sarcorex, Saletamine maleate Salicylic acid, salicyl alcohol, salicylamide, salicylic acid meglumine, salicylic acid, salme Terol, Salnacediin, Salsalat, Samezin, Sanpatrilat Sancyclin, Sanfetolinem, Sanguinalium chloride, Saperconazole, Sap Risartan, sapropterin, saquinavir, salafloxacin hydrochloride, salalacin acetate SarCNU, Sarcophytol A, Salglamostim, Salmoxicillin, Salpicillin Sarpogrelate, salplase, saterinone, satigrel, satumomab pentetide, cy Control drugs for the test: scopafungin, scopolamine hydrobromide, scrazypine (scraz aipine hydrochloride, Sdi 1 mimoid, secalciferol, secobarbital, silzone (See Izone, seglycide acetate, selegiline, selegiline hydrochloride, selenium sulfide, selenomethionine Se 75, Cellhotel, Sematilide, Sendulamycin, Semothiazil, Semustine, Sense oligonucleotides, sepazonium chloride, seperidol hydrochloride, seprilose, se Proxetine hydrochloride, ceractide acetate, cergolexol maleate, serine, cermeta Syn, cermorelin acetate, certaconazole, certindol, sertraline, setiput Phosphorus, Cetoperone, Sevilumab, Sevoflurane, Cezoramide, Cibopyridine, Sibutramide cin hydrochloride, signaling inhibitors, silandrone, silipide, silteplase, silver nitrate, sil Mendan, simtrazene, simvastatin, cinkalid, synefungin, cynitrodil, Sinnabidol, sipatrigine, sirolimus, shisomycin, citglucid , schizophyllan, sobuzoxane, sodium amylosulfate, sodium iodide I-123, nitrite Sodium ropruside, sodium oxybate, sodium phenylacetate, salicylic acid Sodium, sorbol, solipertine tartrate, somarapol, somantadi Somatomedin hydrochloride, somatomedin B, somatomedin C, somatorem, somatropin, somenopol, so Somidobov, Sonelmin, Sorbinyl, Sorivudine, Sotalol, Soterenol Sparfloxacin hydrochloride, Sparfosate sodium, Sparfosic acid, Sparsomy Syn, spartein sulfate, spectinomycin hydrochloride, spicamycin D, spiperone , spiradrine mesylate, spiramycin, spirapril hydrochloride, spiraprilat, spi Germanium hydrochloride, spiromustine, spironolactone, spiroplatin, spiroxine Sason, Suprenopentin, Spongistatin 1, Suprodiamide, Squalamine, Sta Rimycin hydrochloride, stannous pyrophosphate, tin sulfur colloid, stanozolol, statro Staurosporine, stabuzin, stefimycin, stenboron acetate, stepron N, stilbadium iodide, styronium iodide, stipiamid, styripentol, s Tobazine, streptomycin sulfate, streptonicozide, streptonigrin, str Leptozocin, stromelysin inhibitors, strontium chloride Sr 89, succib un), succinylcholine chloride, succinylcholine, sucralfate, sucrosetocario Mu, sudoxicam, sufentanil, sufothidine, surazepam, sulbactam pivoxil , sulconazole nitrate, sulfabenz, sulfabenzamide, sulfacetamide, Sulfacitin, sulfadiazine, sulfadoxine, sulfarene, sulfamella Sulfamethazine, sulfamethizol, sulfamethoxazole Sulfamonomethoxine, sulfamoxol, zinc sulfanilate, sulfanitrate Sulfasalazine, sulfasomisole, sulfazamethoxazole, sulfinalol hydrochloride Sulfinosine, sulfinpyrazone, sulfisoxazole, sulfomyxin, sul Honterol hydrochloride, sulfoxamine, sulinldac, sulmarin, sulni Dazole, suloctidyl, slofenul, slopenem, thuroxifen oxalate, sulpi Lido, Sulprostone, Sultamicillin, Sultiam, Sultopride, Sulkast, Suma Roten, sumatriptan, suncillin sodium, suprocron, s Profen, suradista, suramin, sulfomer, suricainide maleate , Slitozol, Thronacrine maleate, Sxemellid sulfate, Swinesonin, Shima Kalim (symakalim), symcrocene, cimetine hydrochloride, synthetic glycosaminoglycan, tasi Taciamine hydrochloride, tacrine hydrochloride, tacrolimus, talampicillin hydrochloride, Leranol, talithomycin, talimustine, talmethacin, talniflumart, taro Lam hydrochloride, tarosalate, tametraline hydrochloride, tamoxifen, tampramide fumarate N, tamsulosin hydrochloride, tandamine hydrochloride, tandospirone, tapgen, tap Rosten, tasosartan, tauromustine, taxane, taxoid, tazadren succinate Tazanolast, tazarotene, tadiphylline hydrochloride, tazobactam, tazoferon, tazo Loll hydrochloride, tebuferon, tebuquin, bicisot technetium (Tc)-99m, teclozan Tecogalan sodium, teecleukin, teflurane, tegaflu, tegre Tor, Teicoplanin, Terenzepine, Terrapyrilium, Termestain, Termisa Rutan, telomerase inhibitors, teloxantrone hydrochloride, terdipine hydrochloride, temafloxacin Sacin hydrochloride, tematropium methylsulfate, temazepam, temelastine, temocapril Temocillin, temoporfin, temozolomide, tenidap, teniposide, tenosal, te Noxicam, tepilindol, tepoxalin, teprotide, terazosin, terbinafine Terbutaline sulfate, terconazole, terfenadine, terflavoxate, terug Lido, teriparatide acetate, tellacilene, terlipressin, telodiline, teloxalene Hydrochloride, teroxylone, tertatrol, tecicam, tesimide, testolactone, test Steron, tetracaine, tetrachlorodecaoxide, tetracycline, tetrahydro Zoline hydrochloride, tetramisol hydrochloride, tetrazolast meglumine, tetrazomine, teto Lophosmin, tetroquinone, tetroxoprim, tetridamine, talibrastin, thalidol Myodo, theofibrate, theophylline, thiabendazole, thiamiprine, thiamph Enicol, thiamylal, thiazessim hydrochloride, thiadinamium chloride, thiethylperazine , thimerosal sodium, thimerosal, thiocholalin, thiofedrine ne), thioguanine, thiomarinol, thiopental sodium, thioperamide, thio Ridazine, thiotepa, thiothixen, tifenamil hydrochloride, tifeniclin potassium, Lamb, tozarinone, threonine, thrombin, thrombopoietin, thrombopoietin mimicry Substances: thymalfacin, thymopoietin receptor agonist, thymotrinan, thyromedan hydrochloride Salt, thyroxine I-125, thyroxine I-131, thiacrilast, thiacrilast sodium, Chiagavin, thiamenidine, thianeptin, tiapafant, tiapamil salt Salts, tiaramide hydrochloride, thiazofrine, tibenelast sodium, tiborone, tibrunic acid , ticabesone propionate, ticarbodine, ticacyl cylingresyl sodium, ticlat , ticlopidine, ticlinafen, thienoxolol, tifrac sodium, tigemona Mudicolin, Tigestol, Tiretamine hydrochloride, Tyrizine hydrochloride, Tyrisolol, Tirno Profen albamel, tyrolone hydrochloride, disodium chydronate, chydronate, chydronate, Meflon, thymovesone acetate, timolol, tin ethylethiopropylpurine, tinabinol, thi Midazole, tinzaparin sodium, thioconazole, thiodazocin, thiodniu chloride Thioperidone hydrochloride, thiopinac, thiospirone hydrochloride, thiothidine, thiotropin bromide Pium, thioxidazole, tipentosine hydrochloride, typredan, typrenolol hydrochloride, Chiprinastmeglumine, tipropidil hydrochloride, tiquesid, tikinamide hydrochloride, tilan Darizine, Chirapazamine, Chirilazad, Tyrofiban, Tylopramide, Titanose dichloride N, thixanox, thixocortol pivalate, tizanidine hydrochloride, tobramycin, Kainid, Tocanfil, Tofenacin hydrochloride, Tramolol, Trazamide, Trazoline Hydrochloride, tolbutamide, tolcapone, tolcyclate, tolfamide, tolgavid, lamocrate Trigin, Trimidone, Trindart, Tolmetine, Tolnaftate, Tolpovidone I-13 1. Tolpyramide, Torrestat, Tomerkast, Tomoxetine hydrochloride, Tona Mesylate Zosyn, Topiramate, Topotecan, Topotecan Hydrochloride, Topsentin, Topterone, Quizin, Torasemide, Toremifene, Torsemide, Tosiphen, Tosufloxacin, Allpotent Sex stem cell factor, tracazolate, trafermin, tralonide, tramadol hydrochloride, Ramazoline hydrochloride, trandolapril, tranexamic acid, tranilast, transcaine Translation inhibitors, traxanox, trazodone hydrochloride, trazodone-HCl, trebenzominamine Hydrochloride, trefentanil hydrochloride, treloxinate, trepipam maleate, tre acetate Stron, tretinoin, triacetin, triacetyluridine, triaphungin, tri Amcinolone, triampidine sulfate, triamterene, triazolam, tribenoside, Tricaprylin, Tricetamide, Trichlormethiazide, Trichohyalin, Trisilibine , tricitrate compounds, triclophenolpiperazine, triclophos sodium, tri Chronid, Trien Trifenagrel, Triflavin, Triflosin, Triflubazam, Triflumid Trifluperazine hydrochloride, trifluperidol, triflupromazine, triflupro Mazine hydrochloride, trifluridine, trihexyphenidyl hydrochloride, trilostane, trimazo Syn hydrochloride, trimegestone, trimeprazine tartrate, trimethadione, cansilate Rimetaphan, Trimethobenzamide hydrochloride, Trimethoprim, Trimethodine, Trimeth Lexart, Trimipramine, Trimoprostil, Trimoxamine hydrochloride, Triolein I-125, Triolein I-131, Trioxyfen Mesylate, Tripamide, Triperenamine Salt Salts, triprolidine hydrochloride, triptorelin, trisulfapyrimidine, troclocene Potassium, troglitazone, trolamin, troleandmycin, thrombodipine, 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 Binzolidined sulfate, biprostol, Virginiamycin, pyridofluvin, viroxime Vitaxin, Borazosin, Voriconazole, Borozol, Voxelgolide, Warfari Sodium xanoxate, xamoterol, xanomeline, xanoxate sodium, nicotinic acid Xanthinol, xemerylofiban, xenalipin, xenbusine, xylobam, ximo Profen, xypamide, xolphanol mesylate, xylamidine tosylate, xylamidine Zinc hydrochloride, xylometazoline hydrochloride, xylose, yanganbin, zabisipril, zako Prid, Zafirlukast, Zalcitabine, Zaleplon, Zarospirone, Zaltidine hydrochloride Salt, zaltoprofen, zanamivir, zanquilen, zanoterone, zantac, zariluruka Zarirlukast, Zatebrazine, Zatosetron, Zatosetron maleate, Zenares Tat, zenazosin mesylate, zeniplatin, zeranol, zidomethacin, zidovudine, Diflosylon, Dilantel, Zilascorb, Ziloton, Dimerzine hydrochloride, Undecile Zinc phosphate, zindotrin, dinoconazole hydrochloride, dinostatin, sinterol hydrochloride, Zinviroxime, ziprasidone, Zobolt, zofenopril calcium, zofenopril Noprilat, Zolamine hydrochloride, Zolazepam hydrochloride, Zoledronic acid, Zoreltin hydrochloride, Zo Lumitriptan, zolpidem, zomepirac sodium, zometapine, zonicresol hydrochloride Salt, zonisamide, zopiclone, zopolrestat, zolbamycin, sol It contains bicine hydrochloride, zotepine, and zucapsaicin.

[0113] 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.

[0114] 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 (Tesaglitazal) , 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.

[0115] 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.

[0116] Active ingredients or therapeutic agents for the treatment of headaches and / or migraines are also available for use in this specification. The specific examples of active ingredients are not limited to triptans, such as eletripta. Naratriptan, rizatriptan (rizatriptan benzoate), sumatriptan, and This includes zolmitriptan, etc. In one embodiment, the active ingredient is lyzatriptan. It may be optionally combined with NSAIDs.

[0117] In one embodiment, the pharmaceutically active ingredient is a benzodiazepine, such as diazepam or lorazepam. Mu, midazolam, chlorazepate, temazepam, triazolam, clonazepam, flurazepam Oxazepam, chlordiazepoxide, estazolam, quazepam, or alprazolam Lamb would also be fine.

[0118] (Polymer matrix) This composition may include a polymer matrix. Any desired polymer matrix It can be used as long as it is orally soluble or disintegrable. This dosage form is easily removable. It must have sufficient bioadhesion to prevent condensation and must form a gel-like structure upon administration. These must be moderately soluble in the oral cavity and particularly effective in delivering the active pharmaceutical ingredient. Suitable, but also all of the immediate-release, delayed-release, controlled-release, and sustained-release compositions are also , included in various intended embodiments.

[0119] 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.

[0120] 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. These offer superior advantages and are therefore suitable for bulk production in large quantities. The properties of these polymers, apart from their spherical structure, include abundant functional groups, intramolecular cavities, low viscosity, and They have high solubility. Dendritic polymers have been used in several drug delivery applications. For example, the phrase "Dendrima as a drug carrier," incorporated herein by reference, -: Application of drugs via different routes of administration (Dendrimers as Drug Carriers: Applications in Dif See "Fair Routes of Drug Administration," J Pharm Sci, VOL. 97, 2008, 123-143. I want to be illuminated.

[0121] 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.

[0122] 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.

[0123] Other examples of highly branched polymers include poly(amine), polycarbonate, and poly(etherket). Polyurethane, polycarbosilane, polysiloxane, poly(esteramine), poly( Sulfonamines), poly(urethane urea), and polyether polyols, such as polyglycerides. It contains serine.

[0124] The film is a combination of at least one polymer and a solvent, optionally containing other components. It can be prepared using water, polar organic solvents, or other solvents, though not limited to these. For example, methanol, ethanol, isopropanol, acetone, or any combination thereof. However, that is also acceptable. In some embodiments, the solvent may be a nonpolar organic solvent such as methylene chloride. The film is produced using a selected casting or deposition method and a controlled drying process. It can be manufactured by the following: For example, the film is heated and / or released into the wet film matrix. A controlled drying process, including the application of radiant energy to form a viscoelastic structure. The preparation may be carried out in a manner that controls the uniformity of the contents of the film. The drying process involves using air alone, heat alone, or heat and air together, on the top or bottom of the film. The underside of the film, or the support for the cast, coated, or extruded film. To bring into contact with the substrate, or to bring two or more tables into contact with the substrate at the same time or at different points during the drying process. This may include bringing the surface into contact with the surface. Some such processes are in the United States This is further described in U.S. Patent No. 8,765,167 and U.S. Patent No. 8,652,378, which are cited below. The film is incorporated herein by reference. As described in the published U.S. Patent Application Publication No. 2005 / 0037055A1, the extruded It's okay.

[0125] 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 or water-insoluble polymers may also be used. It may contain cellulose, cellulose derivatives, or gum. Specific examples of usable water-soluble polymers. These include, but are not limited to, polyethylene oxide, pullulan, and hydroxypropyl Methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, poly Vinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate Thorium, polyethylene glycol, xanthan gum, tragacanth gum, guar gum Acacia gum, gum arabic, polyacrylic acid, methyl methacrylate copolymer, Contains ruboxy vinyl copolymer, starch, gelatin, and combinations thereof. Usable. Specific examples of suitable water-insoluble polymers are not limited to ethylcellulose, hydroxycellulose, and hydroxycellulose. Roxypropyl ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose Contains cellulose phthalates and combinations thereof. For higher doses, use a lower dose. In some cases, it is desirable to incorporate polymers that provide a high level of viscosity relative to their quantity. .

[0126] 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. It may also be water-swellable. Furthermore, this material is water-soluble or water-swellable at a pressure lower than atmospheric pressure. However, this is also acceptable. In some embodiments, a film formed from such a water-soluble polymer is It may also be water-soluble to the extent that it can dissolve upon contact with bodily fluids.

[0127] Other polymers that can be incorporated into films include biodegradable 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 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 anhydride Polyacetate, polycaprolactone, poly(orthoester), polyamino acid, poly Aminocarbonate, polyurethane, polycarbonate, polyamide, poly(alkyl) This includes anoacrylates, as well as mixtures and copolymers thereof. Additional uses are available. Possible polymers include L- and D-lactic acid stereopolymers, bis(p-carboxyphenoxy) polymers. Ropanic acid and sebaciic acid copolymer, sebaciic acid copolymer, caprolactone copolymer Poly(lactic acid) / poly(glycolic acid) / polyethylene glycol copolymer, polyurethane Copolymers of α-amino acids and (poly(lactic acid)), α-amino acid copolymers, α-amino acids and capron Acid copolymers, α-benzyl glutamate esters and polyethylene glycol copolymers Remers, succinate esters and poly(glycol) copolymers, polyphosphazenes, poly It contains hydroxyalkanoates or mixtures thereof. The polymer matrix is ​​1. It may contain two, three, four, or more ingredients.

[0128] 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 longer. Intervals may be required. Therefore, in some embodiments, one or more water-soluble substances are used as described above. Polymers are sometimes used to form films. However, in other embodiments, A water-soluble polymer and a water-swellable, water-insoluble and / or biodegradable polymer as described above. It may be desirable to use it in combination with Mar. Water swellable, water insoluble and / or By including one or more biodegradable polymers, a film formed solely from water-soluble polymers can be formed. This allows for the provision of films with a slower dissolution or decay rate than conventional films. This film can adhere to mucosal tissue for longer periods, such as up to several hours. This would be desirable for the delivery of certain pharmacoactive ingredients.

[0129] (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, its active pharmaceutical ingredients, dosage forms, enhancers, and other components it contains. The additives, as well as the desired dimensions of the distribution unit, are optimized by those skilled in the art. This is possible. When this film formulation is placed in the user's buccal oral cavity or sublingual region, It must have good adhesion. Furthermore, this film formulation disperses and dissolves at a moderate rate. It must be dispersed within approximately 1 minute and dissolved within approximately 3 minutes. In some embodiments, this film formulation is used for approximately 1 to 30 minutes, for example, approximately 1 to 20 minutes, or 1 Over a minute, over 5 minutes, over 7 minutes, over 10 minutes, over 12 minutes, over 15 minutes, over 20 minutes, over 30 minutes, approximately 30 minutes, or less than 30 minutes. Distributed within less than 20 minutes, less than 15 minutes, less than 12 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, or less than 1 minute. It may also be possible to dissolve it. The dispersion rate under the tongue is lower than the dispersion rate on the buccal side of the oral cavity. It's fine.

[0130] For example, in some embodiments, the film contains polyethylene oxide alone or a It may be contained in combination with a dipolymer component. The second polymer may be another water-soluble polymer, water Swellable polymers, water-insoluble polymers, biodegradable polymers, or any combination thereof Good. Suitable water-soluble polymers include, but are not limited to, those presented above. No. In some embodiments, the water-soluble polymer is a hydrophilic cellulose-based polymer. For example, hydroxypropyl cellulose and / or hydroxypropyl methylcellulose, etc. It may include one or more water-swellable, water-insoluble and / or biodegradable polymers. In some embodiments, one or more water-swellable, water-insoluble and / or biodegradable polymers. The material can also be incorporated into a polyethylene oxide-based film. Any of the indicated water-swellable, water-insoluble, or biodegradable polymers can be used. Second polymer - The components are present in amounts ranging from approximately 0% to approximately 80% by weight of the polymer components, more specifically, from approximately 30% to approximately 70% by weight. It may be used in amounts of %, and more specifically, about 40% to about 60% by weight, which is 5% by weight. Over %; 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%, or 5% Includes less than.

[0131] (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, fragrances, release modifiers, adjuvants, plasticizers, flow accelerators, mold release agents, polymer All, granulating agent, diluent, binder, buffer, absorbent, lubricant, adhesive, anti-adhesion agent, acidity Agents, softeners, resins, lubricants, solvents, surfactants, emulsifiers, elastomers, anti-sticking agents, bands It contains antistatic agents and mixtures thereof. These additives may be used in conjunction with the pharmaceutically active ingredient(s). It can also be added to the active pharmaceutical ingredient. The term "stabilizer" as used herein refers to an active pharmaceutical ingredient, a separate To prevent aggregation or other physical and chemical degradation of the excipients, or combinations thereof. It refers to an excipient that can be used in this way.

[0132] Stabilizers may also be antioxidants, metal ion chelating agents, pH adjusters, emulsifiers and / or surfactants. It may be classified as a stabilizing agent or an ultraviolet (UV) stabilizer.

[0133] 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 so Esters of sesame oil sesamol, benzoin resin coniferyl benzoic acid, nordihydr Nordihydroguaietic resin and nordihydroguaiaretinic acid (NDG A) Gallate esters (especially methyl gallate, ethyl gallate, propyl gallate) (amyl gallate, butyl gallate, lauryl gallate), butylated hydroxyanisose (BHA / BHT, also known as butyl-p-cresol); ascorbic acid and its salts and esters (for example) acorbyl palmitate, erythorbic acid (isoas) Corbic acid) and its salts and esters, monothioglycerol, sodium formaldehyde Dehydr sulfoxylate, sodium disulfite, sodium bisulfite, sodium sulfite Potassium disulfite, butylated hydroxyanisole, butylated hydroxytoluene (BHT) ), contains propionic acid. Typical antioxidants include tocopherols, for example, α-tocopherol. toluene and its esters, butylated hydroxytoluene and butylated hydroxyanisole The term "tocopherol" also includes tocopherol esters. The term "alpha-tocopherol" refers to alpha-tocopherol. It contains esters of ethanol (e.g., α-tocopherol acetate).

[0134] Metal ion chelating agents (i.e., host-gated compounds with other compounds such as the active ingredient or other excipients) Any compound that can participate in the formation of a stent complex (also called a chelating agent) is calcium chloride. M, ethylenediaminetetraacetate calcium disodium, glucono delta-lactone, glucon Sodium phosphate, potassium gluconate, sodium tripolyphosphate, sodium hexametaphosphate This includes thorium and combinations thereof. Metal ion chelating agents also include cyclic oligosaccharides, for example. Cyclodextrin, cyclomannin (5 or more α-D-linked molecules linked at the 1,4 positions by α-bonds) Mannopyranose units, cyclogalactin (five or more units linked at positions 1 and 4 by β-bonds) β-D-galactopyranose unit), cycloalthrin (linked at positions 1 and 4 by α-bonds, 5 This includes one or more α-D-altropyranose units, and combinations thereof.

[0135] pH adjusters or stabilizers include acids (e.g., tartaric acid, citric acid, lactic acid, fumaric acid, phosphoric acid, Ascorbic acid, acetic acid, succinic acid, adipic acid and maleic acid), acidic amino acids (for example, Glutamic acid, aspartic acid, etc.), inorganic salts with the aforementioned acidic substances (alkali metal salts, aluminium Potassium earth metal salts, ammonium salts, etc.), the aforementioned acidic substances and organic bases (for example, lysine, aluminium Salts of basic amino acids such as ginine, meglumine, etc., and solvates thereof (e.g., hydrated It contains (substances). Other examples of pH adjusters include silicified microcrystalline cellulose and aluminometasilicate. Calcium salts of magnesium or phosphate (for example, anhydrous calcium hydrogen phosphate or Hydrates, calcium, sodium, or potassium carbonates or bicarbonates, and milk Calcium carboxylate, or mixtures thereof), carboxymethylcellulose, or cross-linked carboxymethylcellulose. Sodium and / or calcium salts of methylcellulose (e.g., croscarmellose sodium Thorium and / or calcium salts), potassium polaritrin, sodium alginate and B / or calcium, sodium doxate, magnesium stearate, calcium , aluminum or zinc salts, magnesium palmitate, and magnesium oleate This includes , sodium stearyl fumarate, and combinations thereof.

[0136] 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 grafted onto a hydrophobic main chain, lecithin, glyceryl monostearate Serine, Glyceryl Monostearate / Polyoxyethylene Stearate, Ketosteal Alcohol / Sodium Lauryl Sulfate, Carbomer, Phospholipid, (C 10 ~C 20 ) alkyl and Alkylene carboxylates, alkyl ether carboxylates, aliphatic alcohol sulfates Salts, aliphatic alcohol ether sulfates, alkylamide sulfates and sulfonates, fatty acids Alkylamide polyglycol ether sulfates, alkanesulfonates and hydroxya Lucansulfonate, olefin sulfonate, isethionic acid acyl ester, α- Sulfo fatty acid esters, alkylbenzene sulfonates, alkylphenol glycols Ether sulfonates, sulfosuccinates, monoesters and diesters of sulfosuccinates Alkaline, aliphatic alcohol ether phosphate, protein / fatty acid condensation product, alkyl mono Glyceride sulfates and sulfonates, alkylglyceride ether sulfonates, fatty acids Methyl taurid, fatty acid sarcosinate, sulfolysine oleate and acyl glutamate T, quaternary ammonium salts (for example, di-(C) 10 ~C 24 ) Alkyl-dimethylammonium chloride Lido or bromide), (C 10 -C 24 ) Alkyl-dimethylethylammonium chloride or bro Mido, (C 10 -C 24 ) Alkyl-trimethylammonium chloride or bromide (e.g., cetyl (C)trimethylammonium chloride or bromide), (C 10 -C 24 ) Alkyl-dimethylbenz Ammonium chloride or bromide (for example, (C 12 -C 18 ) Alkyl-dimethylbenzyl (C)(C) 10 -C 18 ) Alkyl-pyridinium chloride or bromide (for example) , N-(C 12 -C 16 )alkyl-pyridinium chloride or bromide), N-(C 10 -C 18 ) alkyl- Soquinolinium chloride, bromide or monoalkyl sulfate, N-(C 12 -C 18 ) Aruki 2-Polyoylaminoformylmethylpyridinium chloride, N-(C 12 -C 18 ) Alkyl-N-methyl Tylmorpholinium chloride, bromide or monoalkyl sulfate, N-(C 12 -C 18 )a Lukyl-N-ethylmorpholinium chloride, bromide or monoalkyl sulfate, (C1 6-C 18 ) Alkyl-pentaoxetylammonium chloride, diisobutylphenoxyeth Xyethyldimethylbenzylammonium chloride, N,N-diethylaminoethyl-stear Salts of lylamide and -oleylamide with hydrochloric acid, acetic acid, lactic acid, citric acid, and phosphoric acid, N-A Sylaminoethyl-N,N-diethyl-N-methylammonium chloride, bromide, or monoal Kyl sulfate, and N-acylaminoethyl-N,N-diethyl-N-benzylammonium Chlorides, bromides, or monoalkyl sulfates (in the foregoing, "acyl" is This includes, for example, stearyl or oleyl, as well as combinations thereof.

[0137] Examples of ultraviolet (UV) stabilizers include UV absorbers (e.g., benzophenone), UV quenchers ( In other words, instead of causing decomposition with UV energy, the energy is dissipated as heat. (any compound), scavenger (i.e., remove free radicals resulting from exposure to UV radiation) This includes any of the compounds that are removed, and combinations thereof.

[0138] 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 disulfite, sodium bisulfite Um, propyl gallate, glutathione, thioglycerol, singlet oxygen quencher, Hydroxyl radical scavenger, hydroperoxide remover, reducing agent, metal cleaner Includes nitrating agents, cleaning agents, chaotropes, and combinations thereof. "Singlet oxygen quencher The term "-" is not limited to alkylimidazoles (e.g., histidine, L- Camosine (camosine, histamine, imidazole 4-acetic acid), indole (e.g., tryptose) Fans and their derivatives, for example, N-acetyl-5-methoxytryptamine, N-acetyl serotonin Nin, 6-methoxy-1,2,3,4-tetrahydro-β-carbolin), sulfur-containing amino acids (e.g., methyl Onine, Ethionine, Gencoric acid, Lanthionine, N-Formylmethionine, Felinine , S-allyl cysteine, S-aminoethyl-L-cysteine), phenolic compounds (for example, Tyrosine and its derivatives), aromatic acids (e.g., ascorbic acids, salicylic acid, and so on) (These are derivatives), azides (e.g., sodium azide), tocopherol and related vitamin E derivatives) It contains a conductor, as well as carotene and related vitamin A derivatives. "Scavenger" is not limited to azide, dimethyl sulfoxide, and hi It contains stidine, mannitol, sucrose, glucose, salicylic acids, and L-cysteine. It is said that "hydroperoxide removers" are not limited to catalase, pill It contains vinyl acids, glutathione, and glutathione peroxidase. It is classified as a "reducing agent". This includes, but is not limited to, cysteine ​​and mercaptoethylene. The term "rate-forming agent" is not limited to EDTA, EGTA, o-phenanthroline, and quac Contains enoic acid. While not limited to "cleaning agents," SDS and lauroyl saturates are required. It contains sodium guarcosin. While not limited to "chaotrope," gua This includes nidin hydrochloride, isothiocyanate, urea, and formamide. As discussed, the stabilizer can be present in concentrations of 0.0001% to 50% by weight, which means that In terms of weight, over 0.0001%, over 0.001%, over 0.01%, over 0.1%, over 1%, over 5%, over 10%, over 20%, Over 30%, over 40%, over 50%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 1% This includes full, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001%.

[0139] 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, water-soluble polysaccharides, such as alginate Agar, carrageenan, guar gum, agar, xanthan gum, gellan gum, gum arabic and related gums (Gatti gum, Karaya gum, Tragacanth gum), pectin, etc., cellulose Water-soluble derivatives of the cellulose: alkylcellulose, hydroxyalkylcellulose and hydroxyalkylcellulose Calkylalkylcellulose, for example, methylcellulose, hydroxymethylcellulose hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethyl Cellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose Cellulose esters and hydroxyalkyl cellulose esters, such as acetate cellulose, for example, acetate cellulose. Cellulose acetate (CAP), hydroxypropyl methylcellulose (HPMC); carboxyalkyl Cellulose, carboxyalkylalkylcellulose, carboxyalkylcellulose Stellates, e.g., carboxymethylcellulose and their alkali metal salts; water-soluble synthetic polymers Remers, for example, polyacrylic acid and polyacrylic acid esters, polymethacrylic acid and poly Methacrylic acid ester, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate Tate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVA / vinyl acetate copolymer, or It may contain polycrotonic acid. And also, phthalic acid-treated gelatin is preferred. Succinic acid-treated gelatin, cross-linked gelatin, shellac, water-soluble chemical derivatives of starch, for example It has a tertiary or quaternary amino group such as a diethylaminoethyl group, and optionally a quaternary amino group. Cationically modified acrylates and methacrylates that may be conditioned; or other types They are similar polymers.

[0140] 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 applied to nanoparticles. This includes monomers having functional groups that can be adsorbed and polymerize to form a 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. See also Japanese Patent No. 4598399. The surface stabilizer is tyroxapol (USA). (Patent No. 5,429,824), Polyalkylene Block Copolymer (Patent No. 5,565,188), Sulfate Modification Decorated nonionic block copolymer (U.S. 5,569,448), high molecular weight linear poly(ethylene) Oxide polymer (US Patent No. 5,580,579), butylene oxide-ethylene oxide blottery hydroxypropylcellulose (US Patent No. 5,587,143), hydroxypropylcellulose (US Patent No. 5, It may include patents 591,456, and sugar-based surface stabilizers (U.S. Patent No. 5,622,938). The stabilizer may include a peptide stabilizer. For example, see International Publication WO2006097748A2. See reference. Stabilizers include, for example, L-cysteine ​​hydrochloride, glycine hydrochloride, malic acid, It may contain sodium disulfite, citric acid, tartaric acid, and L-cystine dihydrochloride. For example, see U.S. Patent No. 6,153,223. Stabilizers may include natural compounds. Yes, it is possible. The stabilizer may include synthetic compounds. The stabilizer may include one or more of the above-mentioned compounds It may include a blend of substances or compounds. The stabilizer is used until the desired time. Or, to protect the metabolism of the prodrug until it reaches a specific target, tissue, or environment. It can function in this way.

[0141] 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 5%, and preferably approximately 0.02%. It can be contained in amounts of approximately 2%, which is greater than 0.02%, greater than 0.2%, greater than 0.5%, greater than 1%, greater than 1.5%, and greater than 2%. Greater than 4%, approximately 5%, greater than 5%, less than 4%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, or 0. Includes less than 0.2%.

[0142] 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.

[0143] 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 an aqueous exterior. Insoluble and / or unstable pharmaceutically active ingredients are aerosolized. It fits into the aqueous cavity, thereby creating a water-soluble inclusion complex. Therefore, the inclusion complex The formation of this compound allows highly insoluble and / or unstable pharmaceutically active ingredients to dissolve 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 given due consideration within the scope of the present invention. It's an elephant.

[0144] Suitable colorants include food, pharmaceutical and cosmetic (FD&C) colorants and pharmaceutical and cosmetic (D&C) colorants. ) Contains 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 dye absorbed into aluminum hydroxide. Other examples of colorants include known azo It contains dyes, organic or inorganic pigments, or colorants of natural origin. For example, oxides, or (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 0.0 More than 01%, more than 0.01%, more than 0.1%, more than 0.5%, more than 1%, more than 2%, more than 5%, about 10%, more than 10%, less than 10% Full, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001% Includes.

[0145] 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.

[0146] 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. Bantaime; dihydrochalcone compounds, glycyrrhizin; stevia rebaudiana (ste Biosides; chlorine derivatives of sucrose, e.g., sucralose; sugar alcohols, e.g., sorbitol You can choose from corn, mannitol, xylitol, etc. Also, hydrolyzed hydrogenated starch and artificial sweetener 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiadin-4-one-2,2-dioxide Substances, especially potassium salts (acesulfame-K), and their sodium and calcium salts In addition, powerful natural sweeteners, such as monk fruit (Luo Han Guo), are also intended. Other sweeteners are also It is usable.

[0147] 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. This can result in an uneven film. Simethicone is one particularly useful defoamer and It is a defoaming agent. However, the present invention is not limited thereto, and includes other suitable defoaming agents and / or Defoaming agents can also be used. Simethicone and similar agents are used for the purpose of increasing density. It is also possible to do so. More specifically, such drugs contain air, moisture, and similar substances. This can facilitate the removal of undesirable components, resulting in a finer, and therefore more uniform, product. To provide a film. The agent or component that achieves such a function is a densifying agent or density It is called an improver. As mentioned above, the captured air or undesirable components are in a non-uniform form. It may cause a film to form.

[0148] 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.

[0149] 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 can be 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 acid, citric acid, bicarbonate tartrate, and combinations thereof.

[0150] 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 formed by preparing a wet composition, which contains polymeric It contains a carrier matrix and a therapeutically effective amount of pharmaceutically active ingredient. This wet composition is cast. This is formed into a film, which is then thoroughly dried to form a self-standing film composition. The composition can be cast into individual dosage forms, or cast into sheets and then the sheets can be processed. It may be cut into individual dosage forms.

[0151] 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. , or its use in the local treatment of wounds is particularly clear. This composition transports pharmaceuticals and When applied to and adhered to the mucosal surface, it provides a protective layer, protecting the treatment site, surrounding tissues, and other bodily fluids. The medicine is delivered to the body. Simultaneously with or after delivery, the filtration process in an aqueous solution or bodily fluid such as saliva is performed. Considering the control of erosion and the delay of the natural erosion of the film, this composition is suitable for the treatment area. It provides a suitable residence time for effective drug delivery at the target location.

[0152] The residence time of this composition depends on the disintegration rate of the water-disintegrating polymers used in the formulation and their It is determined by each concentration. The decay rate depends, for example, on components with different solubility properties or chemically different components. polymers such as hydroxyethylcellulose and hydroxypropylcellulose By mixing them together; using the same polymer of different molecular weight grades, for example, low molecular weight. And by mixing with medium molecular weight hydroxyethylcellulose; various lipophilic values ​​or This involves using excipients or plasticizers that have water solubility properties (including components that are essentially insoluble). Furthermore; by using water-soluble organic and inorganic salts; for partial crosslinking, glyoxa By using crosslinking agents such as ru to polymers such as hydroxyethylcellulose; or Changing the crystallinity of the fabricated film or altering the physical state of the film, including phase transitions. These can be adjusted by irradiation or curing after processing. It can be used alone or in combination to modify the disintegration dynamics of the rum. When applied, this drug The composition film adheres to the mucous membrane surface and is retained there. Water absorption occurs in this composition. It softens the mucous membrane, thereby reducing the feeling of a foreign body. When this composition is placed on the mucosal surface, it facilitates drug delivery. This occurs. The residence time is determined by the desired timing of delivery of the selected drug and the desired carrier. Depending on the lifespan, it can be adjusted over a wide range. However, generally, the residence time ranges from about a few seconds to about a few days. It is adjusted between these intervals. Preferably, the residence time of most pharmaceuticals is adjusted to approximately 5 seconds to approximately 24 hours. More preferably, the residence time is adjusted to approximately 5 seconds to approximately 30 minutes. Once the composition adheres to the mucosal surface, it also provides protection for the treatment site and is disintegrable. It acts as a bandage. Lipophilic agents delay disintegration to reduce breakdown and dissolution. It can be designed.

[0153] A highly water-soluble excipient that is sensitive to enzymes such as amylase, for example, a water-soluble organic salt. Furthermore, the disintegration dynamics of this composition can be adjusted by adding inorganic salts, etc. Suitable excipients include sodium and potassium hydrochlorides, carbonates, bicarbonates, and citric acid. Salts, trifluoroacetates, benzoates, phosphates, hydrofluoric acid salts, sulfates, or tartrates It may include. The amount added depends on how much the decay dynamics are altered, as well as other components in the composition. It may vary depending on the amount and properties of the components.

[0154] The emulsifier commonly used in the aforementioned water-based emulsion is preferably an in situ emulsifier. If obtained by means of linoleic acid, palmitic acid, myristoleic acid, lauric acid, stearic acid , cetoleic acid or oleic acid and sodium hydroxide or potassium hydroxide Selected, or sorbitol or lauric acid ester of anhydrous sorbitol, Lumitic acid ester, stearic acid ester, or oleic acid ester, monooleic acid Polyoxyethylene containing monostearate, monopalmitate, and monolaurate. Derivatives, aliphatic alcohols, alkylphenols, allyl ethers, alkylaryl ethers Sorbitan monostearate, sorbitan monooleate and / or sorbitan It is either selected from monopalmitate or one of the other.

[0155] 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 contains less than 0.005%. The amounts of other ingredients may vary depending on the drug or other ingredients, but In terms of composition, these components should not exceed 50%, preferably not exceed 30%, by total weight. And most preferably, it should be configured so as not to exceed 15%.

[0156] The thickness of the film can vary depending on the thickness of each layer and the number of layers. As mentioned above, the layers Both the thickness and the amount can be adjusted to change the collapse dynamics. Preferably, If the composition has only two layers, the thickness is 0.005 mm to 2 mm, preferably 0.01 to 1 mm, more preferably Or, it is in the range of 0.1 to 0.5 mm, which is greater than 0.1 mm, greater than 0.2 mm, approximately 0.5 mm, greater than 0.5 mm, 0.5 mm Includes less than 0.2 mm or less than 0.1 mm. The thickness of each layer is the total thickness of the layered composition. It may fluctuate between 10% and 90%, preferably between 30% and 60%, where greater than 10%, greater than 20%, and 30%. Over %, over 40%, over 50%, over 70%, over 90%, approximately 90%, less than 90%, less than 70%, less than 50%, 40% This includes less than 30%, less than 20%, or less than 10%. Therefore, the preferred thickness of each layer is 0.01 It can vary between 0.9 mm and 0.03 mm and 0.5 mm.

[0157] As those skilled in the art will understand, when systemic delivery, such as transmucosal or transdermal delivery, is desirable, the treatment 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.

[0158] This pharmaceutical composition can also be used as a wound dressing. It is physically compatible. To provide a flexible barrier that is permeable to oxygen and water and can be removed by washing. Furthermore, this film not only protects wounds, but also promotes healing, sterilization, and scarification. To promote, relieve pain, or improve the overall symptoms of the affected person, The medicine can also be delivered. Some of the examples provided below are suitable for application to the skin or wounds. It is suitable. As those skilled in the art will understand, this formulation is suitable for long-term use on dry skin. Incorporate special hydrophilic / hygroscopic excipients that will help maintain good adhesion. It may also be necessary to do so. Another advantage of the present invention when used in this form is that the film However, if you do not want it to be noticeable on the skin, the use of pigments or coloring substances is unnecessary. If you want to make the film stand out, you can use pigments or coloring substances.

[0159] 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]

[0160] (Examples) The proposed drug regimen for diazepam buccal film (DBF) is based on the reference drug diazepam. The exposure achieved when Astat rectal gel (DRG) is administered according to the label of its approved product. It was designed to provide patients with exposure to diazepam equivalent to that of dew (see Table 1 below). The label on Diastat categorizes patients into three age groups: 2-5 years, 6-11 years, and 12 years and older. Therefore, the first category to be categorized, weight-adjusting medication regimens are provided, on a mg / kg basis. The recommended doses for each of the three age groups are approximately 0.5 mg / kg, 0.3 mg / kg, and 0.2 mg / kg. The unit is kg. Within each age group, the recommended dose for individual patients is determined based on seven weight categories. It is determined.

[0161] (Table 1: Dosage regimens for Diastat rectal gel (DRG) based on labeling) [Table 3]

[0162] The invention of a suitable medication regimen for DBF is based on the age group and weight listed on the Diastat label. Based on categories, create a mapping that identifies the appropriate DBF dose (mg) for any given patient. It was equivalent to doing the following. The preferred dose of DBF is the dose indicated on the label of Diastat. This dose is expected to provide an exposure to diazepam equivalent to the exposure provided by [the other party]. The first important point of this trial is to apply this mapping to the adult age group (patients aged 12 and older). The goal was to create a complex model. This trial was conducted to distinguish DBF from DRG by two different observational results. It was messy. (1) The pharmacokinetics of DBF were linear. In DBF, C max Both AUC and dose-to-dose ratio On the other hand, in DRG, C max (2) DBF showed a food effect. DBF C max Fat decreased by an average of approximately 33% after consuming a moderate-fat diet and by an average of approximately 45% after consuming a high-fat diet. Although slight, AUC was not affected. DRG is affected by food because it is administered rectally. It was assumed that there was no significant impact. Approval label for DRG (Diastat Rectal Gel). Therefore, no food efficacy studies have been reported, and the label on Diastat does not contain information regarding food efficacy. No information has been provided at all.

[0163] Example 1 - Two pilot study experiments in healthy volunteers As shown in Figure 1A, in order to cover the dose range shown in Table 1, first two We conducted research on formulations. For low-dose formulations, we used size proportionally to the dose, with 5 mg, 7.5 mg, and A strength of 10 mg was created. Similarly, the size was used in a dose-proportional manner for high-dose formulations, and 12. Strengths of 5 mg, 15 mg, 17.5 mg, and 20 mg were developed. High-dose and low-dose formulations were prepared using 5 mg And in two pilot clinical crossover trials with diastat rectal gel at a dose of 20 mg I tried it.

[0164] The results showed that the PK parameter C was different between 5 mg of DBF and 5 mg of rectal gel. max And excellent in terms of AUC The data showed agreement. The data also supported the dose-proportionality of DRG across the 5–20 mg dose range. However, the DRG suggested that there was no dose-proportional relationship. In the DRG, between the 5 mg dose and the 20 mg dose... C max The increase was lower than dose-proportional. The results of these pilot studies are shown in Table 2. To summarize.

[0165] (Table 2) [Table 4]

[0166] The results of these pilot studies (observational results showed that the mean C after administration of 20 mg of DBF) max is 20 C after DRG administration of mg max Based on this (which was approximately 58.7% higher), the formulation development plan is shown in Table 3 below. It has been corrected accordingly. From the data obtained, the DBF dose of approximately 12.5 mg is equivalent to the DRG dose of 20 mg (maximum C from the dose that was a single point max It was suggested that it would be approximately equal to high Dose formulations were not necessary. In this revised formulation development plan, all dosages were formulated as a single formulation. Prepared from (the low-dose formulation mentioned above).

[0167] (Table 3: Revised Formulation Development Plan) (DBSF dosage explanation) [Table 5]

[0168] The dose-proportionality of DBF was formally demonstrated in a crossover study in healthy volunteers using doses of 5 mg, 10 mg, and 15 mg. The study investigated the 15 mg dose, which established linearity and offered flexibility in possible dosage settings. Therefore, it was included as the highest dose in the proportionality study experiment. This study experiment is shown in Figures 1A and 1B. C max The dose-proportionality of both the saturation curve and AUC was demonstrated.

[0169] Based on these results, we then conducted cross-sectional studies to provide a direct comparison of the pharmacokinetics of DBF and DRG. An experimental study was conducted. In this crossover trial of four treatments over four periods, one DBF dose (15 mg) was administered via rectal gel. The three doses (5 mg, 12.5 mg, and 20 mg) were compared. DBF was shown to be proportional to the dose. Therefore, one dose level of DBF was sufficient. The purpose of this core comparative study was to determine DRG DBF and DRG exposure (C) across the drug dosage range (5-20 mg) max To investigate the relationship between both AUC and The design of the research experiment also allowed for a formal investigation of the dose-proportionality of DRGs.

[0170] C max The results of this research experiment are shown in Figure 1C. Plasma concentration of all treatments for typical subjects. The degree-time curve is shown in Figure 3. This research experiment involved C after DRG administration. max The result is lower than the dose-proportional ratio. This was formally demonstrated (Figure 4B), and it was shown that the AUC after DRG administration is approximately proportional to the dose (Figure 4A), and This study demonstrated that the relative bioavailability of DBF was approximately 118% compared to DRG. The experiment also examined these parameters regarding the doses studied in DRG (5 mg, 12.5 mg, 20 mg) in the DB. Compare the PK parameter C between these formulations to any dose of F. max And it enables the estimation of the AUC ratio. Since DBF was demonstrated to be proportional to the dose, these studies on doses in DRG were conducted. A comparison was immediately possible between all possible doses of DRG and all possible doses of DBF. The comparison was then facilitated by the population PK method, as described in other chapters of this specification. .

[0171] (Research experiment on the effects of food) The applicant conducted two food effect research experiments using DBF, and two cross-sectional studies investigating the effects of a standard high-fat diet. Tests, and the effects of different body positions (upright or reclined) in a fasting state, and reclining A four-group crossover study was conducted to investigate the effects of a standard moderate-fat diet and a standard high-fat diet under specific conditions. In a study of the effects of two food groups, consuming a high-fat meal within 30 minutes of administration resulted in C max on average It was shown that although it decreased by approximately 45%, AUC was not affected. In the 4-group study experiment, body position ( It was shown that whether the patient was standing or reclining did not affect diazepam PK. The effect of a high-fat diet (reclining position) in the 4-group study experiment was observed in the 2-group study experiment. was almost identical to the effect. When a medium-fat meal was ingested within 30 minutes after administration, C max was on average reduced by about 33% but the AUC was not affected. Food was also associated with a delay in T max . The median T during fasting was about 1 hour, but the median T max under feeding conditions was 2 - 3 hours max . (For comparison, the T after administration of Diastat reported in the Diastat label is 1.5 hours.) of <000008​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​This study was conducted to determine the effect of a moderate-fat diet on [something]. Another objective of this research experiment was to [something] The objective was to determine whether the administration procedure could be modified to promote transmucosal absorption. The increase in the initial part of the profile (transmucosal) is followed by T max Sufficient to reduce This is possible. To achieve this, a second fasting group was added.

[0174] In the above research experiment using DBF, DBF was applied to the buccal mucosa inside the oral cavity of subjects in an upright sitting position. The drug was administered by applying it for 5 minutes. At this time, the subject swallowed all of the remaining medication. To promote absorption, DBF is used with the subject in a side-lying reclining position, and the film is placed in the mouth. The drug was administered with the injection site positioned on the lower mucous membrane on the buccal side of the oral cavity (so that all saliva would accumulate at the injection site). (to). For subjects in this reclining position, DBF is administered under the conditions of fasting, moderate-fat diet, and high-fat diet. The drug was administered using a cross-administration method. The time required for the subject to swallow was extended from 5 minutes to 15 minutes. This extended the residence time. (Fourth treatment - administration in an upright position while fasting was added as a control.) ) Residence time is usually reported routinely as one of the three main factors that promote transmucosal absorption. (The other two are surface area and permeation dynamics.) As shown in Figure 6, in a fasting state, Posture (upright vs. reclined) did not have an effect. The effect of a high-fat diet in this study experiment was: The effect observed in a two-group study where DBF was administered to subjects in an upright position was almost the same as that observed with a high-fat diet. Therefore, changing the administration method for the purpose of increasing the residence time is not appropriate for fasting or feeding. No significant effects were observed in any of the conditions. A moderate-fat diet compared to a high-fat diet. This worked solely to increase the height of the second part of the bimodal profile. , the separation of the time between buccal absorption in the oral cavity after ingestion and gastrointestinal absorption was observed under feeding conditions, providing further evidence for the explanation of the delayed T It should be noted that after ingestion of a medium-fat diet, C max was reduced by about 33%, significantly less than the about 45% reduction observed after ingestion of a high-fat diet. C max was reduced by about 33%, significantly less than the about 45% reduction observed after ingestion of a high-fat diet. It should be noted that after ingestion of a medium-fat diet, C

[0175] (Population pharmacokinetic analysis modeling) Pharmacokinetic (PK) studies in healthy volunteers showed that DBF is not biologically equivalent to DRG. DBF differed from DRG in the following points: (1) DBF showed higher bioavailability than DRG. (2) The PK behavior of DBF was linear. Specifically, for DBF, both C and AUC increased proportionally with the dose. In contrast, the PK behavior of DRG was not linear. Specifically, for DRG, C max increased with the dose, although less than dose-proportionally, while AUC increased proportionally with the dose. (3) DBF showed a food effect (after ingestion of a high-fat diet, the average of C decreased by about 45%, and after ingestion of a medium-fat diet, the average decreased by about 33%, but there was no change in AUC). In contrast, DRG is considered not to be affected by food because of the rectal administration route. C max increased with the dose, although less than dose-proportionally, while AUC increased proportionally with the dose. (3) DBF showed a food effect (after ingestion of a high-fat diet, the average of C decreased by about 45%, and after ingestion of a medium-fat diet, the average decreased by about 33%, but there was no change in AUC). In contrast, DRG is considered not to be affected by food because of the rectal administration route. max decreased by about 45%, and after ingestion of a medium-fat diet, the average decreased by about 33%, but there was no change in AUC). In contrast, DRG is considered not to be affected by food because of the rectal administration route. decreased by about 45%, and after ingestion of a medium-fat diet, the average decreased by about 33%, but there was no change in AUC). In contrast, DRG is considered not to be affected by food because of the rectal administration route. In contrast, DRG is considered not to be affected by food because of the rectal administration route.

[0176] Therefore, Aquestive used population PK modeling to select a dosing regimen to correct for the PK differences between DBF and DRG (Table 4). Briefly, the recommended DBF doses corresponding to each adult weight class specified on the label of the Diastat rectal gel were adjusted so that (1) the predicted median of diazepam C after ingestion of a medium-fat diet would be the same as the label of the Diastat rectal gel. For each adult weight class specified on the label of the Diastat rectal gel, the recommended DBF dose was adjusted so that (1) the predicted median of diazepam C after ingestion of a medium-fat diet would be the same as the label of the Diastat rectal gel. max after ingestion of a medium-fat diet would be the same as the label of the Diastat rectal gel. C after administration of the stated dose max Provide a sufficiently high dose to ensure it is similar to the median. (2) Diazepam C obtained in a fasting state max The predicted median for Phase 1 healthy volunteers in DBF is C has been observed in human trials and its safety has been demonstrated. max Provide a dose that will not exceed the median. Therefore, we made the following selection. The simulation based on population PK modeling was performed under the condition of a moderate-fat diet. The proposed DBF medication regimen is for each weight class, using diastat rectal gel. Predicted C after administration of the labeled dose max Similar to C max It was demonstrated that it generates .

[0177] (Table 4: DBF medication algorithm) [Table 6] *The performance of this medication regimen is based on the clinical study reported below (Diamonds of Blood Flow in Epilepsy Patients). Evaluation was performed using a cross-reaction test with STATT (DRG).

[0178] (Epilepsy Monitoring Unit (EMU) Research Experiment) A research experiment was conducted on epilepsy patients, comparing patients in the interictal state (without seizures) and patients during seizures / In patients in the peripheral phase of an attack (during an attack or within 5 minutes after an attack has been stopped), if DBF is administered, DBF may be harmful. This study determined whether the pharmacokinetics of diazepam, administered as a drug, were altered. The study was conducted with a predetermined dose of DBF (12.5 mg for all patients), regardless of body weight. Therefore, the weight-adjusted dosage regimens shown in Table 5 were not used.

[0179] The applicant conducted a single-dose cross-referencing study using plasma samples to determine diazepam concentration. Pharmacokinetic parameters were measured from the following C max , AUC, and T max The value is the incidence of epilepsy. Obtained after administering 12.5 mg of DBF to humans.

[0180] (Table 5) [Table 7]

[0181] As shown in the data above, when no seizure activity is observed in the preceding 3 hours (interictal period), Administer 12.5 mg DBF within 5 minutes of the seizure (peri-seizure period), and then continue for up to 4 hours. A single-dose crossover trial involves collecting plasma samples at various time points to determine diazepam concentrations. Pharmacokinetic parameters were derived from the experiment. The subjects of the research experiment were patients with uncontrollable tonic-clonic seizures. The group consisted of 35 adult men and women aged 17-65 years with impaired consciousness or focused seizures. Both treatments were Not completed (4 subjects), important time points were missing (6 subjects), diazepam concentration before medication. The degree is C max More than 5% (2 subjects), or DBF was administered in a manner contrary to the instructions for use. Patients who were affected (5 subjects) were excluded from the analysis. max and AUC 0-4h The value is the geometric mean, T max value This is the median. The geometric 90% confidence interval (CI) value is determined using ln-transformed data. T max The difference was not statistically significant, p = 0.5708 (Wilcoxon signed-rank test). The values ​​shown represent data from 18 evaluable subjects. Plasma concentration-time curve 0-4 hours after drug administration. Area under the line (AUC) 0-4h , the maximum plasma drug concentration C max until the maximum plasma concentration is reached. The time is T max From the literature of Rogawski et al. For example, the entire work is incorporated by citation. Rogawski MA, Gong H, Liow K, Aboumatar S, Klein P, Gelfand MA, Jung C, War The paper, "Diazepam buccal in adult epilepsy patients," by Gacki S, Mehta R, and Heller AH, states that diazepam buccal in adult epilepsy patients is a common ailment. Pharmacokinetics of soluble films: Ratio of bioavailability in administration during the pericillal and interictal periods. comparison(Pharmacokinetics of diazepam buccal soluble film in adult patients with epile psy: comparison of bioavailability with periictal and interictal administration) See summary 2.453, American Epilepsy Association Annual Meeting, www.aesnet.org, 2018.

[0182] (Research experiment on usefulness) In EMU's research experiments, a usefulness evaluation was conducted. The following measurement results were obtained. (Table 6) [Table 8]

[0183] The results of the usefulness evaluation of the interictal-periictal crossover test are listed above. These values ​​are 33. The numbers are obtained from human subjects. Percentages are shown in parentheses. From the literature of Jung et al. ng C, Dubow J, Gong H, Liow K, Klein P, Gelfand MA, Wargacki S, Mehta R, Rogawsk. i MA, Heller AH., paper, "Diazepam as an oral treatment in adult epilepsy patients" The usability of diazepam buccal soluble film as an o "Ral treatment in adult patients with epilepsy" Abstract 3.468, American Epilepsy Society Annual Meeting General Assembly, www.aesnet.org, 2018.

[0184] This research experiment showed that exposure to diazepam in patients after DBF administration was administered to patients during seizures. It was shown to be consistent regardless of whether it was done or not. The subjects of this research experiment (epilepsy) The patient showed lower plasma concentrations than healthy volunteers after the dose was adjusted. Lower plasma concentrations in epilepsy patients associated with higher diazepam clearance are mentioned in the literature. It is well known and fully predictable that liver enzyme induction from incidental anticonvulsant medications taken by the patient is possible. This is due to the effects of guidance (the entirety of which is incorporated by citation in the literature of Dhillon and Richens). (See 1981). In the following research experiment involving patients (described below), DRG was administered. We confirmed that the same size and effect were observed in the administered patients.

[0185] (Crossover trial of DBF with diastat (DRG) in epilepsy patients) The applicant evaluated the performance of the proposed DBF drug regimen with Diastat in a 1:1 cross-ratio over two periods. The comparison was tested in patients (Tables 7-8). The initial objective was to compare DBF administered after consuming a moderate-fat diet with moderate-fat diets. The objective was to compare the pharmacokinetic (PK) performance of diastat (DRG) administered after consuming a high-fat meal. DBF was The medication is administered according to the proposed weight adjustment regimen described in Table 4, and the diastat is DRG was administered according to the FDA-approved dosing regimen for diastat. Furthermore, patients The participant may register for any third period in which DBF is administered after consuming a high-fat diet. The second objective of this research experiment was to compare DBF administered after consuming a high-fat diet with DBF administered after consuming a moderate-fat diet. The objective was to compare the PK performance of the given diastats (DRGs). The results of the initial comparison are shown below. This is shown in Table 7.

[0186] C in this one-on-one research experiment max The ratio of values ​​(geometric mean) [DBF / DRG] is 96.70%, and the 90% CI is 70.53-132. The figure was 0.58% (Table 7 shows the results after consuming a moderate-fat diet and taking diazepam C max C after administration of the labeled dose of DRG m ax We successfully demonstrated that it was similar to (consistent with predictions from population PK modeling). The result is as follows. This result helps to validate the proposed DBF medication algorithm. AUC value (AUC (0-inf) The geometric mean ratio [DBF / DRG] is equal to or lower than the mg dose of DBF. Furthermore, the fact that it exceeded 100% indicates that DBF shows higher bioavailability than DRG. It is also noteworthy that these results are consistent with those obtained from population PK modeling.

[0187] (Table 7: After administering weight-adjusted DBF and DRG to adults with epilepsy following a moderate-fat diet) (pharmacokinetic parameters) [Table 9]

[0188] The proposed DBF medication regimen also works well within each weight category, and diastach C was more consistent across the weight category than after administration of the drug. max A value was generated.

[0189] The results of the second comparison (comparison of DBF and DRG after consuming a high-fat diet) are shown in Table 8. max Value (Geometric Plane) The average ratio [DBF (high-fat diet) / DRG] was 82.67%, and the 90% CI was 55.61–122.91%. The rate (approximately 82.5%) is consistent with the predicted value from population PK modeling, and the proposed DBF dosage It is equally useful for verifying algorithms.

[0190] (Table 8: DBF after weight adjustment following a high-fat diet, DRG after weight adjustment following a moderate-fat diet) Pharmacokinetic parameters after administration to adults with epilepsy. [Table 10]

[0191] The concentration profiles observed in DBF research experiments showed that the onset of the absorption profile was associated with food. Therefore, it does not show a significant change, but a clear bimodal absorption profile is observed. The larger of the two absorption profiles appears to originate from the oral portion of the profile. Huh, T max Also, when the entire dose is taken orally, and a higher concentration is present to promote absorption, It is shifted out significantly more than would be measured. To test this hypothesis, and DBF To attempt to quantify the transmucosal delivery amount achieved during administration, mathematical peak decomposition was performed. The absorption modes in the observed profile were explained using the saturation. Next, The profiles can be analyzed individually, and high biological activity arises from both absorption pathways. For academic use, the contribution from each pathway can be estimated.

[0192] (Peak deconvolution) Use the procedure described below to perform several profile analysis for peak deconvolution. I selected the file. The resulting profile was then processed using Prism software for AUC. 0-t to We then analyzed the following: Next, we looked at the AUC0 from each profile for the combined profile. -t The ratio is used to assign percentages to the transmucosal and oral absorption pathways. The selected profile involves administering 15 mg of DBF while fasting and standing upright, followed by 15 mg after consuming a moderate-fat meal. DBF administration, 15 mg DBF administration after consuming a high-fat meal, and finally 5 mg DBF from a dose-proportional study. The mean profile was obtained from a four-group crossover study using the administration conditions. The plasma levels observed in the profile are shown in Table 9 below.

[0193] (Table 9: Diazepam plasma concentrations after DBF administration under various conditions) [Table 11] TIFF2026076173000015.tif92170

[0194] Summary of some of the experiments described in this specification: Theoretical basis: Diazepam buccal film (DBF) is used to control increased seizure activity. It is under development for the management of refractory epilepsy patients requiring intermittent use of diazepam. This is a novel dosage form of diazepam. The inventors have identified it as a body-based formulation as recommended on the FDA-approved label. Compared to diazepam rectal gel (DRG) administered according to a regimen (dose range 12.5-20 mg) It is administered to adults with epilepsy according to a weight-based regimen (dose range 12.5-17.5 mg). The pharmacokinetic (PK) performance of DBF was evaluated.

[0195] Method: Adult males aged 18-65 with epilepsy who have a stable regimen of one or more anticonvulsant medications. Sex and female (no changes in the 30 days prior to administration of the investigational drug, and no changes were expected throughout the study). (Not expected) was enrolled in a 2-period crossover study (NCT03953820), and either DBF or DRG was administered as a single dose. The drugs were administered in a randomized order, with a 28-day drug-free period in between each treatment phase. The drug was administered within 30 minutes of consuming a standardized moderate-fat diet. The subjects were monitored for up to 24 hours after administration. The samples were kept within the facility. Diazepam plasma samples were taken before administration and at intervals of up to 10 days after administration. And, maximum plasma concentration (C max ), C max Time until (T max ), the bottom of the curve up to the last measurable concentration Product(AUC 0-T ), and the AUC(AUC) extrapolated to infinite time. 0-INF This made it possible to analyze the subject, Adverse events (AEs) were monitored throughout the experimental process.

[0196] Results: Of the 31 registered subjects, PK profiles valid for both DBF and DRG analysis were found in 2 It was available to 8 participants (13 males, 15 females, mean [SD] weight 84.6 ± 20.6 kg). Both Treatment was not completed (n=2), or the diazepam concentration before medication was C max It exceeded 5% (n=1) The subjects were excluded from the analysis. The mean (SD) dose of diazepam was 15.4 ± for both DBF and DRG. The doses were 1.9 mg and 17.1 ± 3.0 mg. Table 7 shows the PK parameters for the entire research population (N=28). Geometric mean and geometric mean ratio (DBF / DRG), and C in each weight category max The geometric mean and The corresponding ratios are shown. In the entire research experimental population, the geometric mean C of DBF and DRG is max The values ​​are 204.26 ng / mL (Geometric SD [GSD] 136.12~306.49) and 211.22 ng / mL (GSD 87.71~508.6) 3) (see Figure 7), and C after DBF administration max The values ​​were similar, but C after DRG administration max The value is greater than There was little variation (P<0.0001). The AUC value was higher for DBF than for DRG. T max The median times were 1.0 hours and 0.52 hours, respectively (P<0.05). The pair of 28 patients after DRG administration Three of the subjects failed to achieve a plasma concentration of 70 ng / mL or higher. Serious adverse reactions related to the investigational drug were reported. There were no adverse events (AEs).

[0197] Conclusion: These results suggest that in adults with epilepsy, a weight-based regimen after consuming a moderate-fat diet is appropriate. If DBF is administered as a single dose according to the instructions, the dose of diazepam will be similar to the recommended dose of DRG. Demonstrate that exposure is provided with significantly less variability. C after DBF administration max Geometric mean The values ​​were consistently above 150 ng / mL in each weight category.

[0198] Another summary is as follows: (Introduction) Patients with refractory epilepsy typically experience seizures with short (or shorter than usual) interictal intervals, and continuous seizures. Experiencing an exacerbation of seizures called "recurrent acute seizures" (ARS), which describe a series of seizures that become repetitive. There are cases where this occurs. -ARS is also commonly known as cluster seizures or consecutive seizures.

[0199] ARS is characterized by post-seizure psychotic disorder, physical injury, frequent emergency room visits, hospitalization, or absence from school. Risks associated with seizures, including social and economic consequences of missing workdays. Concerns include the possibility of persistent neurological damage or death due to status epilepticus. This increases concerns about the condition (References 1-7). Despite these increased risks, many epileptic patients who experience ARS are treated in the emergency room. They do not have a prescription for therapeutic medication and / or a seizure action plan in case of a cluster seizure (Reference) References 1, 8-10).

[0200] • Diazepam buccal film (DBF) is used to control increased seizure activity. A novel dosage form is under development for the management of patients with refractory epilepsy requiring intermittent use. It is diazepam (References 11, 12). -DBF is a rectangular patch smaller than the size of a postage stamp that is applied to the oral buccal mucosa on the inside of the cheek. It consists of films. - Diazepam is transported within the soluble polymer matrix of the film and absorbed transmucosally. And then it gets swallowed up.

[0201] Currently, we offer diazepam rectal gel (DRG; Diastat®, AcuDial® rectal gel). Valeant Pharmaceuticals, Bridgewater, NJ, USA) and Midazolam Nasal Spray (Ny Ziram® Nasal Spray (UCB Biopharma, Smyrna, GA, USA) is a breakthrough product. - It is the only treatment approved by the FDA for seizures or cluster seizures (References 2, 13-1) 6) Current treatments using these methods have certain limitations. -Rectal administration can be difficult and time-consuming, and there are other issues related to embarrassment and social acceptance. This concern poses a problem for many patients and caregivers (References 13, 17, 18). - Intranasal administration is often unacceptable to patients and negatively impacts medication compliance. It may give.

[0202] • Pharmacokinetic (PK) data from Phase 1 studies in healthy adults showed that DBF was better than DRG. exposure (area under the concentration-time curve [AUC], maximum plasma concentration [C max ]) indicates high overall consistency As shown (Reference 12).

[0203] (the purpose) This research experiment aims to evaluate the PK performance of DBF in people with epilepsy for use in the treatment of ARS. This was done to compare it with DRG, the only FDA-approved diazepam preparation currently available.

[0204] (Research experiment design and patients) Randomized, multicenter, single-dose, open-label, two-group, two-permutation crossover study (NCT03953820). -Adult epilepsy patients receiving a stable anticonvulsant regimen, with a single dose of DBF and Students were randomized to receive a single dose of DRG in a crossover manner. - A 28-day drug-free period was included between administrations of the investigational drug. -Administer DRG according to the FDA-approved label weight-based regimen (dose range 10-20 mg), DBF C max A weight-based regimen (dose range 10-17) that is predicted to have PK performance similar to that of DRG. The drug was administered according to the prescribed dosage of 0.5 mg (Table 10). - The therapeutic drug was administered after consuming a moderate-fat meal.

[0205] (Table 10: Research experiments on drug administration based on patient weight categories) [Table 12] a :DRG was administered according to the weight-based regimen recommended on the FDA-approved label (see reference). Reference 16).

[0206] • For each administration of the investigational drug, patients will be required to take the medication from approximately 14 hours before administration until 24 hours after administration. I was kept at the clinic until after my blood test. - Patients may also need to return to the clinical facility for blood sampling 24 hours after medication, or have a home care nurse administer the sample. It can also be used to collect items. - While staying at the clinic, patients should be given a standardized moderate-fat diet before being offered at least 10 I fasted overnight for a period of time.

[0207] (Evaluation of research experiments) • During each period, blood samples for PK analysis were collected before and after drug administration at concentrations of 0.5, 0.75, 1, and 1. Samples were collected at 5, 2, 3, 4, 6, 9, 12, 24, 48, 72, 96, 120, 144, 192, and 240 hours, and PK evaluation was performed. It made the price possible. - Blood samples taken within the first 8 hours after administration should be taken within ±1 minute, and within 8-24 hours after administration. A time range of ±3 minutes is acceptable for the collected sample, and ±60 minutes for all subsequent blood samples. It was done. • The main target PK parameter is C max , C max Time until (T max ), from time zero to the end (AUC) up to non-zero concentration 0-t ), and the AUC (AUC) extrapolated from time zero to infinite time. 0-INF )of include. Adverse events (AEs) were monitored throughout the research experiment.

[0208] (Data analysis) • The safety study population includes all patients who received at least one dose of the investigational drug. This PK population completed both the first and second periods and did not commit any significant violations of the study protocol. This included all patients whose PK profiles could be appropriately characterized. • PK data was analyzed using descriptive statistics for the entire study population and for each weight category. It was summarized as follows. • The AUC obtained by logarithmically transforming the ANOVA method with an α of 0.05. 0-t AUC 0-INF , and C max It was executed in the model. The contributing factors were the sequence, the subjects within the sequence, the duration, and the treatment. max Nonpa The analysis was performed using the Lametric Wilcoxon signed-rank test. • Geometric mean of 90% confidence interval based on least squares mean from ANOVA of logarithmically transformed data The ratios are applied to all subjects regardless of weight category, and to subjects within each weight category. C max AUC 0-t , and AUC 0-INF Calculate the DBF value for the DRG value related to this. Ta.

[0209] (result) (patient) Of the 31 registered patients, 28 had PK profiles valid for both DBF and DRG analysis. It was available to the following subjects (13 men, 15 women, mean [SD] weight: 84.6 [20.6 kg]). - Treatment for both DBF and DRG was not completed (n=2), or the diazepam concentration before administration was C max Patients exceeding 5% (n=1) were excluded from the PK analysis. The mean (SD) dose of diazepam was 15.4 (1.9) mg and 17.1 (3.0) mg in DBF and DRG, respectively. Ta.

[0210] (Pharmacokinetics and safety) • The entire research and experimental population (C max and T max For this, N=28, AUC 0-t and AUC 0-INF (N=27) Table 11 shows the geometric mean and geometric mean ratio (DBF / DRG) of the PK parameters. -AUC 0-t and AUC 0-INF The value for DBF was higher than that for DRG. - Overall, T max DRG was significantly shorter than DBF (P<0.05). - Of the 28 subjects who received DRG, 3 failed to achieve a plasma concentration of 70 ng / mL or higher (70 ng / mL is associated with an elevated seizure threshold determined by pharmacodynamic PK studies in rats. This is the estimated threshold plasma concentration of diazepam (Reference 19).

[0211] (Table 11: DBF and DRG after moderate-fat diet intake in the entire study population of adults with epilepsy (N=28) (Pharmacokinetic parameters after administration) [Table 13] a :expression e (difference) The calculation was performed using the least squares mean according to the multiplier of 100. b 90% geometric confidence intervals using log-transformed data. c N=27. d P < 0.05 for DBF.

[0212] Figure 7 shows the geometric mean diazepam plasma concentrations over time in the entire study population after DBF and DRG administration. show. -In the entire study population, the geometric mean C after DBF and DRG administration. max The values ​​are 204.26 ng / mL (geometric SD[ The GSD values ​​were 136.12-306.49 and 211.22 ng / mL (GSD 87.71-508.63), which are the values ​​after DBF administration. C max The value is C after DRG. max The values ​​were similar, but the variation was significantly less (P<0.000). 1) This is shown (insert in Table 11 and Figure 7). The graphed values ​​are geometric mean (geometric SE) plasma concentrations. Regarding the inserted portion, the geometric mean ( Geometric SD)C max Value, observed maximum plasma drug concentration C max DBF stands for diazepam buccal film. DRG stands for Diazepam Rectal Gel, SD stands for Standard Deviation, and SE stands for Standard Error. ·C max The geometric mean and the corresponding percentages within each weight category are shown in Table 12. -C max The values ​​showed less variation in DBF compared to DRG (Figure 8).

[0213] (Table 12. Maximum plasma concentrations of DBF and DRG by weight category (N=28) (C MAX )) [Table 14] a :expression e (difference) The calculation was performed using the least squares mean according to the multiplier of 100. b 90% geometric confidence intervals using log-transformed data. c The maximum weight category includes four individuals weighing between 112 and 124.5 kg. CI, confidence interval; C max , watch Observed maximum plasma drug concentration; DBF, diazepam buccal film; DRG, diazepam rectal gel . No serious adverse events (AEs) related to the investigational drug were reported.

[0214] (Conclusion) These results indicate that the incidence of epilepsy follows a weight-based regimen after consuming a moderate-fat diet. When administered to adults, a single dose of DBF provides the same level of diazepam exposure as DRG. Furthermore, we demonstrate that the variability is significantly less. • C after DBF administration max The geometric mean was consistently ≥ 150 ng / mL across all weight categories. These results, despite being achieved through treatment with antiepileptic drugs, represent a breakthrough. An easily administered DRG alternative for epilepsy patients experiencing seizures or cluster seizures. I support the further development of DBF as a medicine.

[0215] References (Each reference is incorporated in its entirety through citation.) [Table 15]

[0216] Other embodiments are within the scope of the following claims.

Claims

1. The delivery of diazepam from the matrix, and the fact that at least some of the diazepam is absorbed into the mucosal tissue Dia in a multimodal delivery profile, including facilitating permeation through the weave. How to administer zepam.

2. The multimodal profile is a bimodal delivery profile, according to claim 1. Method of description.

3. The method according to claim 1, further comprising delivering a permeable enhancer from the matrix. Law.

4. The method described in claim 1 involves administering at least approximately 5-50% of diazepam via the oral transmucosal route. Method of loading.

5. The method according to claim 1, wherein at least about 5% of diazepam is administered via the gastrointestinal route.

6. The method according to claim 1, wherein diazepam is administered as a prophylactic treatment.

7. The method according to claim 1, wherein diazepam is administered as an emergency treatment drug.

8. The method according to claim 1, wherein diazepam is administered to treat CNS disorders.

9. The method according to claim 1, wherein diazepam is administered to treat seizures.

10. The method according to claim 1, wherein diazepam is administered to treat generalized seizures.

11. The method according to claim 1, wherein diazepam is administered to treat a focal seizure.

12. The method according to claim 1, wherein diazepam is administered to treat a focal, pre-conscious seizure.

13. The method according to claim 1, wherein diazepam is administered to treat a focal impairment of consciousness seizure.

14. The method according to claim 1, wherein diazepam is administered to treat bilateral tonic seizures.

15. The method according to claim 1, wherein diazepam is administered to treat absence seizures.

16. The method according to claim 1, wherein diazepam is administered to treat atypical absence seizures.

17. The method according to claim 1, wherein diazepam is administered to treat tonic-clonic seizures.

18. The method according to claim 1, wherein diazepam is administered to treat cataplexy.

19. The method according to claim 1, wherein diazepam is administered to treat clonic seizures.

20. The method according to claim 1, wherein diazepam is administered to treat tonic seizures.

21. The method according to claim 1, wherein diazepam is administered to treat myoclonic seizures.

22. The method according to claim 1, wherein diazepam is administered to treat laughter and crying fits. 。

23. The method according to claim 1, wherein diazepam is administered to treat febrile seizures.

24. The method according to claim 1, wherein diazepam is administered to treat non-epileptic seizures.

25. The method according to claim 1, wherein diazepam is administered to treat refractory seizures.

26. The method according to claim 1, wherein diazepam is administered in a food-like state.

27. Furthermore, the dose is increased to ensure that the subject achieves a safe and effective dose while consuming food. The dose of diazepam is adjusted to correct the food effect by counteracting it. The method according to claim 1, comprising:

28. The method according to claim 1, wherein diazepam is administered to a fasted state.

29. The method according to claim 1, wherein approximately 2.5 to 30 mg of diazepam is delivered.

30. The method according to claim 1, wherein approximately 2.5 mg of diazepam is delivered in a single dose.

31. The method according to claim 1, wherein approximately 5 mg of diazepam is delivered as a single dose.

32. The method according to claim 1, wherein approximately 7.5 mg of diazepam is delivered in a single dose.

33. The method according to claim 1, wherein approximately 10 mg of diazepam is delivered as a single dose.

34. The method according to claim 1, wherein approximately 12.5 mg of diazepam is delivered in a single dose.

35. The method according to claim 1, wherein approximately 15 mg of diazepam is delivered as a single dose.

36. The method according to claim 1, wherein approximately 17.5 mg of diazepam is delivered in a single dose.

37. The method according to claim 1, wherein approximately 20 mg of diazepam is delivered as a single dose.

38. The method according to claim 1, wherein approximately 25 mg of diazepam is delivered as a single dose.

39. The method according to claim 1, wherein approximately 30 mg of diazepam is delivered as a single dose.

40. The method according to claim 1, wherein the dose of diazepam is administered according to a body weight-based regimen.

41. The method according to claim 1, wherein the matrix is ​​a mucosal adhesion matrix.

42. Diazepam, in chewable or gelatin form, or lyophilized or inhaled form. In the form of a spray, gum, gel, cream, film, capsule, or tablet, it can be administered as a liquid. The method according to claim 1.

43. The matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 30 minutes, as described in claim 1. method.

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

45. The matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 10 minutes, as described in claim 1. method.

46. The matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 5 minutes, as described in claim 1. Law.

47. The method according to claim 1, wherein the permeation enhancer comprises a terpenoid.

48. The method according to claim 1, wherein the permeation enhancer comprises an aliphatic alcohol.

49. The method according to claim 1, wherein the permeation enhancer comprises an aromatic alcohol.

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

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

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

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

54. This includes delivering 2.5 to 30 mg of diazepam from an oral matrix within less than one hour. A treatment method for the condition, including administering diazepam in a multimodal profile.

55. The multimodal profile is a bimodal profile, as described in claim 54. The method.

56. The diazepam is delivered via at least a transmucosal route and a gastrointestinal route, as described in claim 54. Method of loading.

57. The process involves delivering diazepam and a permeation enhancer from the matrix, wherein the diazepam Delivered with an effective linear AUC and up to approximately 10 ml of C max To achieve this, multimodal pro A treatment method for the condition, including administering diazepam via a file.

58. The multimodal profile is a bimodal profile, as described in claim 57. The method.

59. The diazepam is delivered via at least a transmucosal route and a gastrointestinal route, as per claim 57. Method of description.

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