Multimodal composition and therapeutic method

Abstract

A method for administering diazepam in a multimodal delivery profile is described.

Description

[Technical Field]

[0001] (Claiming priority) This application claims priority to U.S. Provisional Application No. 62 / 935,460, filed on November 14, 2019, which is incorporated herein by reference in its entirety.

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

[0003] (background) Seizures are sudden, uncontrolled electrical disturbances in the brain. They can cause changes in behavior, actions, or emotions, and in the level of consciousness. If a person experiences two or more seizures or a tendency toward recurrent seizures, they are often diagnosed with epilepsy. Epilepsy is a neurological disorder characterized by sudden, frequent episodes of sensory disturbances, loss of consciousness, or convulsions associated with abnormal electrical activity in the brain. Benzodiazepines are often used to treat conditions such as seizures, anxiety disorders, insomnia, alcohol withdrawal disorders, and amnesia. They can be used as muscle relaxants. They may be prescribed before anesthesia, such as before surgery. Some examples of benzodiazepines are alprazolam (Xanax), lorazepam (Ativan), chlordiazepoxide (Librium), and diazepam (Valium). Benzodiazepines can be used to treat CNS (central nervous system) disorders. [Overview of the project]

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

[0005] In one embodiment, the method may further include delivering a permeable enhancer from the matrix. In one embodiment, at least about 5-50% of diazepam is administered via the oral mucosal route. In another embodiment, at least about 5% of diazepam is administered via the gastrointestinal route.

[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. In another embodiment, diazepam can be administered to treat focal presbyopia.

[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, a method of administering diazepam includes adjusting the dose of diazepam to compensate for the food effect by increasing the dose to offset the food effect, so that the subject achieves a safe and effective dose while ingesting food. 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 administered as a chewable tablet, gelatin, lyophilized, or inhalation-based dosage form, spray, gum, gel, cream, film, capsule, or tablet.

[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] Broadly speaking, the treatment of the condition involves administering diazepam in a multimodal profile, including delivering 2.5 to 30 mg of diazepam from an oral matrix within less than one hour.

[0021] In one embodiment, the method for treating the condition includes administering 2.5 to 30 mg of diazepam in a bimodal profile. In one embodiment, the method for treating the disease includes delivering 2.5 to 30 mg of diazepam via at least a transmucosal route and a gastrointestinal route.

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

[0023] Broadly speaking, the treatment of the condition involves delivering diazepam in a multimodal profile, delivering diazepam and a permeation enhancer from the matrix, so that the diazepam is delivered and has an effective linear AUC and up to approximately 10 ml of C. max This includes achieving the following. A method of treating the condition may include delivering diazepam and a permeation enhancer from a matrix such that diazepam has a multimodal profile, where diazepam has a bimodal profile.

[0024] Treatment for this condition also involves administering diazepam so that it is delivered at least via the transmucosal and gastrointestinal routes. Diazepam has an effective linear AUC and a C1 up to approximately 10 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. [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. Available treatment options remain limited. Benzodiazepines, including diazepam and midazolam, are the mainstay of emergency seizure treatment, including acute recurrent seizures. When parenteral (intravenous or intramuscular) administration is not feasible, non-extraintestinal formulations are used. Currently available non-extraintestinal formulations have limitations in terms of ease of use, accuracy of administration, potential for inflammation (irritation), patient and caregiver acceptance, rate of action, and portability. Benzodiazepines can cause toxic effects and can be overdosed intentionally or accidentally. Therefore, dosing regimens that enable improved dosing and control, medication compliance, rate of action, accountability, and ease of use would provide solutions to important but still unresolved challenges.

[0031] Traditionally, diazepam gel formulations intended for rectal administration (e.g., Diastat® Rectal Gel) have been administered to certain epilepsy patients. This medication is given to patients who require the use of diazepam as needed to control the duration of exacerbated seizure behavior. Common side effects of this medication include somnolence, drowsiness, or hypnosis. Other side effects include dizziness, headache, pain, abdominal pain, nervousness, vasodilation, diarrhea, ataxia or impaired coordination, euphoria, asthma, rhinitis (allergic or cold-like nasal inflammation), and rash. Diazepam, as well as other products currently available for the treatment of ARS and acute seizures, have significant limitations. Rectal administration is difficult to implement and may cause distress to patients and caregivers, and its use may be restricted by social and legal constraints. Intranasal administration is often unacceptable to patients due to improper administration and nasal inflammation, and may negatively impact medication compliance. Most oral tablets of benzodiazepines, such as lorazepam, diazepam, and clonazepam, must be swallowed with water, which is only feasible if the patient is aware and careful. Some sublingual or buccal dosage forms may also require patient cooperation depending on the characteristics of the pharmaceutical composition. While lorazepam in orally dispersible tablet form (Temesta Expidet®) is used sublingually for the treatment of acute attacks in children, lorazepam and other available oral dosage forms may not act as rapidly as rectal diazepam.

[0032] Epileptic patients experiencing worrying seizure exacerbations outside of a medical setting would benefit from prompt treatment by caregivers or bystanders, and even from self-administration. Such seizure exacerbations are classified into a continuum ranging from isolated breakthrough seizures (including seizures more severe or longer-lasting than the patient's usual seizures) to acute recurrent seizures (ARS), and the most severe form, status epilepticus. ARS, also commonly referred to as cluster seizures or sequential seizures, typically describes a series of seizures that are grouped together and have short (or shorter than usual) inter-seizure intervals. More generally, ARS can be seen as a change in seizure frequency that requires treatment. Patients experiencing ARS have drug-refractory epilepsy and experience spontaneous seizures on a recurrent basis. When ARS is identified, concerns arise regarding seizure-related risks, including post-seizure psychotic disorders, injuries from falls or burns, and social and pharmacoeconomic consequences such as frequent emergency room visits, hospitalizations, or missed school or work days; and, importantly, concerns about status epilepticus, which can lead to persistent neurological damage or death. Parenteral (intravenous or intramuscular) administration is preferred for emergency seizure treatment, particularly in the emergency treatment of status epilepticus. If parenteral therapy is not feasible, or if the patient experiences episodes too frequently for parenteral therapy to be practical, non-parental formulations are used as an alternative. The goal of this therapy would be to prevent seizure recurrence, interrupt the progression of a series of seizures, or terminate an ongoing seizure.

[0033] Drug delivery via the oral mucosa is an alternative to systemic drug delivery and offers several advantages over injection, nasogastric, rectal, and enteral administration methods. Because the oral mucosa is highly vascularized, drugs absorbed through the oral mucosa bypass first-pass metabolism in the gastrointestinal tract and liver and enter the systemic circulation directly. For some drugs, this allows for a rapid onset of action via a more comfortable and convenient delivery route than intravenous routes. Absorption via the oral mucosa can be 100%. In some embodiments, absorption via the oral mucosa can be less than 100%. For example, in some embodiments, absorption via the oral mucosa can be less than about 90%. It can be less than about 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%. In some embodiments, absorption via the oral mucosa may exceed approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or even 90%.

[0034] Diazepam buccal film (DBF) is a novel formulation that incorporates diazepam in a soluble polymer matrix in a compact, portable, and easily administered manner. It has a pharmacokinetic profile similar to diazepam administered rectally, but is delivered via multimodal delivery. Multimodal delivery means that the active ingredient is delivered via multiple routes, such as the transmucosal and gastrointestinal routes. DBF is applied to the oral mucosa inside the cheek, where the film adheres, is hydrated, and releases diazepam, which is absorbed through the oral buccal mucosa and also swallowed, allowing for some enteral absorption. Several studies have shown that there was no significant difference in bioavailability in adult epilepsy patients when DBF was applied during the interictal or peripheral seizure period (within 5 minutes of seizure). DBF can be placed successfully even without patient cooperation immediately after a seizure and is generally used without problems. In fact, in a cross-comparison study with diazepam rectal gel (Diastat®) in adult epilepsy patients, DBF performed comparably to the rectal gel but with less variability in peak exposure. DBF is a convenient alternative for out-of-hospital treatment of seizure exacerbations. DBF is also useful for treating acute emergency seizures. It is known to be safe and well-tolerated for pediatric, adolescent, and adult epilepsy patients experiencing emergency seizures, especially out-of-hospital patients. DBF was ultimately well-placed in 99.6% of its uses and was easily administered without difficulty, even when administered by patients and caregivers.

[0035] Diazepam can be administered via a monomodal delivery profile. In other embodiments, diazepam can also be administered via a multimodal delivery profile. Diazepam can also be administered via a bimodal delivery profile.

[0036] The absorption of diazepam through the mucosa is determined by several factors, including (i) the rate of release from the film, (ii) the surface area of the film, (iii) the residence time of the film, and (iv) the ability of the molecule to permeate across the oral mucosa and reach the vascular system. Despite a significant improvement in the permeation rate by incorporating a penetration enhancer into the formulation, only a portion of diazepam is delivered transmucosally. The remainder of the diazepam is washed away or swallowed by the saliva flow and excreted into the gastrointestinal tract and absorbed into the body. The combination of these two absorption pathways allows DBF to provide diazepam blood levels faster than achieved by oral administration alone, but due to its high oral bioavailability, a full dose is provided for all applications. However, the swallowed portion of diazepam is also exposed to variations in the absorption rate due to the well-known food effect.

[0037] 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 T max can also be observed in the range of about 1 to 1.5 hours. However, after ingestion of a medium-fat meal, the onset of absorption may be delayed up to about 45 minutes, and T max is extended to about 2 to 3 hours. Along with the delay in absorption, as absorption occurs over a longer period of time, C max decreases. 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 (1) the predicted median of diazepam C max after ingestion of a medium-fat meal is similar to the median of C max after administration of the dose described on the label of the Diastat rectal gel, and (2) the predicted median of diazepam C max obtained in the fasting state does not exceed the median of C max observed in the first-phase trial of DBF and demonstrated to be safe. The predicted diazepam C maxThe median C was observed in 104 healthy volunteers (adult males and females) who received DBF 15 mg in a fasted state during a Phase 1 trial conducted by Acuestive. max It was demonstrated that the median was not significantly exceeded. C in these 104 healthy subjects (127 DBF doses) max The median was 467 ng / mL. Under conditions of a moderate-fat diet, the proposed DBF dosing regimen was expected to reduce C after administration of the corresponding dose labeled on Diastat rectal gel (DRG). max Similar to C max This generates [the substance]. Finally, high-dose and low-dose formulations were tested in pilot clinical trials against DRG at intensities of 5 mg and 20 mg. The results showed excellent agreement between 5 mg DBF and 5 mg DRG, and also supported dose-proportionality between 20 mg DBF and 5 mg DBF. This is in contrast to the lack of proportionality between 5 mg DRG and 20 mg DRG shown in Figure 1C. 20 mg DBF was predicted to achieve approximately 367 ng / ml, but unexpectedly exceeded 600 ng / ml or 180% of the target C. max It exceeded expectations.

[0039] Unexpectedly, DBF can reach the therapeutic range 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 more than 5 minutes. Under certain conditions, DBF can reach the therapeutic range in more than 10 minutes, more than 15 minutes, more than 30 minutes, or more than 45 minutes. In the therapeutic range of DBF, blood concentrations of DBF of 100 ng / ml or higher, 90 ng / ml or higher, 80 ng / ml or higher, 70 ng / ml or higher, 60 ng / ml or higher, 50 ng / ml or higher, 40 ng / ml or higher, 30 ng / ml or higher, 20 ng / ml or higher, or 10 ng / ml or higher can be observed. In one embodiment, the therapeutic range for DBF is observed when the blood concentration of DBF is ≤10 ng / ml, ≤20 ng / ml, ≤30 ng / ml, ≤40 ng / ml, ≤50 ng / ml, ≤60 ng / ml, ≤70 ng / ml, ≤80 ng / ml, ≤90 ng / ml, or ≤100 ng / ml.

[0040] Even more unexpectedly, 17.5 mg of DBF provides the same bioavailability as DRG. Furthermore, even more unexpectedly, 17.5 mg of DBF provides the same C25% bioavailability as 20 mg of DRG when consumed with a moderate-fat diet. max It was revealed that they would provide it.

[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 C and AUC increased proportionally with dose. In contrast, the PK behavior of DRG was not linear. Specifically, in the case of DRG, C max (3) DBF showed a food effect (C after ingesting a high-fat diet) maxThe 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, DRG is thought to be unaffected by food because it is administered via the rectal route. Compared to diastat gel delivered rectally, transmucosal or transbuccal films can reduce inter-subject variability.

[0042] The applicant used population PK modeling to select the medication regimens to correct the PK differences between DBF and DRG, as shown in the table below.

[0043] [Table 1]

[0044] Simply put, the recommended DBF dose corresponding to each weight class specified on the Diastat rectal gel label is (1) diazepam C produced after consuming a moderate-fat meal. max The predicted median is C after administration of the labeled dose of Diastat rectal gel. max (2) Provides a sufficiently high dose to ensure that it is similar to the median, and (3) diazepam C obtained in a fasted state. max The predicted median was observed in a Phase 1 healthy volunteer trial of DBF, demonstrating safety. max We selected a dose that would not exceed the median. Simulations based on population PK modeling predict that the proposed drug regimen will be effective after administration of the labeled dose of diastat rectal gel under conditions of a moderate-fat diet. max Similar to C max We demonstrated that this was generated for each weight class.

[0045] In another example, the medication regimen may be as shown in the table below. [Table 2] TIFF0007898377000003.tif187170TIFF0007898377000004.tif186170

[0046] Population pharmacokinetic modeling was used to model the pharmacokinetic profiles of DBF and Diastat rectal gel in fasting and food intake states. This modeling can show acceptable profiles in a fasting state, after a moderate-fat diet, or after a high-fat diet. This profile can distinguish between male and female subjects. Female subjects may have lower plasma concentrations. Treatment methods for the condition include delivery of 0.1–0.4 mg / kg of diazepam, for example, 0.1–0.3 mg / kg of diazepam.

[0047] In some embodiments, the dose may be lower than the equivalent dose of diastat for a certain weight class of subject, for example, in a fasting state. In other embodiments, the dose may be higher than the equivalent dose of diastat for a certain weight class of subject, for example, in a food-consuming state.

[0048] Regarding Figures 1A and 1B (same study), plasma diazepam concentrations were measured in a single-dose, randomized, open-label, 3-period diazepam buccal film (DBF) crossover study of 5 mg, 10 mg, and 15 mg diazepam in 30 fasted, healthy adult male volunteers. Data points represent mean ± SD maximum plasma concentration (C). max ) and the region below the concentration-time curve extrapolated from zero time to infinite time (AUC 0-inf This represents the relationship between the two values. The best-fitting line indicates 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 showed C maxIt showed sublinear dose-proportional pharmacokinetics. Recent animal model studies have shown that plasma diazepam concentrations in the 70 ng / ml range are associated with an elevation of seizure threshold. See, for example, Dhir A, Rogawski MA, “Determination of minimal steady-state plasma level of diazepam causing seizure threshold elevation in rats,” Epilepsia. 2018 May; 59(5):935-944. doi: 10.1111 / epi.14069. Electronically published April 6, 2018, PubMed PMID: 29682729; PubMed Central PMCID: PMC5934328. The mean plasma concentration after a 15 mg DBF dose exceeds this level (70 ng / ml) 15 minutes after application to the oral buccal mucosa.

[0050] Regarding Figure 1B, the applicant found that exposure to diazepam during the interictal and pericillinary periods demonstrated adequate performance of DBF, even when administered to the oral buccal mucosa immediately after an attack, with no significant difference. (18-55 years old, weight 83.5±11.4 kg, BMI 26.7±2.2 kg / m²) 2 In a crossover study, 30 healthy adult males (mean ± SD) received a single dose of DBF containing 5 mg, 10 mg, or 15 mg of diazepam under fasting conditions, in an open-label, randomized order, for three periods, with a 21-day rest period between each treatment period. In Figure 1A, each subject received at least one DBF dose. Data points represent 25–30, which are the mean ± SEM of plasma concentration measurements taken 4 hours after administration. Error bars are not shown if they are smaller than the symbol size.

[0051] Linear interpolation C of 12.5 mg DBF dose in fasted healthy volunteers maxThe value, based on the data shown in Figure 1A, is 417 ng / mL, and is the geometric mean C obtained from studies in subjects with epilepsy. max The value is substantially higher than predicted. Diazepam is N-demethylated by CYP3A4 and CYP2C19, and its clearance is increased by inducers of these isozymes. See, for example, Riss J, Cloyd J, Gates J, and Collins S, "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics," Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111 / j.1600-0404.2008.01004.x. Electronically published March 31, 2008. Review. PubMed PMID: 18384456. Lower C than predicted in epileptic subjects. max The values ​​may, in part, be due to incidental induction from anticonvulsant medications taken by many subjects. AUC consistent with CYP induction. 0-inf There was also a decrease in the average C of the epilepsy population. Additional, yet-to-be-identified factors, such as the effect of food on drug absorption rates due to the subjects not being fasted, also contributed to the decrease in the average C of the epilepsy population. max It will likely play a role in preventing the value from decreasing.

[0052] The food effect observed after DBF administration is clearer than that described for orally administered diazepam. This is presumably a result of the portion of the dose absorbed through the oral buccal mucosa and the portion absorbed orally. Since this portion of the dose is not affected by food, in the food intake state, only a portion of the absorption profile travels for a longer period of time. max The profile (where both absorption pathways are combined in a fasted state) unexpectedly decreased, not only because the portion absorbed orally is reduced by the presence of food, but also because the oral profile is separated from the oral buccal profile.

[0053] (Transparency Enhancer) The in vivo solubility and permeability of pharmacoactive ingredients can vary considerably, particularly within the oral cavity of the target organism. Certain types of permeability enhancers can improve the in vivo uptake and bioavailability of pharmacoactive ingredients. In particular, when delivered to the mouth via a film, permeability enhancers can improve the permeability of pharmacoactive ingredients through the target mucosa into the bloodstream. A permeation enhancer can improve the absorption rate and amount of the pharmaceutically active ingredient by more than 5%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 150%, about 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%, less than 30%, less than 20%, less than 10%, or less than 5%, or a combination of these ranges, depending on the other components in the composition. Examples of suitable permeation enhancers are shown, for example, in U.S. Patent Application No. 15 / 587,364 and U.S. Patent Application No. 15 / 791,249, both of which are incorporated in whole by reference.

[0054] In one embodiment, the pharmaceutical composition comprises a suitable non-toxic, non-ionic alkyl glycoside having a hydrophobic alkyl group linked by bonding with a hydrophilic sugar, in combination with a mucosal delivery promoter selected from the following: (a) an agglutination inhibitor; (b) a charge modifier; (c) a pH adjuster; (d) a degrading enzyme inhibitor; (e) a mucolytic or mucolytic agent; (f) a ciliary movement inhibitor (ciliostatic (g) Membrane penetration enhancers selected from the following: (i) Surfactants; (ii) Bile salts; (ii) Phospholipid additives, mixed micelles, liposomes, or carriers; (iii) Alcohols; (iv) Enamines; (v) Nitric oxide donors; (vi) Long-chain amphiphilic molecules; (vii) Low molecular weight hydrophobic penetration enhancers; (viii) Sodium or salicylic acid derivatives; (ix) Glycerol acetoacetate esters; (x) Cyclodextrin or β-cyclodextrin derivatives; (xi) Medium-chain fatty acids; (xii) Chelating agents; (xiii) Amino acids or their salts; (xiv) N-acetylamino acids or their salts; (xv) Selected membrane components (ix) a degradable enzyme; (x) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; and (xi) any combination of the membrane penetration enhancers listed in (i) to (x); (h) a modifier of epithelial binding physiological function; (i) a vasodilator; (j) a selective transport enhancer; and (k) a delivery-stabilizing vehicle, carrier, mucosal adhesive substance, support, or complex-forming species to which the compound is effectively combined, associated, contained, encapsulated, or bound together, resulting in enhanced transmucosal delivery stabilization of the compound, wherein the combination of the compound with the transmucosal delivery enhancer provides increased bioavailability of the compound in the blood plasma of the subject. The penetration enhancer is described in the literature of J. Nicolazzo et al., J. of Controlled Disease, 105 (2005) 1-15, which is incorporated herein by reference.

[0055] (oral mucosa) There are many reasons why the oral mucosa is an attractive site for the delivery of therapeutic drugs into the systemic circulation. Direct blood drainage from the oral buccal epithelium to the internal jugular vein can bypass first-pass metabolism in the liver and intestines. First-pass effect when administered orally can be a major reason for the poor bioavailability of some compounds. In addition, the mucous membrane covering the oral cavity is easily accessible, ensuring that the dosage form is applied to the required site and can be easily removed in emergencies. However, like the skin, the oral buccal mucosa acts as a barrier to the absorption of xenobiotics, which can hinder the permeation of compounds through this tissue. The absence or minimal irritation of oral irritation is also a crucial factor when using transmucosal delivery systems. Therefore, identifying safe and effective penetration enhancers is a primary goal in the search for improved drug delivery through the oral mucosa.

[0056] Chemical osmosis enhancers are substances that control the rate of drug permeation across biological membranes, either co-administered or sequentially. While extensive research has focused on gaining a better understanding of how osmosis enhancers alter enteral and transdermal permeability, little is known about the mechanisms involved in enhancing oral buccal and sublingual osmosis.

[0057] The oral buccal mucosa is located on the inner wall of the cheek, and extends over the area between the gums and the upper and lower lips, and is 100 cm long. 2 It has an average surface area of ​​500-600 μm. The surface of the buccal mucosa inside the oral cavity is made up of stratified squamous epithelium, which is separated from the underlying connective tissue (lamina propria and submucosa) by a gently undulating basement membrane (a continuous layer of extracellular material about 1-2 μm thick). This stratified squamous epithelium consists of differentiated cell layers, which change in size, shape, and content as they move from the basal region to the surface region, and cells are shed in the surface region. There are about 40-50 cell layers, and 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 of the oral cavity, but its epithelium is 100-200 μm thick. This membrane is also non-keratinized and relatively thin, making it more permeable than the buccal mucosa of the oral cavity. Blood flow to the sublingual mucosa is slower than to the buccal mucosa of the oral cavity, at 1.0 ml / min. -1 / cm -2 It is in the order of magnitude. However, because saliva flow to the sublingual region is greater than that to the buccal mucosa of the oral cavity, there is a risk that the drug will be quickly diluted and swallowed before it can penetrate the sublingual mucosa.

[0059] The permeability of the buccal mucosa of the oral cavity is greater than that of the skin, but less than that of the intestines. This difference in permeability is a result of structural differences between the tissues. Because organized lipid lamellae are not present in the intercellular spaces of the buccal mucosa of the oral cavity, it exhibits greater permeability of foreign compounds compared to keratinized skin epithelium. However, the increased thickness and lack of tight junctions of the buccal mucosa of the oral cavity result in lower permeability than intestinal tissue.

[0060] The primary barrier properties 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 have discovered that the permeable barrier of the non-keratinized oral mucosa that extends beyond the surface epithelium can also be the result of the contribution of contents extruded from the granules covering this membrane into the intercellular spaces of the epidermal cells.

[0061] The intercellular lipids in the non-keratinized areas of the oral cavity are more polar than those in the epidermis, palate, and gingiva, and these differences in the chemical properties of the lipids likely contribute to the differences in permeability observed between these tissues. Therefore, it is clear that a more effective barrier is created not only by a greater degree of intercellular lipid filling within the stratum corneum of keratinized epithelium, but also by the chemical properties of the lipids present within that barrier.

[0062] (Paracellular transport and transcellular transport) The presence of hydrophilic and lipophilic regions within the oral mucosa led researchers to hypothesize the existence of two drug transport pathways through the buccal mucosa of the oral cavity: a paracellular (intercellular) pathway and a transcellular (intracellular) pathway.

[0063] Drug delivery through the buccal mucosa of the oral cavity is limited by the barrier properties of the epithelium and the area available for absorption; therefore, various enhancement strategies are needed to deliver therapeutically appropriate amounts of drugs into the systemic circulation. Various methods, including the use of chemiopermeable enhancers, permeable prodrugs, and physical methods, can be used to overcome the barrier properties of the buccal mucosa of the oral cavity.

[0064] Chemical permeability enhancers, or absorption promoters, are substances added to pharmaceutical formulations to increase the membrane permeability or absorption rate of co-administered drugs without causing membrane damage and / or toxicity. Numerous studies have investigated the effects of chemical permeability enhancers on the delivery of compounds through the skin, nasal mucosa, and intestines. In recent years, more attention has been paid to the effects of these agents on permeability through the oral buccal mucosa. Since permeability through the oral buccal mucosa is considered a passive diffusion process, the steady-state flux (Jss) should increase with increasing donor chamber concentration (CD), according to Fick's first law of diffusion.

[0065] (Surfactants, bile salts, and other permeation enhancers) Surfactants and bile salts have been shown to enhance the permeability of various compounds through the oral mucosa both in vitro and in vivo. Aromatic and aliphatic alcohols, such as benzyl alcohol, can enhance the permeability of various compounds through the oral mucosa both in vitro and in vivo. Data obtained from these studies strongly suggest that the enhancement of permeability is due to the action of surfactants on the intercellular lipids of the mucosa. Permeation enhancers can be applied to the oral mucosa, for example, via intraoral buccal or sublingual administration. Permeation enhancers may be synthetic compounds. In some embodiments, permeation enhancers may be biosynthetic compounds. In some embodiments, permeation enhancers may be natural compounds. In other embodiments, permeation enhancers may include combinations of compounds selected from one or more of these compound species.

[0066] Fatty acids have been shown to enhance the permeability of many drugs through the skin, and differential scanning calorimetry and Fourier transform infrared spectroscopy have indicated that this is related to increased intercellular lipid fluidity.

[0067] Furthermore, it has been shown that pretreatment with ethanol enhances the permeability of tritium-labeled water and albumin through the ventral lingual mucosa, and also enhances caffeine permeability through the buccal mucosa of the oral cavity of pigs. In addition, several reports have been made regarding the enhancing effect of Azone® on the permeability of compounds through oral mucosa. Moreover, it has been shown that chitosan, a biocompatible and biodegradable polymer, enhances drug delivery through various tissues, including the intestinal and nasal mucosa.

[0068] Oral transmucosal drug delivery (OTDD) is the administration of pharmaceutically active agents to achieve systemic effects through the oral mucosa. Permeation pathways and predictive models for OTDD are described, for example, in M. Sattar's paper, "Oral transmucosal drug delivery—Current status and future prospects," Int'l. Journal of Pharmaceutics, 47(2014) 498-506, which is incorporated herein by reference. OTDD continues to attract the attention of academic and industrial scientists. Despite limited characterization of oral permeation pathways compared to cutaneous and nasal delivery pathways, the outlook is bright due to our recent advances in understanding the extent to which ionized molecules permeate the oral buccal epithelium, the emergence of new analytical techniques for studying and experimenting in the oral cavity, and the progress in the development of in silico models to predict oral buccal and sublingual permeability.

[0069] To deliver a wider range of drugs through the oral buccal mucosa, reversible methods should be used to reduce the potential barrier properties of this tissue. This need drives research and experimentation with penetration enhancers that can safely alter the limitations of oral buccal mucosal permeability. It has been shown that penetration through the oral buccal mucosa can be improved by using various types of transmucosal and transdermal penetration enhancers, including bile salts, surfactants, fatty acids and their derivatives, chelating agents, cyclodextrins, and chitosan. Of these chemicals used to enhance drug permeability, bile salts are the most common.

[0070] In vitro studies on the enhancing effect of bile salts on the oral buccal permeability of compounds are discussed in Sevda Senel's paper, "Drug permeation enhancement via buccal route: possibilities and limitations," Journal of Controlled Release 72 (2001) 133-144, which is incorporated herein by reference. This paper also discusses recent research on the effects of dihydroxybile salts, sodium glycodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC), as well as trihydroxybile salts, sodium glycocholate (GC) and sodium taurocholate (TC) on oral buccal epithelial permeability at a concentration of 100 mM, including changes in permeability related to histological effects. Fluorescein isothiocyanate (FITC) and morphine sulfate were used as model compounds, respectively. Chitosan has also been shown to enhance the absorption of polar small molecules and peptide / protein drugs through the nasal mucosa in animal models and human volunteers. Other studies have shown an enhancing effect on the penetration of compounds through the intestinal mucosa and cultured Caco-2 cells.

[0071] The permeation enhancer may be a plant extract. The plant extract may be an essential oil or composition containing an essential oil extracted by distillation of a plant material. In some cases, the plant extract may contain a synthetic analog of a compound extracted from a plant material (i.e., a compound made by organic synthesis). The plant extract may contain phenylpropanoids, such as phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamic acid esters, cinnamaldehyde, hydrocinnamic acid, chavicol, or safrole, or a combination thereof. The plant extract may also be an essential oil extract of the clove plant, such as an essential oil extracted from the leaves, stems, or flower buds of the clove plant. The clove plant may be the clove tree (Syzygium aromaticum). The plant extract may contain 20-95% eugenol, 40-95% eugenol, 60-95% eugenol, or, for example, 80-95% eugenol. The extract may also contain 5% to 15% eugenol acetate. The extract may also contain caryophyllene. The extract may also contain up to 2.1% α-humulene. Other volatile compounds present in clove essential oil at low concentrations may be β-pinene, limonene, farnesol, benzaldehyde, 2-heptanone, and ethyl hexanoate. Another permeation enhancer may be added to the composition to improve drug absorption. Suitable permeation enhancers include natural or synthetic bile salts, such as sodium fusidate; glycocholic acids or deoxycholic acids and their salts; fatty acids and derivatives, such as sodium laurate, oleic acid, oleyl alcohol, monoolein, or palmitoylcarnitine; chelating agents, such as disodium EDTA, sodium citrate and sodium lauryl sulfate, azone, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynonyl-9, laureth-9, polysorbate, sterol, or glycerides, such as caprylocaproyl polyoxylglyceride or labrasol. Permeation enhancers may also include derivatives of plant extracts and / or monolignols. The permeation enhancer may also be a fungal extract.

[0072] Some natural products of plant origin are known to have vasodilatory effects. Several mechanisms or modes exist by which plant-based products can induce vasodilation. For a review, see the literature by JR McNeill and TM Jurgens, Can. J. Physiol. Pharmacol. 84:803-821 (2006), which is incorporated herein by reference. Specifically, the vasodilatory effect of eugenol has been reported in numerous animal studies. For example, see the literature by Lahlou, S. et al., J. Cardiovasc. Pharmacol. 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 WR, J. Dent Res. 62(9):1013-15 (1983), each incorporated herein by reference. Calcium channel blockade has been suggested to be the cause of vasodilation induced by plant essential oils, or their main component, eugenol. See the literature by Interaminense LRL et al., Fundamental & Clin. Pharmacol. 21: 497-506 (2007), incorporated herein by reference.

[0073] Fatty acids can be used as inactive components in drug formulations or drug vehicles. Fatty acids can also be used as pharmaceutical components due to their special functional properties and biocompatibility. Fatty acids, both as free lipids and as part of complex lipids, are major metabolic fuels (storage and transport energy) and essential components of all membranes and gene regulators. For a review, see Rustan AC and Drevon, CA, “Fatty Acids: Structures and Properties, Encyclopedia of Life Sciences” (2005), incorporated herein by reference. Essential fatty acids metabolized in the human body belong to two families: ω-3 and ω-6 polyunsaturated fatty acids (PUFAs). If the first double bond is located between the third and fourth carbon atoms from the ω-carbon, these are called ω-3 fatty acids. If the first double bond is located between the sixth and seventh carbon atoms, these are called ω-6 fatty acids. PUFAs are further metabolized in the body through the addition of carbon atoms and desaturation (removal of hydrogen). Linoleic acid, an omega-6 fatty acid, is metabolized into gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenaline, tetracosatetraenoic acid, tetracosapentaenoic acid, and docosapentaenoic acid. Alpha-linolenic acid, an omega-3 fatty acid, is metabolized into octadecatetraenoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and docosahexaenoic acid (DHA).

[0074] Fatty acids such as palmitic acid, oleic acid, linoleic acid, and eicosapentaenoic acid are Na + K +It has been reported that relaxation and hyperpolarization of porcine coronary artery smooth muscle cells were induced via a mechanism involved in the activation of the APTase pump, and that the efficacy increased with increasing cis-unsaturation of the fatty acid. See Pomposiello, SI et al., Hypertension 31:615-20 (1998), incorporated herein by reference. Interestingly, the pulmonary vascular response to arachidonic acid, a metabolite of linoleic acid, can be either vasoconstrictive or vasodilatory, depending on the dose, animal species, mode of arachidonic acid administration, and tone of pulmonary circulation. For example, arachidonic acid has been reported to cause cyclooxygenase-dependent and cyclooxygenase-independent pulmonary vasodilation. See also the works of Feddersen, CO et al., J. Appl. Physiol. 68(5):1799-808(1990); Spannhake, EW et al., J. Appl. Physiol. 44:397-495(1978); and Wicks, TC et al., Circ. Res. 38:167-71(1976), each incorporated herein by reference.

[0075] Numerous studies have reported the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on vascular responsiveness after administration in orally ingestible forms. Several studies have found that EPA-DHA or EPA alone inhibited the vasoconstrictive effect of norepinephrine or enhanced the vasodilatory response to acetylcholine in the forearm microcirculation. See Chin, JPF et al., Hypertension 21:22-8 (1993), and Tagawa, H. et al., J Cardiovasc Pharmacol 33:633-40 (1999), respectively, which are incorporated herein by reference. Another study found that both EPA and DHA tended to increase systemic arterial compliance and decrease pulse pressure and total vascular resistance. See Nestel, P. et al., Am J. Clin. Nutr. 76:326-30 (2002), which is incorporated herein by reference. On the other hand, one study found that DHA, not EPA, enhanced the vasodilatory mechanism and attenuated the systolic response in the forearm microcirculation of overweight men with hyperlipidemia. See Mori, TA et al., Circulation 102:1264-69 (2000), which is incorporated herein by reference. Another study found the vasodilatory effect of DHA on rhythmic contraction of isolated human coronary arteries in vitro. See Wu, K.-T. et al., Chinese J. Physiol. 50(4):164-70 (2007), which is incorporated herein by reference.

[0076] (In the order of permeation enhancers (multiple may be used) and active pharmaceutical ingredients (multiple may be used)) The arrangement, order, or sequence of penetration enhancers(s) and active pharmaceutical ingredients(s) (APIs) delivered to a desired mucosal surface is variable to deliver a desired pharmacokinetic profile. For example, the penetration enhancers(s) may be applied first by film, swab, spray, gel, rinse, or by the first layer of film, followed by the APIs(s) by a single film, swab, or by the second layer of film. This order can also be reversed or modified, for example, by applying the APIs(s) first by film, swab, or by the first layer of film, followed by the penetration enhancers(s) by film, swab, spray, gel, rinse, or by the second layer of film. In another embodiment, the penetration enhancers(s) may be applied by film and the drug by another film. For example, depending on the desired pharmacokinetic profile, a permeation enhancer(s) film may be placed beneath a film containing an API(s), or a film containing an API(s) may be placed beneath a film containing a permeation enhancer(s).

[0077] For example, a penetrating enhancer(s) can be used as a pretreatment, either alone or in combination with at least one API, to precondition the mucosa for further absorption of the API(s). This treatment can be followed by another treatment with neat penetrating enhancer(s), leading to the application of the at least one API to the mucosa. This pretreatment can be applied as a separate 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 contained within a separate domain of a single film designed to dissolve and release into the mucosa, followed by the release of a second domain containing or not containing the penetrating enhancer(s) or API(s). The active ingredient can then be delivered from the second treatment, either alone or in combination with additional penetrating enhancers(s). A third treatment or domain may exist that delivers additional penetration enhancers and / or at least one API or prodrug in different proportions to each other or in proportions different from the total load of other treatments. This makes it possible to obtain a tailored pharmacokinetic profile. Thus, the product may have one or more domains comprising penetration enhancers and APIs, whose application order, composition, concentration, or total load to the mucosa can be varied to lead to a desired absorption amount and / or absorption rate that achieves the intended pharmacokinetic profile and / or pharmacodynamic effect.

[0078] This film format may be such that there is no distinct side, or the film may have at least one side of a multilayer film where multiple ends are shared ends (having or joining one shared boundary or limit).

[0079] The pharmaceutical composition may be in the form of a chewable, gelatinous, lyophilized, or inhalation-based dosage form, such as a spray, gum, gel, cream, tablet, capsule, liquid, or film. The composition may, for example, include textures such as microneedles or micro-protrusions on its surface. Recently, the use of micron-scale needles in increasing skin permeability has been shown to significantly increase transdermal delivery, particularly of macromolecules. Most drug delivery studies have emphasized solid microneedles, which have been shown to increase in vitro skin permeability for a wide range of molecules and nanoparticles. In vivo studies have demonstrated the delivery of oligonucleotides, insulin-induced blood glucose reduction, and induction of immune responses from DNA vaccines. For these studies, needle arrays are used to pore the skin to increase diffusion or iontophoresis-mediated transport, or as drug carriers to release drugs into the skin from microneedle surface coatings. Hollow microneedles have also been developed and have been shown to deliver small amounts of insulin to diabetic rats. For the practical application of microneedles, it was found that the ratio of microneedle fracture strength to skin insertion strength (i.e., safety margin) is optimal for needles with a small tip radius and large wall thickness. Microneedles inserted into the skin of human subjects were reported to be painless. In summary, these results suggest that microneedles are a promising technology for delivering therapeutic compounds into the skin with a range of applicability. Using tools from the microelectronics industry, microneedles are fabricated in a variety of sizes, shapes, and materials. Microneedles may be, for example, fine polymer needles that deliver encapsulated drugs in a minimally invasive manner, but other suitable materials can also be used.

[0080] Microneedles may be used to enhance drug delivery through the oral mucosa, particularly in conjunction with the claimed composition. The microneedles create micron-sized pores in the oral mucosa, which can enhance drug delivery through the mucosa. Solid, hollow, or soluble microneedles can be fabricated from suitable materials, including, but not limited to, metals, polymers, glass, and ceramics. Microfabrication processes may include photolithography, silicon etching, laser cutting, metal electroplating, metal electropolishing, and molding. The microneedles may also be solids used to pre-treat tissue and removed before application of the film. The drug-supported polymer films described in this application can be used as the matrix material for the microneedles themselves. These films may have microneedles or micro-protrusions fabricated on their surface that dissolve after forming microchannels in the mucosa, through which drugs can permeate.

[0081] The term “film” can include films and sheets of any shape, including rectangular, square, or other desired shapes. Films may have any desired thickness and size. In preferred embodiments, films may have a thickness and size such that they can be administered to a user, for example, placed in the user’s oral cavity. Films may have a relatively thin thickness of about 0.0025 mm to about 0.250 mm, or they may have a slightly thicker thickness of about 0.250 mm to about 1.0 mm. In some films, the thickness may be greater, i.e., greater than about 1.0 mm, or thinner, i.e., less than about 0.0025 mm. Films may be single-layer, or they may be multilayer, including laminated films or multiple-cast films. The permeation enhancer and the pharmaceutically active ingredient may be combined within a single layer, contained in separate layers, or contained in separate regions of the same dosage form. In one embodiment, the pharmaceutically active ingredient contained within the polymer matrix may be dispersed within the matrix. In another embodiment, the permeation enhancer contained within the polymer matrix may be dispersed within the matrix.

[0082] Oral-soluble films can be divided into three main categories: immediate solubility, moderate solubility, and slow solubility. Oral-soluble films may also include any combination of the above categories. Immediately soluble films dissolve in the mouth in approximately 1 to 30 seconds, including more than 1 second, more than 5 seconds, more than 10 seconds, more than 20 seconds, or less than 30 seconds. Moderately soluble films dissolve in the mouth in approximately 1 to 30 minutes, including more than 1 minute, more than 5 minutes, more than 10 minutes, more than 20 minutes, or less than 30 minutes, while slow-dissolving films dissolve in the mouth over more than 30 minutes. As a general trend, immediately soluble films may contain (or consist of) low molecular weight hydrophilic polymers (e.g., polymers with a molecular weight of approximately 1,000 to 9,000 daltons, or polymers with a molecular weight of up to 200,000 daltons). In contrast, slow-dissolving films generally contain high molecular weight polymers (e.g., with a molecular weight of several million). Moderately soluble films tend to fall somewhere between immediately soluble and slowly soluble films.

[0083] It is sometimes preferable to use a moderately soluble film. A moderately soluble film can dissolve fairly quickly, but also has a good level of mucosal adhesion. A moderately soluble film is also flexible, quickly wettable, and usually non-irritating to the user. Such a moderately soluble film can provide a sufficiently rapid dissolution rate, most preferably about 1 to 20 minutes, while providing an acceptable level of mucosal adhesion that prevents the film from easily peeling off once placed in the user's oral cavity. This ensures the delivery of the pharmaceutically active ingredient to the user.

[0084] A pharmaceutical composition may contain one or more pharmaceutically active ingredients. These pharmaceutically active ingredients may be a single pharmaceutically active ingredient or a combination of pharmaceutically active ingredients. The pharmaceutically active ingredient may be an anti-inflammatory analgesic, a steroidal anti-inflammatory, an antihistamine, a local anesthetic, a bactericide, a disinfectant, a vasoconstrictor, a hemostatic agent, a chemotherapeutic agent, an antibiotic, a keratolytic agent, a cauterizing agent, an antiviral agent, an antirheumatic agent, an antihypertensive agent, a bronchodilator, an anticholinergic, an anxiolytic, an antiemetic compound, a hormone, a peptide, a protein, or a vaccine. These pharmaceutically active ingredients may be pharmaceutically acceptable salts of drugs, prodrugs, derivatives, drug conjugates, or analogs of drugs.

[0085] The term “prodrug” refers to a biologically inactive compound that can be metabolized in the body to produce a biologically active drug, or a “prodrug” may be a biologically active compound that, in addition to its intrinsic biological activity, is metabolized to produce a drug having another or more preferred biological activity. In some embodiments, a prodrug may also have its own biological activity, which may be similar to or different from that of the active drug. For example, a prodrug may be an ester of epinephrine, such as dipivefrin, which is hydrolyzed to epinephrine. See, for example, J. Anderson et al., “Site of ocular hydrolysis of a prodrug, dipivefrin, and a comparison of its ocular metabolism with that of the parent compound, epinephrine,” Invest., Ophthalmol. Vis. Sci. July 1980. The prodrug may be a benzodiazepine prodrug such as abizafone, which is a prodrug of diazepam. Another prodrug from the benzodiazepine chemical series that falls within the scope of this invention is ethyl loflazepate. All chemical derivatives, analogs, or prodrugs of benzodiazepines are considered to fall within the scope of this invention.

[0086] In some embodiments, the film may contain more than one pharmaceutically active ingredient. This pharmaceutically active ingredient may include ACE inhibitors, anti-anginal drugs, antiarrhythmic drugs, anti-asthmatic drugs, anticholesterolemia drugs, analgesics, anesthetics, anticonvulsants, antidepressants, antidiabetics, antidiarrheal preparations, antidetoxins, antihistamines, antihypertensive drugs, anti-inflammatory drugs, anti-lipid drugs, anti-mania drugs, anti-nausea drugs, anti-stroke drugs, anti-thyroid preparations, amphetamines, antitumor drugs, antiviral drugs, acne drugs, alkaloids, amino acid preparations, antitussives, antiuricemia drugs, antiviral drugs, anabolic drugs, etc. Dispensing drugs, systemic and non-systemic anti-infective drugs, antineoplastic drugs, antiparkinson's disease drugs, antirheumatic drugs, appetite stimulants, blood modifiers, bone metabolism regulators, cardiovascular drugs, central nervous system stimulants, cholinesterase inhibitors, contraceptives, decongestants, nutritional supplements, dopamine receptor agonists, endometrial regulators, enzymes, erectile dysfunction drugs, fertility agents, gastrointestinal drugs, homeopathic remedies, hormones, drugs for managing hypercalcemia and hypocalcemia, immunomodulators, etc. Epidemic suppressants, migraine medications, motion sickness medications, muscle relaxants, obesity control medications, osteoporosis medications, uterine contraction drugs, parasympathetic blockers, parasympathetic mimetic drugs, prostaglandins, psychotropic drugs, respiratory drugs, sedatives, smoking cessation aids, sympathetic blockers, tremor medications, urethral drugs, vasodilators, laxatives, antacids, ion exchange resins, antipyretics, appetite suppressants, expectorants, anxiolytics, anti-ulcer drugs, anti-inflammatory substances, coronary vasodilators, cerebral vasodilators, peripheral vasodilators, Psychotropic drugs, stimulants, antihypertensive drugs, vasoconstrictors, migraine medications, antibiotics, tranquilizers, antipsychotics, antitumor drugs, anticoagulants, antithrombotic drugs, hypnotics, antiemetics, antinausea drugs, anticonvulsants, neuromuscular drugs, hyperglycemia and hypoglycemia drugs, thyroid and antithyroid preparations, diuretics, seizure suppressants, uterine relaxants, antiobesity drugs, erythropoiesis-forming agents, antiasthmatic drugs, antitussives, mucolytics, DNA and genetic modification agents, diagnostic agents, contrast agents, dyes, or tracers, as well as combinations thereof. Suitable active ingredients used in the films described herein include, but are not limited to, the following therapeutic types: ACE inhibitors, adrenergic agents, corticosteroids, corticosteroids, aldosterone antagonists, alkaloids, amino acids, anabolic drugs, stimulants, analgesics, anesthetics, appetite suppressants, antiacids, anti-adrenergic agents, anti-allergic agents, anti-amebic agents,Anti-anemia drugs, anti-angina drugs, anti-anxiety drugs, anti-arthritis drugs, antiarrhythmic drugs, anti-asthma drugs, anti-atherosclerotic drugs, anticholesterolemia drugs, antibacterial drugs, antibiotics, anticholinergics, anticoagulants, anticonvulsants, antidepressants, antidiabetic drugs, antidiarrheal drugs, antidiuretics, antitoxin drugs, antiemetics, antiepileptic drugs, antifibrinolytics, antifungal drugs, hemostatic drugs, antihistamines, antihyperlipidemic drugs, antihypertensive drugs, vasopressors, antiinfective drugs (both systemic and non-systemic), anti-inflammatory drugs, antilipid drugs, antimanic drugs, antimicrobial drugs, antimigraine drugs, mitotic inhibitors, antifungal drugs, antinausea drugs, antineoplastic drugs, antineutropenia drugs, antiobesity drugs, Antiparasitic drugs, antiparkinson's disease drugs, antiproliferative drugs, antipsychotics, antipyretics, antirheumatic drugs, antiseborrheic drugs, secretion inhibitors, seizure inhibitors, antistroke drugs, antithrombotic drugs, antithyroid drugs, antitumor drugs, antitussives, antiulcer drugs, antiuricemia drugs, antiviral drugs, appetite suppressants, appetite stimulants, biological response modifiers, blood glucose regulators, blood modifiers, blood metabolism modifiers, bone resorption inhibitors, bronchodilators, cardiovascular drugs, central nervous system stimulants, cerebral vasodilators, contraceptives, coronary vasodilators, cholinergics, antitussives, decongestants, inhibitors, diagnostic aids, nutritional supplements, diuretics, dopamine agonists, enzymes, estroneous steroids Geno receptor agonists, endometrial regulators, expectorants, erectile dysfunction medications, erythropoiesis, ibrinolytics, fertility drugs, fluorescent agents, free radical oxygen scavengers, gastric acid inhibitors, gastrointestinal motility effectors, gene modifiers, glucocorticoids, hair growth stimulants, hemostatic agents, histamine H2 receptor antagonists, homeopathic remedies, hormones, hypercalcemia control agents, hypocalcemia control agents, hypocholesterolemia control agents, hypoglycemic agents, lipid-lowering agents, antihypertensive agents, ion exchange resins, contrast agents, immunotherapy drugs, immunomodulators, immunotherapy drugs Immunostimulants, immunosuppressants, keratolytics, laxatives, LHRH agonists, mood regulators, motion sickness medications, mucolytics, muscle relaxants, mydriatics, nasal congestion inhibitors, neuromuscular blockers, neuroprotective agents, NMDA antagonists, non-hormonal sterol derivatives, osteoporosis medications, uterine contraction agents, parasympathetic blockers, parasympathetic agonists, plasminogen activators, platelet-activating factor antagonists, platelet aggregation inhibitors, prostaglandins, psychotropic drugs, antipsychotics, radiopharmaceuticals, respiratory drugs, scabies insecticides, sclerosing agents, sedatives, sedative hypnotics,Selective adenosine A1 antagonists, serotonin antagonists, serotonin inhibitors, serotonin receptor antagonists, smoking cessation medications, steroids, stimulants, sympathomimetic drugs, terine relaxants, thyroid hormones, thyroid inhibitors, thyroid mimetic drugs, tranquilizers, tremor medications, amyotrophic lateral sclerosis medications, ischemic drugs, Paget's disease medications, unstable angina medications, vasoconstrictors, vasodilators, weight management medications, wound healing medications, xanthine oxidase inhibitors, and combinations thereof.

[0087] Examples of suitable active ingredients used herein include antacids, H2 antagonists, and analgesics. For example, antacids may be prepared using calcium carbonate alone or in combination with magnesium hydroxide and / or aluminum hydroxide. Furthermore, antacids may be used in combination with H2 antagonists.

[0088] Analgesics include opioids and opioid derivatives, such as oxycodone (available on the market as Oxycontin®); ibuprofen (available on the market as Motrin®, Advil®, Motrin Children's®, Motrin IB®, Advil Children's®, Motrin Infants'®, Motrin Junior®, Ibu-2®, Proprinal®, Ibu-200®, Middle Cramp Formula®, Bufen®, Motrin Migraine Pain®, Addaprin®, and Haltran®); aspirin (available on the market as Empirin®, Ecotrin®, Genuine Bayer®, and Halfprin®); and acetaminophen (available on the market as Silapap Infant's®, Silapap Children's®, Tylenol®). This includes Children's®, Tylenol Extra Strength®, Tylenol Infants' Original®, Tylenol Infants'®, Tylenol Arthritis®, T-Painol®, Q-Pap®, Cetafen®, Dolono®, Tycolene®, APAP®, and Aminofen® (available on the market), as well as combinations thereof that may optionally contain caffeine.Other pain relievers that can be used in this invention include meperidine hydrochloride (available on the market as Demerol®), capsaicin (available on the market as Qutenza®), morphine sulfate and naltrexone hydrochloride (available on the market as Embeda®), hydromorphone hydrochloride (available on the market as Dilaud®), propoxyfen napsylate and acetaminophen (available on the market as Darvocet-N®), fentanyl (Duragesic®, Onsolis®, and Fentor Available on the market as a (registered trademark), sodium hyaluronate (available on the market as Euflexxa (registered trademark)), adalimumab (available on the market as Humira (registered trademark)), sumatriptan succinate (available on the market as Imitrex (registered trademark)), fentanyl for iontophoresis (available on the market as Ionsys (registered trademark)), orphenadyl tetrahydrate (available on the market as Norgesic (registered trademark)), magnesium salicylate tetrahydrate (available on the market as Novasal (registered trademark)), oxymorphone hydrochloride (Opana It may also include ER (available on the market as registered trademark), methocarbamol (available on the market as registered trademark Robaxin), carisoprodol (available on the market as registered trademark Soma), tramadol hydrochloride (available on the market as registered trademark Ultracet and registered trademark Ultram), morphine sulfate (available on the market as registered trademark MS Contin), metaxalone (available on the market as registered trademark Skelaxin), oxycodone hydrochloride (available on the market as registered trademark OxyContin), acetaminophen / oxycodone hydrochloride (available on the market as registered trademark Percocet), oxycodone / aspirin (available on the market as registered trademark Percodan), hydrocodone tartrate / acetaminophen (available on the market as registered trademark Vicodin), hydrocodone tartrate / ibuprofen (available on the market as registered trademark Vicoprofen), nepafenac (available on the market as registered trademark Nevanac), and pregabalin (available on the market as registered trademark Lyrica).

[0089] The films disclosed herein may further contain drugs such as NSAIDs, for example, etodolac (available on the market as Lodine®), ketrolactromethamine (available on the market as Acular® or Acuvail®), naproxen sodium (available on the market as Anaprox® or Naprosyn®), flurbiprofen (available on the market as Ansaid®), diclofenac sodium / misoprostol (available on the market as Arthrotec®), celecoxib (available on the market as Celebrex®), sulindac (available on the market as Clinoril®), oxaprozin (Daypro®), and These include piroxicam (available on the market as Feldene®), indomethacin (available on the market as Indocin®), meloxicam (available on the market as Mobic®), mefenamic acid (available on the market as Ponstel®), tolmetin sodium (available on the market as Tolectin®), choline magnesium trisalicylate (available on the market as Trilisate®), diclofenac sodium (available on the market as Voltaren®), diclofenac potassium (available on the market as Cambia® or Zipsor®), and misoprostol (available on the market as Cytotec®). Opium agonists and antagonists, such as buprenorphine and naloxone, are also examples of drugs for use in the present invention.

[0090] Other drugs for use as specified herein include antidiarrheal agents such as loperamide (available on the market as Imodium AD®, Imotil®, Kaodene®, Imperim®, Diamode®, QC Anti-Diarrheal®, Health Care America Anti-Diarrheal®, Leader AD®, and Imogen®), nitazoxanide (available on the market as Alinia®), and diphenoxylate hydrochloride / atropine sulfate (available on the market as Lomotil®), as well as antihistamines, cough suppressants, decongestants, vitamins, and breath fresheners. Common drugs used alone or in combination for colds, pain, fever, cough, congestion, runny nose, and allergies, such as acetaminophen, ibuprofen, chlorpheniramine maleate, dextromethorphan, dextromethorphan HBr, phenylephrine HCl, pseudoephedrine HCl, diphenhydramine, and combinations thereof, such as dextromethophan HBr and phenylephrine HCl (available as Triaminic®), can be included in the film composition of the present invention.

[0091] Other active ingredients available herein include, but are not limited to, alcohol-dependent treatments such as acamprosate calcium (available on the market as Campral®); allergy treatments such as promethazine hydrochloride (available on the market as Fenelgan®), bepotastine besilate (available on the market as Bepreve®), hydrocodone polystyrex / chlorpheniramine polystyrex (available on the market as Tussionex®), cetirizine hydrochloride (available on the market as Zyrtec®), cetirizine hydrochloride / pseudoephedrine hydrochloride (available on the market as Zyrtec-D®), and promethazine hydrochloride / codeine phosphate (Fenelgan-Codeine (Registered Trademark)). Available on the market as (trademark), pemirolast (available on the market as Alamast®), fexofenadine hydrochloride (available on the market as Allegra®), meclizine hydrochloride (available on the market as Antivert®), azelastine hydrochloride (available on the market as Astelin®), nizatidine (available on the market as Axid®), desloratadine (available on the market as Clarinex®), cromolyn sodium (available on the market as Crolom®), epinastine hydrochloride (available on the market as Elestat®), azelastine hydrochloride (available on the market as Optivar®), prednisolone phosphate sodium (available on the market as Orapred ODT®), olopatadine hydrochloride (available on the market as Patanol®), ketotifen fumarate (available on the market as Zaditor®), and montelukast sodium (available on the market as Singulair®);Furthermore, antihistamines, such as diphenhydramine HCl (available as Benadryl®), loratadine (available as Claritin®), astemizole (available as Hismanal®), nabumetone (available as Relafen®), diphenydramine HCl (available as TheraFlu®), and clemastine (available as Tavist®), are included.

[0092] The films of this disclosure further include Alzheimer's treatments, such as tacrine hydrochloride (available on the market as Cognex®), galantamine (available on the market as Razadyne®), donepezil hydrochloride (available on the market as Aricept®), rivastigmine tartrate (available on the market as Exelon®), caprylidene (available on the market as Axona®), and memantine (available on the market as Namenda®); anemia treatments, such as cyanocobalamin (available on the market as Nascobal®) and fermoxitol (available on the market as Feraheme®); and anesthetics, such as antipyrine-benzocaine (Auralg Available on the market as an(registered trademark), Aurodex(registered trademark), and Auroto(registered trademark); angina treatments, e.g., amlodipine besylate (available on the market as Norvasc(registered trademark), nitroglycerin (available on the market as Nitro-Bid(registered trademark), Nitro-Dur(registered trademark), Nitrolingual(registered trademark), Nitrostat(registered trademark), and Transderm-Nitro(registered trademark)), isosorbide mononitrate (available on the market as Imdur(registered trademark), and isosorbide dinitrate (available on the market as Isordil(registered trademark)); cough suppressants, e.g., guaifensin; anti-Alzheimer's drugs, e.g., nicergoline; and Ca H -Antagonists may also be included, such as nifedipine (available on the market as Procardia® and Adalat®).

[0093] The active ingredients that can be used in this disclosure also include antiasthmatic drugs, such as albuterol sulfate (available on the market as Proventil®), ipratropium bromide (available on the market as Atrovent®), salmeterol xinafoate (available on the market as Serevent®), zafirlukast (available on the market as Accolate®), flunisolide (available on the market as AeroBid®), metaproterenol sulfate (available on the market as Alupent®), albuterol inhalant (available on the market as Ventolin®), terbutaline sulfate (available on the market as Brethine®), formoterol (available on the market as Foradil®), and cromolyn sodium (available on the market as Intal®). Revalbuterol hydrochloride (available on the market as Xopenex®), Ziloton (available on the market as Zyflo®), fluticasone propionate / salmeterol (available on the market as Advair®), albuterol sulfate / triamcinolone acetonide (available on the market as Azmacort®), dimethylxanthine (available on the market as theophylline®), and beclomethasone (available on the market as Beclovent®, Beconase®, Qvar®, Vanancenase®, Vanceril®); and angioedema treatments, such as human C1 esterase inhibitors (available on the market as Berinert®) and ecalantide (available on the market as Kalbitor®);The formulation may also include antimicrobial agents, such as trimethoprim / sulfamethoxazole (available on the market as Bactrim®), mupirocin (available on the market as Bactroban®), metronidazole (available on the market as Flagyl®), acetylsulfisoxazole (available on the market as Gantricin®), bismuth subsalicylate and metronidazole / tetracycline hydrochloride (available on the market as Helidac Therapy®), nitrofurantoin (available on the market as Macrodantin®), norfloxacin (available on the market as Noroxin®), erythromycin ethyl succinate / acetylsulfisoxazole (available on the market as Pediazole®), and levofloxacin (available on the market as Levaquin®).

[0094] The films of this disclosure may further contain one or more antibiotics, including amoxicillin (available on the market as Amoxil®), ampicillin (available on the market as Omnipen®, Polycillin®, and Principen®), amoxicillin / clavulanate potassium (available on the market as Augmentin®), moxifloxacin hydrochloride (available on the market as Avelox®), besifloxacin (available on the market as Besivance®), clarithromycin (available on the market as Biaxin®), ceftibutene (available on the market as Cedax®), cefuroxime axetil (available on the market as Ceftin®), cefprodil (available on the market as Cefzil®), ciprofloxacin hydrochloride (available on the market as Ciloxan® and Cipro®), and clindamycin phosphate (Cleocin Available on the market as T(registered trademark), doxycycline helicrate (available on the market as Doryx(registered trademark)), dylithromycin (available on the market as Dynabac(registered trademark)), erythromycin (available on the market as EES(registered trademark), E-Mycin(registered trademark), Eryc(registered trademark), Ery-Tab(registered trademark), Erythrocin(registered trademark), and PCE(registered trademark)), topical erythromycin (available on the market as A / T / S(registered trademark), Erycette(registered trademark), T-Stat(registered trademark)). (Possible), Gemifloxacin (available on the market as Factive®), Ofloxacin (known as Ocuflox® and Floxin®), Telithromycin (available on the market as Ketek®), Lomefloxacin hydrochloride (available on the market as Maxaquin®), Minocycline hydrochloride (available on the market as Minocin®), Fosfomycin tromethamine (available on the market as Monurol®), Penicillin potassium (PenicillinVK (registered trademark, available on the market as Veetids (registered trademark)), trimethoprim (available on the market as Primsol (registered trademark)), ciprofloxacin hydrochloride (available on the market as Proquin XR (registered trademark)), rifampin, isoniazid and pyrazinamide (available on the market as Rifater (registered trademark)), cefditoren (available on the market as Spectracef (registered trademark)), cefixime (available on the market as Suprax (registered trademark)), tetracycline (Achromycin Available on the market as V (registered trademark) and Sumycin (registered trademark), tobramycin (available on the market as Tobrex (registered trademark)), rifaximin (available on the market as Xifaxan (registered trademark)), azithromycin (available on the market as Zithromax (registered trademark)), azithromycin suspension (available on the market as Zmax (registered trademark)), linezolid (available on the market as Zyvox (registered trademark)), benzoyl peroxide and clindamycin (available on the market as BenzaClin (registered trademark)), This includes erythromycin and benzoyl peroxide (available on the market as Benzamycin®), dexamethasone (available on the market as Ozurdex®), ciprofloxacin and dexamethasone (available on the market as Ciprodex®), polymyxin B sulfate / neomycin sulfate / hydrocortisone (available on the market as Cortisporin®), colistin sulfate / neomycin sulfate / hydrocortisone acetate / tonzonium bromide (available on the market as Cortisporin-TC Otic®), cephalexin hydrochloride (available on the market as Keflex®), cefdinir (available on the market as Omnicef®), and gatifloxacin (available on the market as Zymar®).

[0095] Other available active ingredients include cancer treatments, e.g., cyclophosphamide (available on the market as Cytoxan®), methotrexate (available on the market as Rheumatrex® and Trexal®), tamoxifen citrate (available on the market as Nolvadex®), bevacizumab (available on the market as Avastin®), everolimus (available on the market as Afinitor®), pazopanib (available on the market as Votrient®), and anastrozole (available on the market as Arimidex®); leukemia treatments, e.g., ofatumumab (available on the market as Arzerra®); and antithrombotic agents, e.g. Examples include antithrombin recombinant freeze-dried powder (available on the market as Atryn®), prasugrel (available on the market as Efient®); anticoagulants, such as aspirin-sustained-release dipyridamole (available on the market as Agrenox®), warfarin sodium (available on the market as Coumadin®), dipyridamole (available on the market as Persantine®), dalteparin (available on the market as Fragmin®), danaparoid (available on the market as Orgaran®), enoxaparin (available on the market as Lovenox®), heparin (Hep-Lock, Hep-Pak, Hep-Pak) CVC (available on the market as Heparin Lock Flush), tinzaparin (available on the market as Innohep®), and clopidogrel bisulfate (available on the market as Plavix®); antiemetics, such as granisetron hydrochloride (available on the market as Kytril®) and nabilone (available on the market as Cesamet®), trimethobenzuamide hydrochloride (available on the market as Tigan®), and ondansetron hydrochloride (available on the market as Zofran®);Antifungal agents include, for example, ketoconazole (available on the market as Nizoral®), posaconazole (available on the market as Noxafil®), cyclopirox (available on the market as Penlac®), griseofulvin (available on the market as Gris-PEG®), oxiconazole nitrate (available on the market as Oxistat®), fluconazole (available on the market as Diflucan®), sertaconazole nitrate (available on the market as Ertaczo®), terbinafine hydrochloride (available on the market as Lamisil®), cyclopirox (available on the market as Loprox®), nystatin / triamcinolone acetonide (available on the market as Mycolog-II®), econazole nitrate (available on the market as Spectazole®), itraconazole (available on the market as Sporanox®), and terconazole (available on the market as Terazol®). ;

[0096] The active ingredients also include anti-inflammatory drugs, such as hydroxychloroquine sulfate (available on the market as Plaquenil®), fluticasone propionate (available on the market as Cutivate®), canakinumab (available on the market as Llaris®), amcinonide (available on the market as Cyclocort®), methylprednisolone (available on the market as Medrol®), and budesonide (Entocort). Available on the market as EC (registered trademark), anakinra (available on the market as Kineret (registered trademark)), diflorasone diacetate (available on the market as Psorcon (registered trademark)), and etanercept (available on the market as Enbrel (registered trademark)); seizure suppressants, e.g., phenobarbital / hyosciamine sulfate / atropine sulfate / scopolamine hydrobromide (available on the market as Donnatal (registered trademark)); antiviral agents, e.g., oseltamivir phosphate (available on the market as Tamiflu (registered trademark)); antiparasitic agents, e.g., tinidazole (available on the market as Tindamax (registered trademark)); appetite suppressants, e.g., megestrol acetate (Megace Available on the market as ES (registered trademark), phentermine hydrochloride (available on the market as Adipex-P (registered trademark)), and diethylpropion hydrochloride (available on the market as Tenuate (registered trademark)); arthritis medications, such as leflunomide (available on the market as Arava (registered trademark)), certolizumab pegol (available on the market as Cimzia (registered trademark)), diclofenac sodium (available on the market as Pennsaid (registered trademark)), golimumab (available on the market as Simponi (registered trademark)), and tocilizumab (available on the market as Actemra (registered trademark));Bladder control agents, e.g., throspium chloride (available on the market as Sanctura®), desmopressin acetate (available on the market as DDAVP®), tolterodine tartrate (available on the market as Detrol®), oxybutynin chloride (available on the market as Ditropan® or Gelnique®), dalifenacin (available on the market as Enablex®), and solifenacin succinate (available on the market as VESIcare®); vasoconstrictors, e.g., methylergonovine maleate (available on the market as Methergine®); plasmaurinary control agents (plasma uric (manager), e.g., rasburicase (available on the market as Elitek®); iron deficiency anemia treatment, e.g., fermoxitol (available on the market as Ferahem®); lymphoma treatment, e.g., pralatrexate (available on the market as Folotyn®), romidepsin (available on the market as Isodax®); malaria treatment, e.g., artemether / lumefantrine (available on the market as Coartem®); hyponatremia treatment, e.g., tolvatpan (available on the market as Samsca®); von Willebrand disease treatment (available on the market as Wilate®); antihypertensive treatment, e.g., treprostinil (available on the market as Tyvaso®), tadalafil (available on the market as Adcirca®);Cholesterol-lowering drugs include, for example, paricalcitol (available on the market as Altocor®), pitavastatin (available on the market as Livalo®), lovastatin, niacin (available on the market as Advicor®), colestipol hydrochloride (available on the market as Colestid®), rosuvastatin calcium (available on the market as Crestor®), fluvastatin sodium (available on the market as Lescol®), atorvastatin calcium (available on the market as Lipitor®), lovastatin (available on the market as Mevacor®), niacin (available on the market as Niaspan®), pravastatin sodium (available on the market as Pravacol®), and pavastatin sodium-buffered aspirin (Pravigard). This may include PAC (available on the market as registered trademark), cholestyramine (available on the market as registered trademark Questran), simvastatin and niacin (available on the market as registered trademark Simcor), atenolol, chlorthalidone (available on the market as registered trademark Tenoretic), atenolol (available on the market as registered trademark Tenormin), fenofibrate (available on the market as registered trademark Tricor), fenofibrate (available on the market as registered trademark Triglide), ezetimibe / simvastatin (available on the market as registered trademark Vytorin), coleseveram (available on the market as registered trademark WelChol), bisoprolol fumarate (available on the market as registered trademark Zebeta), ezetimibe (available on the market as registered trademark Zetia), bisoprolol fumarate / hydrochlorothiazide (available on the market as registered trademark Ziac), and simvastatin (available on the market as registered trademark Zocor).

[0097] The active ingredients included herein are also used in the treatment of chronic kidney disease, for example, paricalcitol (available on the market as Zemplar®); contraceptives, for example, etonogestrel (available on the market as Implanon®), norethindrone acetate, ethinylestradiol (available on the market as Loestrin 24 FE®), ethinylestradiol, norelgestromine (available on the market as Ortho Evra®), and levonorgestrel (Plan Available on the market as B (registered trademark), levonorgestrel and ethinylestradiol (available on the market as Preven (registered trademark)), levonorgestrel, ethinylestradiol (available on the market as Seasonique (registered trademark)), and medroxyprogesterone acetate (available on the market as Depo-Provera (registered trademark)); COPD treatments, e.g., alformoterol tartrate (available on the market as Brovana (registered trademark)) and ipratropium bromide, albuterol sulfate (available on the market as Combivent (registered trademark)); cough suppressants, e.g., benzonatate (available on the market as Tessalon (registered trademark)), guaifenesin, codeine phosphate (available on the market as Tussi-Organidin NR (registered trademark)), and acetaminophen-codeine phosphate (available on the market as Tylenol-Codeine (registered trademark)); diabetes treatments, e.g., pioglitazone hydrochloride, metformin hydrochloride (ACTOplus Available on the market as met(registered trademark), bromocriptine mesylate (available on the market as Cycloset(registered trademark)), liraglutide (available on the market as Victoza(registered trademark)), saxagliptin (available on the market as Onglyza(registered trademark)), pioglitazone hydrochloride (available on the market as Actos(registered trademark)), glimepiride (available on the market as Amaryl(registered trademark)), rosiglitazone maleate, metformin hydrochloride (available on the market as Avandaryl(registered trademark)), rosiglitazone maleate (available on the market as Avandia(registered trademark)),Exenatide (available on the market as Byetta®), exenatide (available on the market as Bydureon®), chlorpropamide (available on the market as Diabinese®), pioglitazone hydrochloride, glimepiride (available on the market as Duetact®), metformin hydrochloride (available on the market as Glucophage®), glipizide (available on the market as Glucotrol®), glibride, metformin (available on the market as Glucovance® and Fortamet®), metformin hydrochloride (available on the market as Glumetza®), sitagliptin (available on the market as Januvia®), detemir (available on the market as Levemir®), glipizide, metformin hydrochloride (available on the market as Metaglip®), glibride (Micronase( This may include (available on the market as registered trademark), repaglinide (available on the market as Prandin®), acarbose (available on the market as Precose®), nateglinide (available on the market as Starlix®), plumlintide acetate (available on the market as Symlin®), canagliflozin (available on the market as Invokana®), linagliptin (available on the market as Tradjenta®), dapagliflozin (available on the market as Farxiga®), insulin glargine (available on the market as Lantus® or Toujeo®), insulin aspart (available on the market as Novolog®), insulin lispro, empagliflozin (available on the market as Jardiance®), and torazamide (available on the market as Tolinase®).

[0098] Other available active ingredients include digestive agents such as sulfasalazine (available on the market as Azulfidine®), rabeprazole sodium (available on the market as AcipHex®), lubiprostone (available on the market as Amitiza®), dicyclomine hydrochloride (available on the market as Bentyl®), sucralfate (available on the market as Carafate®), lactulose (available on the market as Chronulac®), doxate (available on the market as Colace®), and valsalazid disodium. (Available on the market as Colazal®), losartan potassium (Available on the market as Cozaar®), orsalazine sodium (Available on the market as Dipentum®), chlordiazepoxide hydrochloride, clidinium bromide (Available on the market as Librax®), esomeprazole magnesium (Available on the market as Nexium®), famotidine (Available on the market as Pepcid®), lansoprazole (Available on the market as Prevacid®), lansoprazole and naproxen (Prevacid Available on the market as NapraPAC®, amoxicillin / clarithromycin / lansoprazole (available on the market as Prevpac®), omeprazole (available on the market as Prilosec®), pantoprazole sodium (available on the market as Protonix®), metoclopramide hydrochloride (available on the market as Reglan® or Metozolv®), cimetidine (available on the market as Tagamet®), ranitidine hydrochloride (available on the market as Zantac®), and omeprazole, sodium bicarbonate (available on the market as Zegerid®);Diuretics may include, for example, spironolactone, hydrochlorothiazide (available on the market as Aldactazide®), spironolactone (available on the market as Aldactone®), bumetanide (available on the market as Bumex®), torsemide (available on the market as Demadex®), chlorothiazide (available on the market as Diuril®), furosemide (available on the market as Lasix®), metrazone (available on the market as Zaroxolyn®), and hydrochlorothiazide, triamterene (available on the market as Dyazide®).

[0099] The active ingredients available herein also include emphysema treatments, e.g., tiotropium bromide (available on the market as Spiriva®); fibromyalgia treatments, e.g., milnacipran hydrochloride (available on the market as Savella®); gout treatments, e.g., colchicine (available on the market as Colcrys®) and febuxostat (available on the market as Uloric®); enema treatments, e.g., aminosalicylic acid (available on the market as Mesalamine® and Rowasa®); and epilepsy treatments, e.g., valproic acid (Depake®). This may include ne (available on the market as registered trademark), felbamart (available on the market as registered trademark Felbatol), lamotrigine (available on the market as registered trademark Lamictal), primidone (available on the market as registered trademark Mysoline), oxcarbazepine (available on the market as registered trademark Trileptal), zonisamide (available on the market as registered trademark Zonegran), levetiracetam (available on the market as registered trademark Keppra), and phenytoin sodium (available on the market as registered trademark Dilantin).

[0100] The active ingredients available herein also include ophthalmic drugs and therapeutic agents, such as dipivefrin hydrochloride (available on the market as Propine®), valganciclovir (available on the market as Valcyte®), ganciclovir ophthalmic gel (available on the market as Zirgan®); bepotastine besylate (available on the market as Bepreve®), besifloxacin (available on the market as Besivance®), bromfenac (available on the market as Xibrom®), fluorometholone (available on the market as FML®), pilocarpine hydrochloride (available on the market as Pilocar®), cyclosporine (available on the market as Restasis®), and brimonidine tartrate (Alphagan) Available on the market as P (registered trademark), dorzolamide hydrochloride / timolol maleate (available on the market as Cosopt (registered trademark)), bimatoprost (available on the market as Lumigan (registered trademark)), timolol maleate (available as Timoptic (registered trademark)), travoprost (available on the market as Travatan (registered trademark)), latanoprost (available on the market as Xalatan (registered trademark)), ecothiophate iodide (available on the market as Phospholine Iodide (registered trademark)), and ranibizumab (available on the market as Lucentis (registered trademark)); fluid regulators, e.g., acetazolamide (available on the market as Diamox (registered trademark)); gallstone treatments, e.g., ursodiol (available on the market as Actigall (registered trademark)); gingivitis treatments, e.g., chlorhexidine gluconate (available on the market as Peridex (registered trademark));Headache medications, such as butarvital / codeine phosphate / aspirin / caffeine (available on the market as Fiornal®-codeine), naratriptan hydrochloride (available on the market as Amerge®), alumotriptan (available on the market as Axert®), ergotamine tartrate / caffeine (available on the market as Cafergot®), butarvital / acetaminophen / caffeine (available on the market as Fioricet®), butarvital / aspirin / caffeine (available on the market as Fiorinal®), fluvatriptan succinate (available on the market as Frova®), rizatriptan benzoate (available on the market as Maxalt®), isometeptene mucinate / dichlorphenazone / acetaminophen (available on the market as Midrin®), dihydroergotamine mesylate (Migranal®) This may include: eletriptan hydrobromide (available on the market as Relpax®), and zolmitriptan (available on the market as Zomig®); influenza treatments, such as Haemophilus b-conjugate vaccine; tetanus toxoid conjugates (available on the market as Hiberix®); and cardiac treatments, such as quinidine sulfate, isosorbide dinitrate / hydralazine hydrochloride (available on the market as BiDil®), digoxin (available on the market as Lanoxin®), flecainide acetate (available on the market as Tambocor®), mexiletine hydrochloride (available on the market as Mexitil®), disopyramide phosphate (available on the market as Norpace®), procainamide hydrochloride (available on the market as Procanbid®), and propafenone (available on the market as Rythmol®).

[0101] Other available active ingredients include hepatitis medications such as entecavir (available on the market as Baraclude®), hepatitis B immunoglobulin (available on the market as HepaGam B®), and copegus / rebetol / ribasphere / vilona / virazole (available on the market as ribavirin®); herpes medications such as valacyclovir hydrochloride (available on the market as Valtrex®), penciclovir (available on the market as Denavir®), acyclovir (available on the market as Zovirax®), and famciclovir (available on the market as Famvir®); and antihypertensive medications such as enalaprilat (available as Vasotec®), captopril (available as Capoten®), and lisinopril (available as Zestril®), and verapamil hydrochloride (available as Calan®). , ramipril (available on the market as Altace®), olmesartan medoxomil (available on the market as Benicar®), amlodipine / atorvastatin (available on the market as Caduet®), nicardipine hydrochloride (available on the market as Cardene®), diltiazem hydrochloride (available on the market as Cardizem®), quinapril hydrochloride (available on the market as Accupril®), quinapril hydrochloride / hydrochlorothiazide (available on the market as Accuretic®), perindopril erbumine (available on the market as Aceon®), candesartan cilexetil (available on the market as Atacand®), candesartan cilexetil / hydrochlorothiazide (AtacandAvailable on the market as HCT (registered trademark), irbesartan / hydrochlorothiazide (availide (registered trademark)), irbesartan (available on the market as Avapro (registered trademark)), amlodipine besylate / olmesartan medoxomil (available on the market as Azor (registered trademark)), levobunolol hydrochloride (available on the market as Betagan (registered trademark)), betaxolol hydrochloride (available on the market as Betoptic (registered trademark)), nebibolol (available as Bystolic (registered trademark) (Available on the market as) Captopril / hydrochlorothiazide (Available on the market as Capozide®), Doxazosin mesylate (Available on the market as Cardura®), Clonidine hydrochloride (Available on the market as Catapres®), Carvedilol (Available on the market as Coreg®), Nadolol (Available on the market as Corgard®), Nadolol / bendroflumethiazide (Available on the market as Corzide®), Valsartan (Diov Available on the market as an(registered trademark), isradipine (available on the market as DynaCirc(registered trademark)), guanabenz acetate (available on the market as Wytensin(registered trademark)), guanfacine hydrochloride (available on the market as Tenex(registered trademark) or Intuniv(registered trademark)), losartan potassium / hydrochlorothiazide (available on the market as Hyzaar(registered trademark)), propranolol hydrochloride (available on the market as Indera(registered trademark)), propranolol hydrochloride / hydrochlorothiazide (Available on the market as Inderide®), eplerenone (Available on the market as Inspra®), ambrisentan (Available on the market as Letairis®), enalapril maleate / felodipine (Available on the market as Lexxel®), metoprolol tartrate (Available on the market as Lopressor®), benazepril hydrochloride (Available on the market as Lotensin®), benazepril hydrochloride / hydrochlorothiazide (LotensinAvailable on the market as HCT (registered trademark), amlodipine / benazepril hydrochloride (available on the market as Lotrel (registered trademark)), indapamide (available on the market as Lozol (registered trademark)), trandolapril (available on the market as Mavik (registered trademark)), telmisartan (available on the market as Micardis (registered trademark)), telmisartan / hydrochlorothiazide (available on the market as Micardis HCT (registered trademark)), prazosin hydrochloride (available on the market as Minipress (registered trademark)), amiloride, hydrochlorothiazide (available on the market as Moduretic (registered trademark)), hosinopril sodium (ZZXT Available on the market as Monopril (registered trademark), hosinopril sodium / hydrochlorothiazide (available on the market as Monopril-HCT (registered trademark)), pindolol (available on the market as Visken (registered trademark)), felodipine (available on the market as Plendil (registered trademark)), sildenafil citrate (available on the market as Revatio (registered trademark)), nisoldipine (available on the market as Sular (registered trademark)), trandolapril / verapamil hydrochloride (available on the market as Tarka (registered trademark)), aliskiren (available on the market as Tekturna (registered trademark)), eprosartan mesylate (available on the market as Teveten (registered trademark)), eprosartan mesylate / hydrochlorothiazide (Teveten This includes HCT (available on the market as registered trademark), moexipril hydrochloride / hydrochlorothiazide (available on the market as Uniretic (registered trademark)), moexipril hydrochloride (available on the market as Univasc (registered trademark)), enalapril maleate / hydrochlorothiazide (available on the market as Vaseretic (registered trademark)), and lisinopril / hydrochlorothiazide (available on the market as Zestoretic (registered trademark)).

[0102] The films of this disclosure may contain, as usable active ingredients, HIV / AIDS treatment drugs such as amprenavir (available on the market as Agerase®), tipranavir (available on the market as Aptivus®), efavirenz / emtricitabine / tenofovir (available on the market as Atripla®), lamivudine / zidovudine (available on the market as Combivir®), indinavir sulfate (available on the market as Crixivan®), and lamivudine (Ep Available on the market as ivir (registered trademark), saquinavir (available on the market as Fortovase (registered trademark)), zalcitabine (available on the market as Hivid (registered trademark)), lopinavir / ritonavir (available on the market as Kaletra (registered trademark)), fosamprenavir calcium (available on the market as Lexiva (registered trademark)), ritonavir (available on the market as Norvir (registered trademark)), zidovudine (available on the market as Retrovir (registered trademark)), atazanavir sulfate (Reyataz Available on the market as (registered trademark), efavirenz (available on the market as Sustiva®), abacavir / lamivudine / zidovudine (available on the market as Trizivir®), didanosine (available on the market as Videx®), nelfinavir mesylate (available on the market as Viracept®), nevirapine (available on the market as Viramune®), tenofovir disoproxil fumarate (available on the market as Viread®), stabuzine (available on the market as Zerit®), and abacavir sulfate (available on the market as Ziagen®); homocysteiene scavengers, e.g., anhydrous betaine (available on the market as Cystadane®); pharmaceuticals, e.g., insulin (available on the market as Apidra®, Humalog®, Humulin®, Iletin®, Tresiba®, and Novolin®);Furthermore, it may include HPV therapeutic agents, such as human papillomavirus vaccines (available on the market as Gardasil®) or bivalent human papillomavirus vaccines (available on the market as Cervarix®); and immunosuppressants, such as cyclosporine (available on the market as Gengraf®, Neoral®, Sandimmune®, and Apo-Cyclosporine®).

[0103] The active ingredients available in this disclosure also include prolactin inhibitors, e.g., bromocriptine mesylate (available on the market as Parlodel®); adjuncts to stress testing, e.g., regadenoson (available on the market as Lexiscan®); treatments for alopecia, e.g., finasteride (available on the market as Propecia® and Proscar®); treatments for pancreatitis, e.g., gemfibrozil (available on the market as Lopid®); and hormonal treatments, e.g., norethindrone acetate / ethinylestradiol (available on the market as femHRT®) and goserelin acetate (Zoladex®). Available on the market as (as Progesterone Gel (Prochieve®), Progesterone (Prometrium®), Salmon Calcitonin (Miacalcin®), Calcitriol (Rocaltrol®), Synthroid (Levothroid®, Levoxyl®, Unithroid®), Testosterone (Testopel®, Androderm®, Testoderm®, and AndroGel®);Menopausal medications, such as estradiol / norethindrone acetate (available on the market as Activella®), drospirenone / estradiol (available on the market as Angeliq®), and estradiol / levonorgestrel (Climara). Available on the market as Pro(registered trademark), estradiol / norethindrone acetate (available on the market as CombiPatch(registered trademark)), estradiol (available on the market as Estrasorb(registered trademark), Vagifem(registered trademark) and EstroGel(registered trademark)), esterified estrogens and methyltestosterone (available on the market as Estratest(registered trademark)), estrogen (available on the market as Alora(registered trademark), Climara(registered trademark), Esclim(registered trademark), Estraderm(registered trademark), Vivelle(registered trademark), Vivelle-Dot(registered trademark)), estropipate (available on the market as Ogen(registered trademark)), conjugated estrogens (available on the market as Premarin(registered trademark)) and medroxyprogesterone acetate (available on the market as Provera(registered trademark)); menstrual therapy drugs, e.g., leuprolide acetate (Lupron); This may include tranexamic acid (available on the market as Depot), norethindrone acetate (available on the market as Aygestin); and muscle relaxants, such as cyclobenzaprine hydrochloride (available on the market as Flexeril), tizanidine (available on the market as Zanaflex), and hyosciamine sulfate (available on the market as Levsin).

[0104] The active ingredients available in this specification also include osteoporosis treatments, such as ibrandronate sodium. Sodium (available on the market as Boniva®), risedronate (available on the market as Actonel®), raloxifene hydrochloride (available on the market as Evista®, Fortical®), and alendronate sodium (available on the market as Fosamax®); ovulation stimulants, e.g., clomiphene citrate (available on the market as Serophene®, Clomid®, Serophene®); Paget's disease treatments, e.g., etidronate disodium (available on the market as Didronel®); pancreatic enzyme deficiency treatments, e.g., pancrelipase (available on the market as Pancrease® or Zenpep®); Parkinson's disease treatments, e.g., pramipexole dihydrochloride (available on the market as Mirapex®), ropinirole hydrochloride (available on the market as Requip®), carbidopa / levodopa (Sinemet Available on the market as CR (registered trademark), carbidopa / levodopa / entacapone (available on the market as Stalevo (registered trademark)), selegiline hydrochloride (available on the market as Zelapar (registered trademark)), rasagiline (available on the market as Azilect (registered trademark)), entacapone (available on the market as Comtan (registered trademark)), and selegiline hydrochloride (available on the market as Eldepryl (registered trademark)); multiple sclerosis treatments, such as dalfampridine (available on the market as Ampyra (registered trademark)) and interferol This may include prostate medications such as flutamide (available on the market as Extavia®), nilutamide (available on the market as Nilandron®), dutasteride (available on the market as Avodart®), tamsulosin hydrochloride (available on the market as Flomax®), terazosin hydrochloride (available on the market as Hytrin®), and alfuzosin hydrochloride (available on the market as UroXatral®).

[0105] The films of this disclosure further include antipsychotic drugs, such as alprazolam (available as Niravam®, Xanax®), clozopine (available as Clozaril®), haloperidol (available as Haldol®), fluoxetine hydrochloride (available as Prozac®), sertraline hydrochloride (available as Zoloft®), asenapine (available on the market as Saphris®), iloperidone (Fanapt®), and Available on the market as (and), and paroxtine hydrochloride (available as Paxil®), aripiprazole (available on the market as Abilify®), guanfacine (available on the market as Intuniv®), amphetamine and methamphetamine (available on the market as Adderall® and Desoxyn®), clomipramine hydrochloride (available on the market as Anafranil®), buspirone hydrochloride (available on the market as BuSpar®), Talopram hydrobromide (available on the market as Celexa®), duloxetine hydrochloride (available on the market as Cymbalta®), methylphenidate (available on the market as Ritalin, Daytrana®), divalproex sodium (valproic acid) (available on the market as Depakote®), dextroamphetamine sulfate (available on the market as Dexedrine®), venlafaxine hydrochloride (available on the market as Effexor®), selegiline (Em Available on the market as sam (registered trademark), carbamazepine (available on the market as Equetro (registered trademark)), lithium carbonate (available on the market as Eskalith (registered trademark)), fluvoxamine maleate / dexmethylphenidate hydrochloride (available on the market as Focalin (registered trademark)), ziprasidone hydrochloride (available on the market as Geodon (registered trademark)), ergoloid mesylate (available on the market as Hydergine (registered trademark)), escitalopram oxalate (available on the market as Lexapro (registered trademark)),Chlordiazepoxide (available on the market as Librium®), morindone hydrochloride (available on the market as Moban®), phenelzine sulfate (available on the market as Nardil®), thiothixene (available on the market as Navane®), desipramine hydrochloride (available on the market as Norpramin®), benzodiazepines (e.g., those available as oxazepam®), nortriptyline hydrochloride (available on the market as Pamelor®), tranylcypromine sulfate (available on the market as Parnate®), prochlorperazine, mirtazapine (available on the market as Remeron®), risperidone (Li This may include (available on the market as Spadal®), quetiapine fumarate (available on the market as Seroquel®), doxepine hydrochloride (available on the market as Sinequan®), atomoxetine hydrochloride (available on the market as Strattera®), trimipramine maleate (available on the market as Surmontil®), olanzapine / fluoxetine hydrochloride (available on the market as Symbyax®), imipramine hydrochloride (available on the market as Tofranil®), protriptyline hydrochloride (available on the market as Vivactil®), bupropion hydrochloride (available on the market as Wellbutrin®, Wellbutrin SR®, and Wellbutrin XR®), and olanzapine (available on the market as Zyprexa®).

[0106] The active ingredients available herein also include uric acid-lowering agents, e.g., allopurinol (available on the market as Zyloprim®); seizure treatments, e.g., gabapentin (available on the market as Neurontin®), etotoin (available on the market as Peganone®), vigabatrin (available on the market as Sabril®), and topiramate (available on the market as Topamax®); and herpes zoster treatments, e.g., live herpes zoster vaccine (available on the market as Zostavax®);Skin care therapeutics, such as calcipotriene (available on the market as Dovonex®), ustekinumab (available on the market as Stellara®), televancin (available on the market as Vibativ®), isotretinoin (available on the market as Accutane®), hydrocortisone / iodoquinol (available on the market as Alcortin®), sodium sulfacetamide / sulfur (available on the market as Avar®), azelaic acid (A (Available on the market as zelex® and Finacea®), benzoyl peroxide (available on the market as Desquam-E®), adapalene (available on the market as Differentin®), fluorouracil (available on the market as Efudex®), pimecrolimus (available on the market as Elidel®), topical erythromycin (available on the market as A / T / S®, Erycette®, and T-Stat®), hydrocortisone (Cetacor Available on the market as t(registered trademark), Hytone(registered trademark), Nutracort(registered trademark), metronidazole (available on the market as MetroGel(registered trademark)), doxycycline (available on the market as Oracea(registered trademark)), tretinoin (available on the market as Retin-A(registered trademark) and Renova(registered trademark)), mequinol / tretinoin (available on the market as Solage(registered trademark)), acitretin (available on the market as Soriatane(registered trademark)), calcipotriene hydrate / betamethasone This may include tazone dipropionate (available on the market as Taclonex®), tazarotene (available on the market as Tazorac®), fluocinonide (available on the market as Vanos®), desonide (available on the market as Verdeso®), miconazole nitrate / zinc oxide (available on the market as Vusion®), ketoconazole (available on the market as Xolegel®), and ephalizumab (available on the market as Raptiva®).

[0107] Other active ingredients available herein include sleep disorder medications, e.g., zaleplon (available as Sonata®) and eszopiclone (available as Lunesta®), zolpidem tartrate (available on the market as Ambien®, Ambien CR®, Edluar®), lorazepam (available on the market as Atiban®), flurazepam hydrochloride (available on the market as Dalmane®), triazolam (available on the market as Halcion®), clonazepam (available on the market as Klonopin®), barbiturates (e.g., phenobarbital®), modafinil (available on the market as Provigil®), temazepam (available on the market as Restoril®), and ramelte This includes on (available on the market as Rozerem®), dipotassium clorazepate (available on the market as Tranxene®), diazepam (available on the market as Baylium®), quazepam (available on the market as Doral®), and estazolam (available on the market as ProSom®); smoking cessation medications, e.g., varenicline (available on the market as Chantix®), nicotine, e.g., Nicotrol®, and bupropion hydrochloride (available on the market as Zyban®);Furthermore, steroids, such as alclomethasone dipropionate (available on the market as Aclovate®), betamethasone dipropionate (available on the market as Diprolene®), mometasone furoate (available on the market as Elocon®), fluticasone (available on the market as Flonase®, Flovent®, Flovent Diskus®, Flovent Rotadisk®), fluocinonide (available on the market as Lidex®), mometasone furoate monohydrate (available on the market as Nasonex®), desoximethasone (available on the market as Topicort®), clotrimazole / betamethasone dipropionate (available on the market as Lotrisone®), prednisolone acetate (Pred Forte®, Prednisone®, Budesonide Pulmicort®, Rhinocort) This may include Aqua (available on the market as registered trademark), prednisolone sodium phosphate (available on the market as registered trademark Pediapred), desonide (available on the market as registered trademark Tridesilon), and halobetazole propionate (available on the market as registered trademark Ultravate).

[0108] The film of the present invention may further contain active ingredients useful for the following: thyroid disease treatments, such as hormones TC and TD (available on the market as Armour Thyroid®); potassium deficiency treatments, such as potassium chloride (available on the market as Micro-K®); triglyceride regulators, such as ω-3 fatty acid ethyl esters (available on the market as Omacor®); urinary tract treatments, such as phenazopyridine hydrochloride (available on the market as Pyridium®) and methenamine, methylene blue / phenyl salicylate / benzoic acid / atropine sulfate / hyosciamine (available on the market as Urised®); vitamins for pregnant women (available on the market as Advanced Natalcare®, Materna®, Natalins®, Prenate Advance®); and weight control treatments, such as orlistat (available on the market as Xenical®) and sibutramine hydrochloride (available on the market as Meridia®).

[0109] Reputable H2 antagonists intended for use herein include cimetidine, ranitidine hydrochloride, famotidine, nizatidien, ebrotidine, miphentidine, roxatidine, pisatidine, and aceroxatidine (roxatidine acetate).

[0110] Active antacid components include, but are not limited to, the following: aluminum hydroxide, dihydroxyaluminum aminoacetate, aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodium carbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, bismuth subsilysilate, calcium carbonate, calcium phosphate, citrate ions (acid or salt), aminoacetic acid, magnesium aluminate sulfate hydrate, magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, monobasic or dibasic aluminum calcium phosphate, tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminosilicate, tartaric acid, and salts.

[0111] The activators used in the present invention may include allergens or antigens, such as, but are not limited to, plant pollen derived from grasses, trees, or ragweed; animal dander, which is fine scales that fall from the skin and fur of cats and other furry animals; insects, such as house dust mites, honeybees, and wasps; and drugs, such as penicillin.

[0112] Examples of specific active ingredients, but not limited to, include: 16-α-fluorocstradiol, 16-α-gitoxin, 16-epiestriol, 17-α-dihydroecurenin, 17-α-estradiol, 17-β-estradiol, 17-hydroxyprogesterone, l-α-hydroxyvitamin D2, 1-dodecpyrrolidinone, 20-epi-1,25-dihydroxyvitamin D3, 22-oxacalcitriol, 2CVV, 2'-nor-cGMP, 3-IsobutylGABA, 5-Ethinyluracil, 6-FUDCA, 7-Methoxytacrine, Abamectin, Abanokil, Abecarnil, Abiraterone, Abulukast, Abulukast sodium, Acadecin, Acamprosate, Acarbose, Acebutrol, Acecainide hydrochloride, Acezidine, Aceclofenae, Acedapson, Aceglutamide aluminum, Acemannan, Acetaminophen, Acetazolamide, Acetohexamide, Acetohydroxamic acid, Acetomepregenol, Acetophenazine maleate, Ace Sodium tosulfone, acetylcholine chloride, acetylcysteine, acetyl-L-carnitine, acetylmetadol, acifuran, acipimox, acitemate, acitretin, acibicin, acralubicin, acratonium, acodazole hydrochloride, aconiazid, acrisolcin, acribastine, acronin, actisomid, actodigin, acyclovir, acylfluben, adafenoxate, adapalene, adapalene, adatanserine, adatanserine hydrochloride, adesipenor, adesipenor, adefovir, adelmid Roll, ademethionine, adenosine, azinazolam, adipheinine hydrochloride, adiposin, adzeresin, adrafinil, adrenaline, airbutamine, alacepril, alamesin, alanine, alaproclate, alaptide, albendazole, arborablin, albuterol, arbutoin, alclofenae, alclomethasone dipropionate, alcloxa, aldekalmycin, aldesleukin, aldioxa, alendronate sodium,Alendronate, Alentemol, Alentemol hydrobromide, Aretamin hydrochloride, Aleuronium chloride, Alexidine, α-Calcidol, Alfentanil hydrochloride, Alfuzosin, Algestone acetonide, Alglucerase, Aliflurane, Alinastine, Alipamid, Allantoin, Arobarbital, Allopurinol, ALL-TK antagonist, Alogliptin, Aronimide, Alosetron, Alosetron hydrochloride, Alovudine, Alpertin, α-Amylase, α-Idosone, Alpidem, Alprazolam, Alprenolol hydrochloride, Alprenoxime hydrochloride, Alpro Stadil, Alrestatin sodium, Altanserine tartrate, Alteplase, Althiazide, Altrethamine, Altromycin B, Alverinc citrate, Albilceptosudotox, Amazinone acetate, Amantadine hydrochloride, Ambamustine, Ambomycin, Ambrutisine, Ambuphylline, Ambusid, Amsinafar, Amcinonide, Amdinocillin, Amdinocillin pivoxil, Amedalin hydrochloride, Ameromethasone, Ameltolide, Amesergid, Amethantrone acetate, Methyl sulfur Amezinium acid, amfebutamon, amfenac sodium, amflutisol, amicycline, amidephrine mesylate, amidox, amifloxacin, amiphostin, amikacin, amiloride hydrochloride, aminacline hydrochloride, potassium aminobenzoate, sodium aminobenzoate, aminocaproic acid, aminoglutethimide, sodium aminohippurate, aminolevulinic acid, aminophylline, aminorex, sodium aminosalicylate, aminosalicylic acid, amiodarone, amyprilose hydrochloride, amikinsin hydrochloride Salt, amisulpride, amitraz, amitriptyline hydrochloride, anlexanox, amlodipine, amobarbital sodium, amodiaquin, amodiaquin hydrochloride, amorolphin, amoxapine, amoxicillin, amfechloral, amphetamine sulfate, amphomycin, amphotericin B, ampicillin, ampiroxicam, ampiridine sulfate, amquinate, amrinone, amrinone, amrubicin, amsacrin, amylin, amithiamycin, anagestone acetate, anagrelide, anakinra, ananaine,Analithide, Analithide acetate, Anastrozole, Anazolen sodium, Anclod, Andrografolide, Androstenedione, Angiogenesis inhibitors, Angiotensinamide, Anidoxime, Anilelisine, Anilopam hydrochloride, Aniracetam, Anilorac, Methylanisotropin bromide, Anistreplase, Anitrasafen, Anoldrin, Antagonist D, Antagonist G, Antarelix, Antazoline phosphate, Anthermycin, Anthraline, Anthramycin, Antiandrogens, Acedapson, Ferbamate, Antiestrogens, Antineoplaston, Antipyrine, Antisense oligonucleotides, Apadrin, Apafant, Aparcillin sodium, Apaxifylline, Apazon, Aphydicolinglycine Apixifylline, apomorphine hydrochloride, apraclonidine, apraclonidine hydrochloride, apramycin, aprindine, aprindine hydrochloride, aproslat sodium, aprotinin, aptazapine maleate, aptiganel, aprinic acid, aprinic acid, aranidipine, aranotin, albaprostil, arbekicin, arbidol, albutamine hydrochloride, alclophenin, aldepane sodium, argatroban, arginine, argypressin tannate, aryldone, aripiprazole, arotinolol, arpinocid, artefren, altilide fumarate, acimadrine, asparaton, asparaginase, aspartic acid Acid), aspartosin, asperfuran, aspirin, aspoxylin, asprelin, astemizole, astromycin sulfate, asraculin, atamestan, atenolol, atevirdin, atipamezole, atiprosin maleate, attrid, atorvastatin calcium, atosiban, atovaquone, atopenin B, atracurium besylate, atlimustin, atrinositol, atropine, auranofin, aureobasidine A, aurothioglucose, aviramycin, avoparcin, abridine, Axid, axinastatin 1, axinastatin 2, axinastatin 3, azavon, azacitidine, azachlordine hydrochloride, azaconazole, azadirachtin,Azalanstat dihydrochloride, azaroxane fumarate, azanator maleate, azanidazole, azaperone, azalibine, azaserin, azasetron, azatadine maleate, azathioprine, azathioprine sodium, azatoxin, azatyrosine, azelaic acid, azelastine, azelnidipine, azepindol, azetepa, azimilide, azithromycin, azurocillin, azolimine, azosemide, azotomycin, aztreonam, azmoren sodium, bacampicillin hydrochloride, baccatin III, bacitracin, baclofen, bacoside A Bacoside B, Bactovoramine, Valanol, Valadipon, Valhimycin, Balofloxacin, Valsalazide, Bambermycin, Bambuterol, Bametan sulfate, Bamifilin hydrochloride, Bamidazole, Baofoside 1, Balmastine, Barnidipine, Basifungin, Batanoprid hydrochloride, Vateblast, Vateraphine maleate, Batimastat, Bebericin, Becanton hydrochloride, Becaprelmin, Becliconazole, Beclomethasone dipropionate, Befloxatone, Beinserazide (beinserazide), verphosdil, belladonna, beroxamide, bemethetron, bemitrazine, bemoradan, benapridine hydrochloride, benazepril hydrochloride, benazeprilat, bendakarol mesylate, bendazac, bendroflumethiazide, benflumetol, benidipine, benorterone, benoxaprofen, benoxaprofen, benoxynate hydrochloride, bemperidol, bentazepam, bentromid, benurestat, benzbromarone, benzethonium chloride, benzetimide hydrochloride, benzylonium bromide, benzidopyrine hydrochloride, benz Nzoisoxazole, benzocaine, benzochlorine, benzocamine hydrochloride, benzodepa, benzidazoxane, benzonatate, benzoyl peroxide, benzoylpas calcium, benzoylstaurosporine, benzquinamide, benzthiazide, benztropin, benztropin mesylate, benzydamine hydrochloride, benzylpenicilloyl polylysine, bepridil, bepridil hydrochloride, belatant, beraprost, berefrin, perraphenone, vertamil, berithromycin, besipyridine, β-aretin, betacramycin B, betamethasone,Betamipron, betaxolol, betaxolol hydrochloride, betanidine sulfate, betulinic acid, bevantrol, bevantrol hydrochloride, bezafibrate, bFGF inhibitors, bialamicol hydrochloride, biapenem, bicalutamide, bicifadine hydrochloride, biclodil hydrochloride, bidisomide, bifemelan, bifonazole, bimalim, bimitil, vindalit, viniramycin, vinospirone, bioxalomycin α2, bipenamol hydrochloride, biperiden, bifenamine hydrochloride, biliperone, bisanthren, bisalamil, bi Suaziridinylspermine, bis-benzimidazole A, bis-benzimidazole B, bisnafide, bisobrine lactate, bisoprolol, bispirithione Magsulfex, bistramide D, bistramide K, bistratin A, sodium bithionolate, bitolterol mesylate, bivalirudin, bizeresin, bleomycin sulfate, boranediol dipropionate, borasterone, boldenone undecylenate, borzin, borenol, bormantalate, bopindolol, bosentan, voxidin, breferdin, breflat, brequinaruna Thorium, Bretazenil, Bretylium tosylate, Brifentanil hydrochloride, Brimonidine, Brinolase, Brocrecin, Broclinat, Brophoxin, Bromadrine maleate, Bromazepam, Bromochlorenone, Bromelain, Bromfenac, Brominidione, Bromocriptine, Bromodifenhydramine hydrochloride, Bromoxamide, Bromperidol, Bromperidol decanoate, Brompheniramine maleate, Broperamol, Bropyrimin, Brotizolam, Bucainide maleate Bucindolol, buclidine hydrochloride, bucromarone, budesonide, budipine, budotitanium, buformin, bumetamide, bunaprolast, bunazosin, bunolol hydrochloride, bupicomid, bupivacaine hydrochloride, buprenorphine hydrochloride, bupropion hydrochloride, bramart, busererin acetate, buspirone hydrochloride, busulfan, butabarbital, butacetin, butacramole hydrochloride, butarbital, butamben, butamirto citrate, butaperazine, butaprost, tetrasodium butedronate, butenafine, buteridine,Butionine sulfoximine, buticacin, butylphenine, butyrosine sulfate, butixilate, butixocort propionate, butoconazole nitrate, butonate, butopamine, butopridine hydrochloride, butorphanol, butoxamine hydrochloride, buttriptyline hydrochloride, kakutinomycin, cadexoma iodine, caffeine, caranolid A, calcifediol, calcipotriene, calcipotriol, calcitonin, calcitriol, calcium undecylenate, carphostin C, carsterone, cambendazole, camonagrel, camptothecin derivatives, canagliflozin, canariapox IL-2, candesartan, candicidine, candoxatril, candoxatrillat, caniglibose, potassium canrenoate, can, Lennon, capecitabine, sodium capobenate, capobenic acid, capreomycin sulfate, capromab, capsaicin, captopril, capride, carasemide, carbacol, carbadox, carbamazepine, carbamide peroxide, carbantel lauryl sulfate, carbaspirin calcium, carbazelan, carbazomycin C, carbenicillin potassium, carbenoxolone sodium, carbetimer, carbetocin, carbidopa, carbidopa-levodopa, carbinoxamine maleate, carbifen hydrochloride, carbochloral, carbocysteine, carbol-fuchsin, carboplatin, carboprost, carbovir, carboxamide-aminotriazole, carboxamide triazole, carboxymethylated β-1,3-glucan, carbuterol hydrochloride, CaRest M3, carfentanyl citrate, carisoprodol, carmantadine, carmustine, CARN 700, camidazole, caloxazone, carperitide, carphenazine maleate, carprofen, carsatrin succinate, cartazolate, carteolol, carteolol hydrochloride, cartilage-derived inhibitors, carbicin hydrochloride, carmonam sodium, carvedilol, carbotroline, carbotroline hydrochloride, carzeresin, casein kinase inhibitors (ICOS), castanospermine, caurumonam, sevaracetam, cecropin B, cedefingol, cefaclor, cefadroxil, cephamandol, cephaparol, cefatidine, cefazalure sodium, cefazolin, cefbuperazone, cefcapene pivoxil, tosylate Cefdaroxime pentexil, cefdinir, cefditoren pivoxil, cefepime, cefetameth, cefetecor, cefixime, ceffluprenum, cefinenoxime hydrochloride, cefinetazole, cefminlox, cefozidime, cefonisid sodium, cefoperazone sodium, cefolamide, cefoselis, cefotaxime sodium, cefotetan, cefotiam, cefoxitin, cefozopran, cefpimisole, cefpyramide, cefpirome, cefpodoxime proxetil, cefprodil, ceffloxazine, cefsulodine, ceftazidime,Cefteram, ceftibuten, ceftizoxime sodium, ceftriaxone, cefuroxime, cerastrol, cericalim, ceriprolol, cepacidiine A, cepacetril sodium, cephalexin, cephaloglysin, cephaloridine, cephalothin sodium, cefapillin sodium, cefradiin, cericlamin, cerivastatin, seronapril, certoparin sodium, ceruretide, cetaben sodium, cetalconium chloride, cetamolol hydrochloride, cetiesil, cetirizine, cetophenicol, cetrax Cetylpyridinium hydrochloride, cetrolex, cetylpyridinium chloride, kenodiolus, clofedianol hydrochloride, chloral betaine, chlorambucil, chloramphenicol, chlordantoin, chlordiazepoxide, chlorhexidine gluconate, chlorine, chlormadinone acetate, chloroorientisin A, chloroprocaine hydrochloride, chlorpropamide, chloroquine, chloroquinoxaline sulfonamide, chlorothiazide, chlorotrianicene, chloroxin, chloroxylenol, chlorphenesin carbamate, chlorpheniramine maleate Salt, chlorpromazine, chlorpropamide, chlorprothixene, chlortetracycline bisulfate, chlorthalidone, chlorzoxazone, cholestyramine resin, chromonal hydrochloride, cibenzoline, cicaprost, cyclafrine hydrochloride, cyclazine dol, ciclesonide, cicletanin, cyclopirox, cycloprofen, cycloprolol, cidofovir, sidoxepine hydrochloride, cyfenlin, siglitazone, siladopa hydrochloride, silancetron, cilastatin sodium, cilazapril, cilnidipine, silobamine mesylate, silobradine, silofungin Cilostazol, simaterol, cimetidine, simetropium bromide, cinalcast, cinanserin hydrochloride, cinepazet maleate, cinflumid, cingestol, sinitaprid, cinnamedrin, cinnarizine, cinorazepam, cinoxacin, simperen, cinlomid, syntazone, cintriamide, cioteronel, sipamphylline, cyprefadol succinate, cyprosinonide, cyprofibrate, ciprofloxacin, cyprosten, silamadol, ciloremycin, cisapride, cisatracrium besylate, cisnasol, cisplatin,cis-porphyrin, cystinexin, citalopram, citenamide, citicoline, citreamycin α, cladribine, clamoxyquin hydrochloride, clarithromycin, clausenamide, potassium clavulanate, clazolam, clazolimin, clevoprid, clemastine, clentizem maleate, clidinium bromide, clinafloxacin, clindamycin, clioquinol, clioxamide, criprofen, clobazam, clobetasol propionate, clobetazone butyrate, crocoltrone acetate, clodanolene, clodazone Hydrochloride, clodronate, clofazimine, clofibrate, clofyllium phosphate, clogestone acetate, chromacran phosphate, clomegestone acetate, clometerone, clomethiazole, clomiphene analog, clominorex, clomiphene, clomipramine hydrochloride, clonazepam, clonidine, clonitrate, clonixeryl, clonixin, clopamide, clopentixol, cloperidone hydrochloride, clopidogrel, clopimodide, clopipazan mesylate, clopirac, cloprednol, cloprostenol sodium, dipotassium clorazepate Chloretate, Chlorexolone, Chloroperone hydrochloride, Chlorprenaline hydrochloride, Chlorthrone, Chlorthermine hydrochloride, Closantel, Clocilamine acetate, Clotiapine, Clothixamide maleate, Cloticasone propionate, Clotrimazole, Cloxacillin benzathine, Cloxiquin, Clozapine, Cocaine, Coccidioidin, Codeine, Codoxime, Colchicine, Colestimide, Colestipol hydrochloride, Colestron, Colforcin, Colphosseryl palmitate, Colistimate sodium, Colistin sulfate, Corismycin A, Corismycin B, Corterol Mesylate, Combretastatin A4, Combretastatin Analogue, Comprestatin, Conagenin, Conorfone Hydrochloride, Contignasterol, Contoltrostatin, Colmetasone Acetate, Corticorelin Ovain Triflutate, Corticotropin, Cortisone Acetate, Cortibazole, Cortodoxone, Cosaran, Costatride, Cosyntropin, Cotinine, Comadin, Coumamycin, Crambesidine 816, Krillvastatin, Cristonol, Clomitril Sodium, Cromolyn Sodium, Crotamiton,Cryptophycin 8, Cucumarioside, Cuprimyxin, Clacin A, Curdlan sulfate, Cryosin, Cyclacillin, Cyclazosin, Cyclazosin, Cyclic HPMPC, Cyclindol, Cycliramine maleate, Cyclizine, Cyclobendazole, Cyclobenzapurine, Cyclobuto A, Cyclobuto G, Cyclocapron, Cycloguanyl pamoate, Cycloheximide, Cyclopentaanthraquinone, Cyclopenthiazide, Cyclopentolate hydrochloride, Cyclofenadine hydrochloride, Cyclophosphamide, Cycloplatam, Cyclopropane, Cycloserine, Cyclosin, Cyclosporine, Cyclothiazin, Cyclothiazide, Cyclothiazin Zomycin, cyheptamide, cypemycin, cypenamine hydrochloride, ciprazepam, cyproheptadine hydrochloride, cyprolidol hydrochloride, cyproterone, xiproximide, cysteamine, cysteine ​​hydrochloride, cystine, cytarabine, cytarabine hydrochloride, cytarabine ocphosphonate, cytochalasin B, cytolytic factor, cytostatin, dacarbazine, dacliximab, dactimycin, dactinomycin, daidzein, daledarin tosylate, dalfopristine, dalteparin sodium, daltroban, dalvastatin, danaparoid, danazol, dantrolene, dapagliflozin, daflunodrin A A) Dapiprazole, Dapitant, Dapoxetine hydrochloride, Dapsone, Daptomycin, Dalglitazone sodium, Dalifenacin, Darulusin A, Darodipine, Dalcidomin, Daunorubicin hydrochloride, Dazadrol maleate, Dazepinyl hydrochloride, Dazmegrel, Dazoprid fumarate, Dazoxyben hydrochloride, Debrisoquin sulfate, Decitabine, Deferipron, Deflazacort, Dehydrocholic acid, Dehydrodidemnin B, Dehi Droepiandrosterone, Delapril, Delapril hydrochloride, Delavirdine mesylate, Derequamin, Delfaprazine, Dermadinone acetate, Dermopinol, Delphinidin, Demepotassium bromide, Demeclocycline, Demecycline, Demoxepam, Denofungin, Deoxypyridinoline, Depacote, Deprodone, Deprostil, Depsidomycin, Delamcycline, Dermatan sulfate, Desciclovir, Decinolone acetonide,Desflurane, desipramine hydrochloride, decilzine, deslanoside, deslorerin, desmopressin, desogestrel, desonide, desoximethasone, desoxoamiodarone, desoxycorticosterone acetate, detadimium bitartrate, deterenol hydrochloride, detirelix acetate, debazepide, dexamethasone, dexamisol, dexbronpheniramine maleate, dexchlorpheniramine maleate, dexcramol hydrochloride, dexetimide, dexfenfluramine hydrochloride, dexifosfamide, dexima Fen, dexivacaine, dexketoprofen, dexroxiglumide, dexmedetomidine, dexormaplatin, dexoxadrol hydrochloride, dexpanthenol, dexpemedorac, dexpropranolol hydrochloride, dexrazoxane, dexsotalol, dextrin disulfate, dextroamphetamine, dextromethorphan, dextrorphan hydrochloride, dextrothyroxine sodium, dexverapamil, dezaguanine, dezinamide, dezosin, diacetol hydrochloride, diamocine cyclamate, diapamide, diatrizoate Glumine, diatrizoic acid, diaveridine, diazepam, diadiquan, diazoxide, dibenzepine hydrochloride, dibenzothiophene, dibucaine, dichliorvos, dichlorphenazone, dichlorphenamide, disylenone, diclofenac sodium, dicloxacillin, dicranin, dicumarol, dicyclomine hydrochloride, didanosine, didemnin B, zidox, dienestrol, dienogest, diethylcarbamazine citrate, diethylhomospermine, diethylnorspermine, diethylpropion hydrochloride, die Chilstilbestrol, diphenoxidine hydrochloride, diphenoxine, diflorazone diacetate, difloxacin hydrochloride, difluanine hydrochloride, diflucortolone, diflumidone sodium, diflunisal, difluprednate, diphthalone, digitalis, digitoxin, digoxin, dihexyverine hydrochloride, dihydrolexidine, dihydro-5-azacitidine, dihydrocodeine bitartrate, dihydroergotamine mesylate, dihydroestosterone, dihydrostreptomycin sulfate, dihydrotachisterol, 9-dihydrotaxol, dilantine,Dilevalol hydrochloride, diltiazem hydrochloride, dimefadan, dimephrine hydrochloride, dimenhydrinate, dimercaprol, dimethadione, dimethindene maleate, dimethisterone, dimethylprostaglandin aluminum, dimethyl sulfoxide, dimethylhomospermine, dimiracetam, dimoxamine hydrochloride, dinoprost, dinoprostone, dioxadrol hydrochloride, dioxamycin, diphenhydramine citrate, diphenidol, diphenoxylate hydrochloride, diphenylspiromustine, dipivefin hydrochloride, dipivefrin, dipriencypron e) Zipraphenone, dipropylnorspermine, dipyridamole, dipyrithione, dipyrone, dylithromycin, discodermolide, disobutamide, disofenine, disopyramide, disoxalil, disulfiram, diteklene, divalproex sodium, disosylpine maleate, dobutamine, docarpamine, dosebenone, docetaxel, doconazole, docosanol, dofetilide, drasetron, ebastine, evilatide, ebro Tizidine, Ebselen, Ekabapid, Ecabet, Ecadotril, Ecdysterone, Excetin, Exestatin, Ecothiophate Iodide, Eclanamine Maleate, Eclazolast, Ecomustine, Econazole, Ectainacidine 722, Edaravone, Edatrexate, Edelfosine, Ediphorone Acetate, Edbacomab, Edoxudine, Edrecolomab, Edroxyphonium Chloride, Edroxyprogestone Acetate acetate), efegatran, eflornithine, efonidipine, egualcen, elantrin, eleatonin, elemen, eletriptan, ergodipine, eribrosyl, erusamitrusine, eltenae, elcaine, emalkalim, emedastine, emetine hydrochloride, emiglitate, emylium tosylate, emiteflu, emoctaquin, empagliflozin, enadrine hydrochloride, enalapril, enalaprilat, enalkyrene, enazadrem, en Siplate, Endralazine Mesylate, Endrison, Enflurane, Englitazone, Enilconazole, Enisoprost, Enrimomab, Enloplatin, Enoferast, Enoricum Sodium, Enoxacin, Enoxacin, Enoxaparin Sodium, Enoximon, Empyroline Phosphate, Emprophylline, Empromart, Entacapone, Enterostatin, Enviraden, Enviroxime, Ephedrine, Epicillin, Epimestrol, Epinephrine, Epinephryl Borate, Epipropidine, Epirizol, Epirubicin, Epitetracycline Hydrochloride, Epithiazide, Epoetin α, Epoetin β, Epoprostenol, Epoprostenol Sodium, Epoxymexlenone,Epristeride, eprosartan, eptastigmine, ekirenin, ekirin, erbrozole, erdosteine, ergoloid mesylate, ergonovine maleate, ergotamine tartrate, elcentide, elsofermin, erythritol, erythrityl tetranitrate, erythromycin, esmolol hydrochloride, esolubicin hydrochloride, esproquine hydrochloride, estazolam, estradiol, estramustine, estramustine analog, estradiol hydrobromide, estriol, estroflate, estrogen agonist, estrogen Antagonist, estrogen, conjugated estrogen, esterified estrone, estropipate, espron, etahedrine hydrochloride, etanidazole, etanterol, etalotene, etazolate hydrochloride, eterobarb, etasidine, sodium ethacrate, ethacrate, ethambutol hydrochloride, etamiban, ethanolamine oleate, esphlorvynol, ether, ethinylestradiol, ethiodized oil, ethionamide, ethnam nitrate, etopropazine hydrochloride, ethosuximide, etotoy Ethoxazene hydrochloride, etibenzutropin, ethyl chloride, dibnate ethyl, ethylestrenol, ethindiol, ethinerone, ethinodiol diacetate, etibendazole, etidocaine, disodium etidronate, etidronic acid, etifenine, ethintidine hydrochloride, etizolam, etodolac, etofenamate, etformin hydrochloride, etomidate, etonogestrel, etoperidone hydrochloride, etoposide, etopurine, etoxadrol hydrochloride, etozolin, etravamine, etretinate, etryptamine acetate, eucatropin hydrochloride Eugenol, Euprosin hydrochloride, Ebeminomycin, Examethadim, Examorelin, Exaprolol hydrochloride, Exemestane, Fadrozol, Ferriefungin, Famciclovir, Famotidine, Fanprizine, Fantofaron, Fantridone hydrochloride, Faropenem, Fasidotril, Fasudil, Fazarabine, Fedotodin, Felbamate, Felbinac, Felodipine, Felypressin, Fenalamide, Fenamol, Fenbendazole, Fenbufen, Fencibutyrol, Fenclofenac, FencloninFenchlorac, Fendosal, Fenestrel, Phenetiline Hydrochloride, Fenfluramine Hydrochloride, Fengabine, Phenimide, Phenisolex, Fenmetozol Hydrochloride, Fenmetramide, Phenobam, Phenocthymine Sulfate, Fenofibrate, Phenoldopam, Fenoprofen, Fenoterol, Fenpiparone, Fenprinast Hydrochloride, Fenprostalen, Fenkizone, Fenretinide, Fenpiride, Fentanyl Citrate, Fenthiazac, Fenticlor, Fenticonazole, Phenilipol Hydrochloride, Feprazino Ferpiphosate sodium, Felisten, Felixan, ferrous sulfate (dried), Fermoxides, Fermoxilate, Fethoxilate hydrochloride, Fexofenadine, Fezolamine fumarate, Fiacitabine, Fiallysine, Fibrinogen I-125, Filgrastim, Philippine, Finasteride, Flavodilol maleate, Flavopyridol, Flavoxate hydrochloride, Flazaron, Flecainide, Frelobuterol, Freloxacin, Frecinoxan, Frestrol sulfate, Fretazepam, Frezelastine, F Lobufen, fluctaphenin, flomoxef, flordipine, florfenicol, floriphenin, flosatidyl, furosekinan, floxacillin, floxuridine, fluasterone, fluazacort, fluvanilate hydrochloride, flubendazole, flucindol, fluchloronide, fluconazole, flucytosine, fludaranine, fludarabine phosphate, fludazonium chloride, fludeoxyglucose F-18, fludrex, fludrocortisone acetate, flufenamic acid, fluphenisal, flumazenil, flumesinol, flumequin, flumeri Don, Flumethasone, Flumetramide, Flumezapine, Fluminorex, Flumizole, Flumoxonide, Flunarizine, Flunidazole, Flunisolid, Flunitrazepam, Flunixin, Fluocalcitriol, Fluocinolone acetonide, Fluocinonide, Fluocortin butyl, Fluocortone, Fluorescein, Fluorodaunorunicin hydrochloride, Fluorodopa F-18, Fluorometholone, Fluorouracil, Fluotracene hydrochloride, Fluoxetine, Fluoxymesterone, Fluparoxane,Fluperamide, fluperolone acetate, fluphenazine decanoate, flupirin, fluprednisolone, fluproquazone, fluprostenol sodium, fluquazone, fluradrine hydrochloride, fluradrenolide, flurazepam hydrochloride, flurbiprofen, fluretofen, flurithromycin, flurocitabine, flulofamide, flurogestone acetate, flurotil, fluroxen, fluspiperone, fluspiren, fluticasone propionate, flutrimazole, flutrolin, fluvastatin, fluvastatin sodium, fluvoxamine, fludinamide, folic acid, follicular regulatory protein, foliclostatin, fomepizol, fonadin mesylate, forasartan, holphenimex, holphenylmex (f Orfenirmex), Formestan, Formocortal, Formoterol, Fosarilate, Fosazepam, Foscarnetosodium, Fosfomycin, Phosphosphatone, Hosinopril, Hosinoprilat, Fospheniroin, Fosquidone, Fostedil, Fostoliesin, Fotemustine, Basic Fuchsin, Fumoxicillin, Fungimycin, Flaprofen, Furazolidone, Furazolium Chloride, Fraglerate Sodium, Flobufen, Flodazole, Furosemide, Fusidic Acid Sodium, Fusidic Acid, Gabapentin, Gadopentate Dimeglumine, Gadopentate, Gadobutrol, Gadodiamide, Gadolinium Texaphylline, Gadopentetate Dimeglumine Dimegiumine), gadoteric acid, gadoteridol, gadobercetamide, galantamine, galandansetron, galandansetron hydrochloride, galamine triethiozide, gallium nitrate, garopamil, galocitabine, ganfexin, gamolenic acid, ganciclovir, ganirelix, gelatinase inhibitors, gemcadiol, gemcitabine, gemeprost, gemfibrozil, gentamicin sulfate, gentiana violet, gepirone, gestaclone, gestodene, gestorone caproate, gestrinone, gevotrolin hydrochloride, glisopam, graspimod, glaucocalyxin A, gremanserin, gliamiride, glibornelide, sodium glycetanyl, gliflumid, glimepiride, glipizide, gloximonam, glucagon, glutapyrone, glutathione inhibitors,Glutethimide, Glybride, Glycopene, Glycopril, Glycopyrrolate, Glyhexamide, Glimidine sodium, Glyoctamide, Glyparaamide, Gold Au-198, Gonadoctrinins, Gonadorelin, Gonadotropin, Goserelin, Gramicidine, Granisetron, Glepafloxacin, Griseofulvin, Guaiapate, Guatiline, Guanabenz, Guanabenz acetate, Guanadrel sulfate, Guancidin, Guanethidine monosulfate, Guanfacine hydrochloride, Guanisoquine sulfate, Guanochlor sulfate, Guan Noctine hydrochloride, guanoxabenz, guanoxane sulfate, guanoxyfen sulfate, gusperimus trihydrochloride, harazepam, halcinonide, halichondrin B, halobetazole propionate, halofantrin, halofantrin hydrochloride, halofenate, halofdinone hydrobromide, halomon, halopemid, haloperidol, halopredone, haloprogesterone, haloprogin, halotan, halukinol, hamycin, human (han) menopausal gonadotropin, hatomamycin, hatomamycin, hatomamycin A, hatomamycin B, hatomamycin C, hatomamycin D, heparin sodium, hepsulfame, heregulin, hetacillin, heteronium bromide, hexachlorophene: hydrogen peroxide, hexafluorenium bromide, hexamethylene bisacetamide, hexedine, hexobenzine, hexoprenaline sulfate, hexylresorcinol, histamine phosphate, histidine, histoplasmin, histrelin, homatropin hydrobromide, foxidyl hydrochloride, human chorionic gonadotropin, hycanthone, hydralazine hydrochloride, hydralazine polystyrene, hydrochlorothiazide, hydrocodone bitartrate, hydro Cortisone, hydroflumethiazide, hydromorphone hydrochloride, hydroxyamphetamine hydrobromide, hydroxychloroquine sulfate, hydroxyfename, hydroxyprogesterone caproate, hydroxyurea, hydroxyzine hydrochloride, himechromone, hyosciamine, hypericin, ivafloxacin, ibandronate, ibogaine, ivopamine, ibudilast, ibufenac, ibuprofen, ibutylide fumarate, icatibanto acetate, icthammol, icotidine, idarubicin, idoxifen, idoxuridine, idramanthon,Remefloxacin, Iesopitron, Ifetroban, Ifosfamide, Ilepeimide, Ilimaquinone, Irmofosin, Ilostat, Ilonidap, Iloperidone, Iloprost, Imafen hydrochloride, Imazodane hydrochloride, Imidapril, Imidazeninil, Imidazacridone, Imidecyliodine, Imidocarb hydrochloride, Imidolin hydrochloride, Imidourea, Imiroxane hydrochloride, Imipenem, Imipramine hydrochloride, Imiquimod, Immunostimulating peptide, Impromidine hydrochloride, Indacrinone, Indapamide, Indecainide hydrochloride, Inderoxadi Indinomethacin hydrochloride, indigotine disulfate sodium, indinavir, indocyanine green, indorapril hydrochloride, indolidan, indomethacin, indomethacin sodium, indoprofen, indoramine, indorene hydrochloride, indoxol, indolilin hydrochloride, innocoterone, inogatran, inorimomab, inositol nicotinate, insulin, interferon, interleukin, intrazol, intriptyline hydrochloride, Obenguan, Iobenzamic acid, Iobitridol, Iocalmic acid meglumine, Iocalmic acid, Iosetam acid, Iodamide, Iodine, Iodipamide meglumine, Iodixanol, Iodoamiloride, Iodoantipyrine I-131, Iodocholesterol I-131, Iododoxorubicin, Iodohippurate sodium I-131, Iodopiracet I-125, Iodoquinol, Iodoxamic acid meglumine, Iodoxamic acid (Iodoxamie Ioglycic acid, iofetamine I-123 hydrochloride, iofractol, ioglucol, ioglucomid, ioglicamic acid, yoglamid, iohexol, iomeprole, iometine I-125, iopamidol, iopanoic acid, iopentol, iofendilate, ioprosemic acid, iopromide, iopronic acid, iopidol, iopidone, iopyrrol, iocefamic acid, ioceric acid, ioslamid meglumine, iosmethic acid, iotasul, iotetoluic acid, sodium iotalamate, iotalamic acid, iotracide, iotrolane, iotroxic acid, iotyrosine I-131, ioversol, ioxadiate (Iox Sodium ioxaglucate, meglumine ioxaglucate, ioxaglucate, ioxiran, ioxotrizoic acid, ipazilide, ipenoxazone, ipidacrine, calcium ipodate, 4-ipomeanol, ipratropium bromide, ipriflavone, iprendol, iprofenin, ipronidazole, iproplatin, iproxamine hydrochloride, ipsapirone, irbesartan, irinotecan, illoxacin, iroplact, ilsogladine, iltemazole, isalstein, isamoxol, isvogrel, isepamycin, isobengazole, isobutamen, isocarboxazide, isoconazole,Isoethalin, isofloxitepine, isoflupredone acetate, isoflurane, isoflurofate, isohomohalicondrin B, isoleucine, isomazole hydrochloride, isomiramine hydrochloride, isoniazid, isopropamide iodide, isopropyl alcohol, isopropyl unoprostone, isoproterenol hydrochloride, isosorbide, isosorbide mononitrate, isothiquimid, isotretinoin, isoxepac, isoxicam, isoxuprine hydrochloride, isradipine, itamelin, itasetron, itazigrel, itop Lido, itraconazole, ivermectin, jaspraquinolide, josamycin, kahalalide F, carafungin, kanamycin sulfate, ketamine hydrochloride, ketanserin, ketazosin, ketazolam, ketoxal, ketipramine fumarate, ketoconazole, ketoprofen, ketorphanol, ketrolac, ketotifen fumarate, kitasamycin, labetalol hydrochloride, lasidipine, lasidipine, lactitol, lactibicin, lacosamide, laennec, lafutidine, lamelin-N-triacetate, lamifibane, lamivudine, lamotrigine, Lanoconazole, Lanoxin, Lamperison, Lanreotide, Lansoprazole, Latanoprost, Lateritin, Laurocapram, Isoquinoline Laurylbromide, Labortidine Succinate, Lazabemide, Recimivide, Reinamycin, Remildipine, Reminoprazole, Renercept, Renikinsin, Renograstim, Renperon, Lentinan Sulfate, Leptin, Leptolstatin, Lelcanidipine, Relgotril, Rerisetron, Retimide Hydrochloride, Letrazuril, Letrozole, Leucine, Leucomycin, Leuprolide Acetate, Leuprolide + Estrogen + Progesterone, leuprorelin, levanfetamine succinate, levamisol, levodobutamine lactobionic acid, leveromakalim, levetiracetam, leveycloserine, levobetaxolol, levovunolol, levobupivacaine, levocabastine, levocarnitine, levodopa, levodropropidine, levofloxacin, levoflartadone, levoleucovorin calcium, levometadil acetate, levometadil acetate hydrochloride, levomoprolol, levonantradol hydrochloride, levonordefrine,Levonorgestrel, levopropoxyfen napsylate, levopropyl sylin potassium, levolmeroxifen, levolphanol tartrate, levocimendan, levosulpiride, levothyroxine sodium, leboxadrol hydrochloride, lexipaphant, lexithromycin, rialozol, ribenzapril, ridamidine hydrochloride, lidocaine, lidofenin, lidoflazine, rifadin, rifibrate, rifibrol, linalotene, lincomycin, linear polyamine analogs, linoglylid, linopyridine, linotropan, lincidomin, phosphate Titrypto, Lintopride, Liothyronine I-125, Liothyronine sodium, Riotrix, Rilexapride, Lisinopril, Lisoclinamide 7, Lixazinone sulfate, Lovaplatin, Lobenzarit sodium, Lobucavir, Loderaben, Rhodoxamide, Lofemizole hydrochloride, Lofentanil oxalate, Lofepramine hydrochloride, Lofexidine hydrochloride, Lombrisin, Lomefloxacin, Lomerizine, Lometraline hydrochloride, Lometrexol, Lomofungin, Lomoxicam, Lomustine, Lonaparen, Lonazolac, Loni Damin, loperamide hydrochloride, loracalbef, loradumine hydrochloride, loratadine, lorazepam, lorvamart, lorcainide hydrochloride, lorecresol, loreinadol, lorglumide, lormetazepam, lornoxicam, lortalamine, lorzafone, losartan, rosigamon, losoxantrone, rosarazine hydrochloride, loteprednol, lovastatin, roviride, loxapine, loxolibine, ruberzol, rucanton hydrochloride, rufilonil, lurosetron mesylate, lulutotecan, luteinizing hormone, lurasidone Lutetium, luterelin acetate, rudindol, riaporate sodium, lycetamin, ridicamycin, ridimycin, linestrenol, represin, lysine, lysophylline, lysostafine, soluble peptide, maduramycin, mafenide, magainin 2-amide, magnesium salicylate, magnesium sulfate, magnolol, mytansine, maletamer, malotochromene, malotojaponin, malotilate, malotilate, mangahodipyl, manidipine, maniwamycin A, mannitol, mannostatin A, manumycin E, manumycin F,Mapinastine, Maprotiline, Marimast, Martek 8708, Martek 92211, Masoprocol, Maspin, Massetrid, Matrilysine inhibitors, Mytansine, Mazapertine Succiniate, Mazindol, Mebendazole, Mebeberine Hydrochloride, Mebrophenin, Mebutamate, Mecamillamine Hydrochloride, Mechloretamine Hydrochloride, Meclocycline, Meclofenamate Sodium, Meclocalon, Mechlorison Dibutyrate, Medazepam Hydrochloride, Medrinone, Medrogestone, Medroxalol, Medroxyprogesterone, Medrinone, Meelizine Hydrochloride, Mefenamic Acid, Mefenidyl, Mefenorex Hydrochloride, Mefexamide, Meflo Potassium hydrochloride, mefluside, megalomycin potassium phosphate, megestrol acetate, meglumine, meglutol, melengestrol acetate, melitracene hydrochloride, melphalan, memotin hydrochloride, menavitan hydrochloride, menoctone, menogalil, menotropin, meobentine sulfate, mepaltricin, mepenzolate bromide, meperidine hydrochloride, mephentermine sulfate, mepheniloin, mefobarbital, mepivacaine hydrochloride, meprobamate, meptazino Methadone hydrochloride, Mekidox, Melalein sodium, Melbaron, Mercaptopurine, Merck phenol chloride, Melisoprole Hg-197, Meropenem, Mesalamine, Mesecrazone, Mesolidazine, Mesterolone, Mestranol, Mespurine hydrochloride, Metarol hydrochloride, Metaproterenol polystyrene, Metalaminol bitartrate, Metaxalone, Meteneprost, Meterine, Metformin, Metacholine chloride, Metacycline, Methadone hydrochloride, Metazyl acetate, Metal Thiazide, methamphetamine hydrochloride, metakalon, metazolamide, methodilazine, metenamine, metenolone acetate, metetoin, methicillin sodium, methimazole, methioninase, methionine, methisazone, methixene hydrochloride, methocarbamol, methhexital sodium, metofolin, methotrexate, methotrimeprazine, methoxatone, methoxyflurane, metosuximide, meticlothiazide, methyl palmoxylate, methylatropine nitrate,Methylbenzethonium chloride, methyldopa, methyldopa hydrochloride, methylene blue, methylergonovine maleate, R-α-methylhistamine, methylinosine monophosphate, methylphenidate hydrochloride, methylprednisolone, methyltestosterone, methinodiol diacetate, methyserzide, methyserzide maleate, methiaamide, methiapine, methioprim, metipamid, metipranolol, methizolin hydrochloride, methcefamide acetate, metoclopramide, iodide methocrine, metogest, metrazone, metopimazine, metoprin, metoprolol, metoxidine, metrifonate, metrizamide, sodium metrizoate, metronidazole, metsuredepa, metyrapone, methirosine, mexiletine hydrochloride, potassium mexrenoate, mezlocillin, muhonelic acid (mfonelic acid) (acid), mianserin hydrochloride, mibefladil, mibefladil dihydrochloride, miboleron, mikeramine B, miconazole, microcholine A, midaflur, midazolam hydrochloride, midodrine, mifepristone, mihobart, miglitol, miracemide, miramelin, mildronate, mirenperon, milipertin, milnacipran, milrinone, miltefosine, minban hydrochloride, minaprin, minaxolone, minoclomil, minocycline, minoxidil, myophradin hydrochloride, myokamycin, mipragoside, milfentanil, mirimostim, milinkamycin hydrochloride, myrisetron maleate, mirtazapine, mismatch double-stranded RNA, misonidazole, misoprostol, mitindomide, mitocalcin, mitocrom Mitogiline, Mitoguazone, Mitractol, Mitomarcin, Mitomycin, Mitonafide, Mitospel, Mitotan, Mitoxantrone, Mibacryl chloride, Mivazerol, Mixampril, Mixidine, Mizolastine, Mizoribine, Moclobemide, Modafinil, Modalin sulfate, Modicainide, Moexipril, Mofalotene, Mofegiline hydrochloride, Mofezolac, Morglamostim, Morinazone, Morindone hydrochloride, Morcidomin, Mometasone, Monatepyr maleate, Monensin, Monoctanoin, Montelukast sodium, Montilelin, Mopidamol, Moracidine, Morantel tartrate, Moricidine, Morniflumart, Morphine sulfate, Sodium morinate, Mosapramine, Mosapride, Motilide,Motoretinide, Moxalactam disodium, Moxazosin, Moxylaprin, Moxnidazole, Moxonidine, Mumps skin test antigen, Mustard anticancer agent, Muzolimin, Micaperoxide B, Mycophenolic acid, Miriapolon, Nabazenil, Nabilon, Navitan hydrochloride, Naboctart hydrochloride, Nabumeton, N-acetyldinaline, Nadide, Nadifloxacin, Nadolol, Nadroparin calcium, Nafadotrid, Nafamostat, Nafarelin, Nafcillin sodium, Nafenopine, Nafimidone hydrochloride, Naflocort, Nahomin malate, Nafoxidine hydrochloride, Naflonil oxalate, Naftifine hydrochloride, Naftopidil, Nagliban, Nagrestip, Nalbufine hydrochloride, Naldemedine, Sodium nalidixate, Nalidixic acid, Nalmefene, Nalmexone hydrochloride, Naloxone + Pentazocine, Naltrexone, Namoxylate, Nandrolone fenpropionate, Nantradol hydrochloride, Napactadine hydrochloride, Napadisyl acids, Napamethol hydrochloride, Napaviin, Naphazoline hydrochloride, Naphterpine, Naproxen, Naproxol, Napsagatran, Naranol hydrochloride, Nalacin, Naratriptan, Naltograstim, Na Salprase, natamycin, nateplase, naxagolide hydrochloride, nebibolol, nebramycin, nedaplatin, nedocromil, nefazodone hydrochloride, neflumozide hydrochloride, nehopam hydrochloride, nerezaprine maleate, nemazoline hydrochloride, nemorubicin, neomycin palmitate, neostigmine bromide, neridronic acid, netylmycin sulfate, neutral endopeptidase, neutramycin, nevirapine, nexeridine hydrochloride, niacin, nibroxan, nicardipine hydrochloride, nicergoline, niclosamide, nicorandil, nicotinyl alcohol, ni Fedipine, nifirmerone, nifluridide, nifladen, niflardesone, nifratel, niflatoron, nifludazil, niflmid, niflupyrinol, nifluquinazole, nifurthiazol, nilutamide, nilvadipine, nimazon, nimodipine, niperotidine, nivololin, niridazole, nisamycin, nisbuterol mesylate, niscin, nisovamart, nisoldipine, nisoxetine, nisterim acetate, nitazoxamide, nitezoxamide, nitecapone, nitrafdam hydrochloride, nitralamine salt Acid salts, nitramisol hydrochloride, nitrazepam, nitrendipine, nitrocycline, nitrodan, nitrofurantoin, nitrofurazone, nitroglycerin, nitromelsol, nitromide, nitromifene citrate, nitrous oxide, nitrogen oxide antioxidants, nitrullyn, nivazole, nibimedon sodium, nizatidine, novellastine, nocodazole, nogaramycin, norinium bromide, nomifensin maleate, noasimesadol hydrochloride, norvoreton, norepinephrine bitartrate, norethindrone, norethinodrel,Norfloxacin, norflurane, norgestimate, norgestmeth, norgestrel, nortriptyline hydrochloride, noscapine, novobiosin sodium, N-substituted benzimide, nufenoxol, nilestriol, nystatin, O6-benzylguanine, ovidoxime chloride, ocaperidone, ocfentanil hydrochloride, osinapron, octanoic acid, octazamide, octenidine hydrochloride, octodrine, octreotide, octriptyline phosphate, ofloxacin, Oformine, oxenone, olanzapine, oligonucleotide Otide, olopatadine, olprinon, olsalazine, olsalazine sodium, olbanil, omeprazole, onapristone, ondansetron, ontazolast, oocyte maturation inhibitors, opipramole hydrochloride, oracin, orconazole nitrate, olgothain, orlistat, ormaplatin, olmethoprim, ornidazole, olpanoxin, orphenadyl cetone, osateron, otenzepad, oxacillin sodium, oxagrelate, oxaliplatin, oxamarin hydrochloride, oxamisol, oxamnicine, oxandro Oxantel pamoate, oxaprotiline hydrochloride, oxaprozin, oxalvazole, oxatomide, oxaunomycin, oxazepam, oxcarbazepine, oxendrone, oxethazaine, oxetron fumarate, oxfendazole, oxphenicin, oxybendazole, oxiconazole, oxidopamine, oxidronic acid, oxyfungin hydrochloride, oxilorphan, oximonam, oximonam sodium, oxyperomide, oxiracetam, oxiramide, oxithran, oxmethidine hydrochloride, oxodipine, fenpro Oxogestone pionic acid, oxolinic acid, oxprenolol hydrochloride, oxtriphylline, oxybutynin chloride, oxychlorocene, oxycodone, oxymetazoline hydrochloride, oxymetholone, oxymorphone hydrochloride, oxypertin, oxyfenbutazone, oxyprinol, oxytetracycline, oxytocin, ozagrel, ozolinone, paclitaxel, parauamine, paldimycin, palinavir, palmitoyl rhizoxine, sodium palmoxylate, pamaquecid, pamatorol sulfate, pamicogrel, disodium pamidronate,Pamidronic acid, panadipron, panamesin, panaxitriol, pancoprid, pancuronium bromide, panipenem, pannoline, panomifene, pantethine, pantoprazole, papaverine hydrochloride, parabactin, parachlorophenol, paraaldehyde, paramethasone acetate, paraniline hydrochloride, parapenzolate bromide, pararosaniline pamoate, parbendazole, parconazole hydrochloride, paregoric, pareptide sulfate, pargiline hydrochloride, parnaparin sodium, paramomycin sulfate, paroxetine, parthenolide, patricin, pau Romycin, Pazeliptin, Padinacron, Pazoxide, Pazufloxacin, Pefloxacin, Pegaspargase, Pegolgotine, Perancerin Hydrochloride, Perdesin, Periomycin, Perretin, Perlinone Hydrochloride, Pemedlac, Pemerido Nitrate, Pemirolast, Pemoline, Penamecillin, Penbutrol Sulfate, Penciclovir, Penfluridol, Penicillin G Benzatine, Penicillin G Potassium, Penicillin G Procaine, Penicillin G Sodium, Penicillin V, Penicillin V Benzatine, Penicillin V Hydrabamine, Penicillin V Potassium Um, Pentabamart, Pentaerythritol tetranitrate, Pentafuside, Pentamidine, Pentamorphone, Pentamustine, Pentapiperium methylsulfate, Pentazocine, Pentetic acid, Pentiapine maleate, Pentigetide, Pentisomicin, Penthizidone sodium, Pentobarbital, Pentomon, Pentopril, Pentosan, Pentostatin, Pentoxifylline, Pentrinitrol, Pentrozole, Pepromycin sulfate, Pepstatin, Perflubron, Perphofamide (pe rfofamide), perphosphamide, pergolide, perhexylline maleate, periryl alcohol, perindopril, perindoprilat, perlapine, permethrin, perospirone, perphenazine, phenasemide, phenaridine, phenazinomycin, phenazopyridine hydrochloride, fenbutazone sodium glycerate, fencarbamide, phencyclidine hydrochloride, fendimethrazine tartrate, phenelzine sulfate, fenmetrazine hydrochloride, phenobarbital, phenoxybenzamine hydrochloride, fenprocumone, fencerin,Phensuccinal, fenximide, phentermine, phentermine hydrochloride, phentolamine mesylate, phentoxifylline, phenyl aminosalicylate, phenyl acetate, phenylalanine, phenylalanyl ketoconazole, phenylbutazone, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, phenylpropanolamine polystyrene, pheniramidol hydrochloride, phenyloin, phosphatase inhibitors, physostigmine, picena Dol, Picibanil, Picotrindiolamine, Piclorib, Picmeterol, Pidotimod, Pifamine, Pillocarpine, Pilsicainide, Pimagedin, Pimetine hydrochloride, Pimirprost, Pimobendan, Pimozide, Pinacidil, Pinadrine, Pindolol, Pinenol, Pinocebrin, Pinoxepine hydrochloride, Pioglitazone, Pipamperone, Pipazetate, Pipecuronium bromide, Piperacetazine, Piperacillin sodium, Piperamide maleate, Piperazine, Pipobroman, Pi Posulfan, Pipothiazine palmitate, Pipoxolane hydrochloride, Piprozoline, Pikindon hydrochloride, Pikidyl hydrochloride, Piracetam, Pyrandamine hydrochloride, Pirarubicin, Pyrazmonam sodium, Pyrazolac, Pyrbenicillin sodium, Pirbuterol acetate, Pirenperone, Pirenzepine hydrochloride, Piretamide, Pirfenidone, Pyridicillin sodium, Pyridronate sodium, Piriprost, Pyritrexime, Pirrimycin hydrochloride, Pirrindol, Pirmagrel, Pirmenol hydrochloride, Pirunabin, Piroctone Pirodavir, pyrodomast, pyroglilide tartrate, pyrolate, pyrorazamide, piroxantrone hydrochloride, piroxicam, piroximon, pirprofen, pirquinozol, pircidomin, preniramine, posterior pituitary, pivampicillin hydrochloride, pivopril, pizotirin, placetin A, platinum compounds, platinum-triamine complex, plicamycin, promethan, povircastoedamine, podophylloxacin, urushi extract, methylsulfate pordin, polyglucusum, sodium polygnate,Polymyxin B sulfate, polythiazide, ponalrestat, porfimer sodium, porphyromycin, potassium chloride, potassium iodide, potassium permanganate, povidone-iodine, praractol, pralidoxime chloride, pramiracetam hydrochloride, pramoxin hydrochloride, planolium chloride, pravadrine maleate, pravastatin (pravacol), prazepam, prazosin, prazosin hydrochloride, prednazate, prednicarbart, prednimustine, prednisolone, prednisone, prednivar, pregnenolone succinate Succiniate), prenalterol hydrochloride, pridefine hydrochloride, Priferon, prilocalne hydrochloride, prilosec, primakine phosphate, primidol, primidone, prinivir, prinomidotromethamine, prinoxodane, prizidilol hydrochloride, proadifen hydrochloride, probenecid, propiclomil calcium, probucol, procainamide hydrochloride, procaine hydrochloride, procarbazine hydrochloride, procaterol hydrochloride, prochlorperazine, prosinonide, proclonal, procyclidine hydrochloride, proziridine hydrochloride, prodolic acid, profadol hydrochloride, progavid, progesterone, proglumide, human proinsulin, proline, prolinetan hydrochloride, promazine hydrochloride, promethazine hydrochloride, propafenone hydrochloride, propagermanium, propanidide, bromide Propantheline, propalacaine hydrochloride, propatil nitrate, propentophylline, propenzolate hydrochloride, propicacin, propiomazine, propionic acid, L-propionylcarnitine, propyram, propyram + paracetamol, propiverine, propofol, propoxycaine hydrochloride, propoxifen hydrochloride, propranolol hydrochloride, propalcid, propylbis-acridone, propylhexedrine, propriodone, propylthiouracil, proquazone, prolenoate potassium, proloxane hydrochloride, proscilaridine, prostalen, prostratin, protamine sulfate, protegurin, protirelin, protosufloxacin, protriptyline hydrochloride, proxazole, proxazole citrate, proxichromil, proxolphan tartrate, prulifloxacin, pseudoephedrine hydrochloride,Puromycin, purpurin, pyrabrom, pyrantel pamoate, pyrazinamide, pyrazofulin, pyrazoloacridine, pyridostigmine bromide, pyriramine maleate, pyrimethamine, pyrinoline, sodium pyrithione, zinc pyrithione, pyrovalerone hydrochloride, pyroxamine maleate, pirocaine, pyrrolfene hydrochloride, pyrrolnitrin, pyrvinium pamoate, quadazosine mesylate, quazepam, quadinone, quazodin, quazolast, quetiapine, quiflapon, quinagolide, quinaldine blue, quinapril, quinaprilato, quinazosine hydrochloride, quinboron, quinctolate, quindecamine acetate, quindonyl bromide, , quinellolan hydrochloride, quinestrol, quinfamide, kingestanol acetate, kingestron, quinidine gluconate, quinielorane hydrochloride, quinine sulfate, quinpyrrole hydrochloride, quinterenol sulfate, quinucrine bromide, quinupristin, kipadin maleate, rabeprazole sodium, racephenicol, racepinephrine, Raf antagonist, rafoxamide, laritrin, raloxifene, laritrexed, ramatroban, ramipril, lamopranin, ramosetron, raneric acid, ranimycin, ranitidine, lanolazine, Indian snakewood, lecanum, lecanum hydrochloride, lecanum. Zepam, regavirumab, reglamostim, relaxin, reromycin, remasemide hydrochloride, remifentanil hydrochloride, remiprostol, remoxiprid, repirinast, repromycin, reproterol hydrochloride, reserpine, resinferatoxin, resorcinol, demethylated reteliptin, reticlon, reviparin sodium, levidinone, rhenium Re-186 etidronic acid, lyzoxin, ribaminol, ribavirin, ribopurine, ribozyme, ricasetron, lidogre Rifabutin, Rifametan, Rifamexil, Rifamide, Rifampin, Rifapentin, Rifaximin, RII Retinamide, Rilopirox, Riluzole, Rimantadine, Limmazole Hydrochloride, Rimexolone, Limiterol Hydrobromide, Rimoprogin, Riodipine, Rioprostil, Lipazepam, Lipisartan, Risedronate Sodium, Risedronic Acid, Lysocaine, Lysotilide Hydrochloride, Rispenzepine, Risperdal, Risperidone, Ritanserin, Litipenem, Ritodrine, Littlecast, Rito Navir, rizatriptan benzoate, locastine hydrochloride, rocuronium bromide, rhodocaine, loflurane, logretimide, rohitzkin, rokitamycin, roletamiside, lorgamidin, loliciprine, lolipram, lolitetracycline, rolodin, lomazarit, lomulutide, ronidazole, ropinirole, lopitoin hydrochloride, ropivacaine, lopidine, lokinimex, rosalamycin, rosiglitazone, loxoxacin, rotoxamine, roxaitidine,Roxarson, Roxindol, Roxithromycin, Rubiginon B1, Ruboxil, Rufloxacin, Rupatidine, Rutamycin, Luzadran, Saberzol, Safingol, Safilonil, Cyntopein, Salbutamol, R-Sarcorex, Saletamide Maleate, Salicyl Alcohol, Salicylamide, Meglumine Salicylate, Salicylic Acid, Salmeterol, Salnacediin, Salsalat, Samezine, Sanpatrilato Sancycline, Sanfetrinem, Sanguinalium chloride, Saperconazole, Supplisartan, Sapropterin, Saquinavir, Salafloxacin hydrochloride, Salaracin acetate, SarCNU, Sarcophytol A, Salglamostim, Salmoxicillin, Salpicillin, Salpogrelate, Salprase, Saterinone, Satigrel, Satsumomab pentetide, Schick test control drug, Scopafungin, Scopolamine hydrobromide, Scrazaipine hydrochloride, Sdi 1 mimoid, Secalciferol, Secobarbital, Seelzone, Seglitide acetate, Selegiline, Selegiline hydrochloride, Selenium sulfide, Selenomethionine Se 75, Cellhotel, Sematilide, Senduramycin, Cemothiazil, Semustine, Sens Oligonucleotide, Sepazonium Chloride, Seperidol Hydrochloride, Seprilose, Seproxetine Hydrochloride, Seractide Acetate, Cergorexol Maleate, Serine, Celmethacin, Cermorelin Acetate, Sertaconazole, Sertindol, Sertraline, Setiptiline, Setoperone, Sevilumab, Sevoflurane, Cezoramide, Sibopyrdin, Sibutramine Hydrochloride, Signal Transduction Inhibitors, Silandrone, Silipid, Silteplase, Silver Nitrate, Shime Ndan, simtrazene, simvastatin, cincalid, synefungin, cinitrodil, cinnabidol, sipatrigine, sirolimus, shisomycin, citglucid, schizophilan, sobuzoxane, sodium amyl sulfate, sodium iodide I-123, sodium nitroprusside, sodium oxybate, sodium phenylacetate, sodium salicylate, sorbrol, solipertine tartrate, somalapol, somantadine hydrochloride, somatomedin B, somatomedin C, somatoremSomatropin, Somenopol, Somidobov, Sonelmin, Sorbinyl, Sorivudine, Sotalol, Soterenol hydrochloride, Sparfloxacin, Sparphosate sodium, Sparphosic acid, Sparsomecin, Spartein sulfate, Spectinomycin hydrochloride, Spicamycin D, Spiperone, Spiradrine mesylate, Spiramycin, Spirapril hydrochloride, Spiraprilat, Spirogermanium hydrochloride, Spiromustine, Spironolactone, Spiroplatin, Spiroxason, S Prenopentin, spongistatin 1, sprodiamide, squalamine, stalimycin hydrochloride, stannous pyrophosphate, tin sulfur colloid, stanozolol, statron, staurosporine, stabudin, stefimycin, stenboron acetate, stepronin, stilbodium iodide, styronium iodide, stipamide, stiripentol, stovadin, streptomycin sulfate, streptonicozide, streptonigrin, streptozocin, stromelysin inhibitors, strontium chloride Sr 89. Succibun, succimer, succinylcholine chloride, sucralfate, sucrosofatopotassium, sudoxicam, sufentanil, sufothidine, surazepam, sulbactam pivoxil, sulconazole nitrate, sulfabenz, sulfabenzamide, sulfacetamide, sulfacitin, sulfadiazine, sulfadoxin, sulfarene, sulfamerazine, sulfameta, sulfamethazine, sulfamethizol, sulfamethoxazole, sulfamonomethoxine, sulfamoxol, sulfanilic acid Zinc, sulfanitran, sulfasalazine, sulfasomisole, sulfazameth, sulfinalol hydrochloride, sulfinosine, sulfinpyrazone, sulfisoxazole, sulfomyxin, sulfonterol hydrochloride, sulfoxamine, sulinldac, sulmarin, sulnidazole, suloctidyl, slofenu, slopenem, thuloxifen oxalate, sulpiride, sulprostone, sultamicillin, sultiam, sultopride, sulkast, smalotene, sumatriptan, suncillin sodium, suprocron, suprofen, suradista, suramin, sulfomer,Slicainide maleate, slitozol, thronacrine maleate, szemerido sulfate, swinesonin, symakalim, symcrocene, cimetine hydrochloride, synthetic glycosaminoglycans, taciamine hydrochloride, tacrine hydrochloride, tacrolimus, tarampicillin hydrochloride, talellanol, talisomycin, talimustine, talmetacin, tarniflumart, talopram hydrochloride, tarosalate, tametraline hydrochloride, tamoxifen, tampramine fumarate, tamsulosin hydrochloride, tandamin hydrochloride, tando Spiron, TAPgen, Taprosten, Tasosartan, Tauromustine, Taxane, Taxoid, Tazadren succinate, Tazanolast, Tazarotene, Tadiphylline hydrochloride, Tazobactam, Tazoferon, Tazolol hydrochloride, Tebuferon, Tebukin, Bicisart technetium (Tc)-99m, Teclozan, Tecogalan sodium, Teecleukin, Teflurane, Tegaflu, Tegretol, Teicoplanin, Terenzepine, Terrapyrilium, Termestain, Telmisartan, Telomerase inhibitor, Tel Xantrone hydrochloride, terdipine hydrochloride, temafloxacin hydrochloride, tematropium methylsulfate, temazepam, temelastine, temocapril, temocillin, temoporfin, temozolomide, tenidap, teniposide, tenosal, tenoxicam, tepirindol, tepoxalin, teprotide, terazosin, terbinafine, terbutaline sulfate, terconazole, terfenadine, terflavoxate, terguride, teriparatide acetate, terlachilen, terlipressin, terodilin, teroxalen hydrochloride, teroxylon, tertatrol, tesica Mu, Tesimide, Testolactone, Testosterone, Tetracaine, Tetrachlorodecaoxide, Tetracycline, Tetrahydrozoline hydrochloride, Tetramisol hydrochloride, Tetrazolastomeglumine, Tetrazomine, Tetrophosmin, Tetroquinone, Tetroxoprim, Tetridamine, Talibrandin, Thalidomide, Theofibrate, Theophylline, Thiabendazole, Thiamiprine, Thiamphenicol, Thiamylal, Thiazesim hydrochloride, Thiazinamium chloride, Thiethylperazine, Thimelfonate sodium, Thimerosal, Thiocoralin,Thiofedrine, thioguanine, thiomarinol, thiopental sodium, thioperamide, thioridazine, thiotepa, thiothixen, tifenamil hydrochloride, tifeniclin potassium, thyram, tozarinone, threonine, thrombin, thrombopoietin, thrombopoietin mimetic, thymalfacin, thymopoietin receptor agonist, thymotrinan, thyromedan hydrochloride, thyroxine I-125, thyroxine I-131, thiacrilast, thiacrilast sodium, thiagabin, thiamenidine, thianeptin, thiapaphan Tiapafant, thiapamil hydrochloride, tiaramide hydrochloride, thiazophrine, tibenelast sodium, tiborone, tibrunic acid, ticabesone propionate, ticarbodine, ticalcyline glesyl sodium, ticlaton, ticlopidine, ticlinafen, thienoxolol, tifrac sodium, tigemonamdicolin, tigestor, tiretamine hydrochloride, tyrizine hydrochloride, tyrisolol, tilnoprofen albamel, tyrolone hydrochloride, tyrdronate disodium, tyrdronic acid, thimeflon, timovesone acetate, timolol, tin ethyl ethiopropyl purpurine N, tinabinol, thymidazole, tinzaparin sodium, thioconazole, thiodazosin, thidonium chloride, thioperidone hydrochloride, thiopinac, thiospirone hydrochloride, thiothidine, tiotropium bromide, thioxidazole, tipentosin hydrochloride, ticpredan, ticprenolol hydrochloride, ticprinastomeglumine, tipropidil hydrochloride, ticeczesid, tikinamide hydrochloride, tilandalidine, tirapazamine, tilirazad, tyrofiban, tilopramide, titanocene dichloride, thixanox, thixocortol pivalate, tizanidine hydrochloride, tobramycin, Tokainide, Tocanfil, Tofenacin hydrochloride, Tramolol, Trazamide, Trazoline hydrochloride, Tolbutamide, Tolcapone, Tolcyclate, Tolfamide, Tolgavid, Lamotrigine, Trimidone, Trindart, Tolmetine, Tolnaphate, Tolpovidone I-131, Tolpyramide, Torrestat, Tomerkast, Tomoxetine hydrochloride, Tonazosin mesylate, Topiramate, Topotecan, Topotecan hydrochloride, Topsentin, Topterone, Toxidine, Torasemide, Toremifene, Tosefen, Tosufloxacin, Pluripotent stem cell factor,Tracasolate, Trafermin, Tralonide, Tramadol hydrochloride, Tramazoline hydrochloride, Trandolapril, Tranexamic acid, Tranilast, Transcainide, Translation inhibitors, Traxanox, Trazodone hydrochloride, Trazodone-HCl, Trebenzominone hydrochloride, Trefentanil hydrochloride, Treloxinate, Trepipam maleate, Trestron acetate, Tretinoin, Triacetin, Triacetyluridine, Triafungine, Triamcinolone, Triampidine sulfate, Triamterene, Triazolam, Tribenoside, Tricaprylin, Tricetamide, Trichlormethiazide, Trichohyalin, Trisirivine, Tricitrate compounds, Triclophenolpiperazine, Triclophos sodium, Triclonide, Triene Trifenagrel, Triflavin, Triflosin, Triflubazam, Triflumidate, Trifloperazine hydrochloride, Trifluperidol, Triflupromazine, Triflupromazine hydrochloride, Trifluridine, Trihexyphenidyl hydrochloride, Trilostane, Trimazosin hydrochloride, Trimegestone, Trimeprazine tartrate, Trimethadione, Trimetaphan cansylate, Trimethobenzamide hydrochloride, Trimethoprim, Trimethodine, Trimethrexate, Trimipramine, Trimoprostil, Trimoxamine hydrochloride, Triolein I-125, Tri Olein I-131, trioxyfen mesylate, tripamide, triperenamine hydrochloride, triprolidine hydrochloride, triptorelin, trisulfapyrimidine, troclocene potassium, troglitazone, trolamine, troleandmycin, thrombodipine, trometamol, tropanserin hydrochloride, tropicamide, tropine ester, tropisetron, trospectomycin, trovafloxacin, trovirdin, tryptophan, tuberculin, tubocurarine chloride, tuburosol hydrochloride, tucarcsol, tulobuterol, tulo Steride, Cibamart, Tyrogenin, Sodium Tyropanoate, Tyrosine, Tyrosulin, Tylphostine, Ubenimex, Urdazepam, Undecylenic Acid, Uracil Mustard, Urapidil, Urea, Uredepa, Uridine Triphosphate, Urofolitropin, Urokinase, Ursodiol, Valacyclovir, Valine, Valnoctamide, Sodium Valproate, Valproic Acid, Valsartan, Vamicamide, Vanadeine, Vancomycin, Vaninolol, Bapiprost Hydrochloride, Bapreotide, Variolin B, Vasopressin, Vecuronium Bromide Veraresol, Vernacrine maleate, Venlafaxine, Belladrine hydrochloride, Veramine, Verapamil hydrochloride, Verzin, Berilopam hydrochloride, Verulukast, Berophylline, Veroxan, Verteporfin, Vesnarinone, Bexivinol, Vidarabine, Vigabatrin, Biloxazine hydrochloride, Vinblastine sulfate, Vinbulinine citrate, Vincophos, Vinconate, Vincristine sulfate, Vindesine, Vindesine sulfate, Vinepidine sulfate, Vingricinate sulfate, Vinleulosine sulfate, Vinorelbine,Vinpocetine, vintoperol, vinxaltine, vinzolidine sulfate, biprostol, Virginiamycin, viridofluvin, viroxime, vitaxin, borazosin, voriconazole, borozol, voxelgolide, warfarin sodium, xamoterol, xanomeline, xanoxate sodium, xanthinol nicotinate, xemirofiban, xenalipin, xenbusin, xilobam, ximoprofen, xipamide, xolphanol mesylate, xylamidine tosylate, xylazine hydrochloride, xylometazoline hydrochloride, xylose, yanganbin, zabishipril, zacoprid, zafirlukast, zalcitabine, zaleplon, zalospirone, zaltidine hydrochloride, zaltoprofen, zanamivir, zanquilen, zanoterone, zantac, zarilurukast ( Zarirlukast), zatebrazine, zatosetron, zatosetron maleate, zenalestat, zenazosin mesylate, zeniplatin, zeranol, zidomethacin, zidovudine, diflosylon, dilantel, zilascorb, ziloton, zimerzine hydrochloride, zinc undecylenate, zindothrin, dinoconazole hydrochloride, zinostatin, dinterol hydrochloride, zinviroxime, ziprasidone, zo This includes Zobolt, zofenopril calcium, zofenoprilat, zolamine hydrochloride, zolazepam hydrochloride, zoledronic acid, zoreltin hydrochloride, zolmitriptan, zolpidem, zomepirac sodium, zometapine, zonicresol hydrochloride, zonisamide, zopiclone, zopolrestat, zolbamycin, zolubicin hydrochloride, zotepine, and zucapsaicin.

[0113] Another pharmaceutically active ingredient permitted for use herein is lumateperone, U.S. Patent Nos. 9745300, 9708322, 7183282, 7071186, 6552017, 8648077, 8598119, 9751883, 9371324, 9315504, 9428506, 8993572, 8309722, 6713471, 8779139, 91 This information is disclosed in U.S. Patent Application Publications 68258, RE039680E1, 9616061, 9586960, and U.S. Patent Application Publications 2017114037, 2017183350, 2015072964, 2004034015, 2017189398, 2016310502, and 2015080404, all of which are incorporated herein by reference.

[0114] Furthermore, examples of antidiabetic active ingredients are not limited to those listed below, but include: JTT-501 (PNU-182716) (Regitazar), AR-H039242, MCC-555 (Netoglitazone), AR-H049020 (Tesaglitazar), CS-011 (CI-1037), GW-409544×, KRP-297, RG-12525, BM-15.2054, CLX-0940, CLX-0921, 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 Contains 2725 (lagaglytazar), L-686398, L-168049, L-805645, L-054852, demethylasteriquinone B1 (L-783281), L-363586, KRP-297, P32 / 98, CRE-16336, and EML-16257.

[0115] The drugs available for use in this specification for the treatment of erectile dysfunction include, but are not limited to, drugs that promote blood flow to the penis, and drugs that act on autonomic nervous system activity, such as by increasing parasympathetic (cholinergic) activity and decreasing sympathetic (adrenergic) activity. The active ingredients available for use in the treatment of erectile dysfunction include, but are not limited to, alprostadil, tadalafil, vardenafil, apomorphine, yohimbine hydrochloride, sildenafil citrate, and any combination thereof. In Embodiment 1, the active ingredient is tadalafil.

[0116] Active ingredients or therapeutic agents for the treatment of headaches and / or migraines are also available herein. Specific examples of active ingredients, but not limited to, include triptans such as eletriptan, naratriptan, rizatriptan (rizatriptan benzoate), sumatriptan, and zolmitriptan. In one embodiment, the active ingredient is rizatriptan, which may optionally be combined with an NSAID.

[0117] In one embodiment, the pharmaceutically active ingredient may be a benzodiazepine, such as diazepam, lorazepam, midazolam, chlorazepic acid, temazepam, triazolam, clonazepam, flurazepam, oxazepam, chlordiazepoxide, estazolam, quazepam, or alprazolam.

[0118] (Polymer matrix) This composition may contain a polymer matrix. Any desired polymer matrix can be used as long as it is orally soluble or disintegrable. This dosage form must have sufficient bioadhesion that is not easily removed and must form a gel-like structure upon administration. These are moderately soluble in the oral cavity and are particularly suitable for the delivery of pharmaceutically active ingredients, but immediate-release, delayed-release, controlled-release, and sustained-release compositions are also included in the various intended embodiments.

[0119] The pharmaceutical composition film may contain dendritic polymers that have various structural architectures and are highly branched polymers. The dendritic polymers may include dendrimers, dendritic polymers (dendritic graft polymers), linear dendritic hybrids, multi-arm star polymers, or highly branched polymers.

[0120] Highly branched polymers are highly branched polymers that have structural imperfections. However, they can be synthesized in a single-step reaction, which can be an advantage over other dendritic structures and makes them suitable for bulk production. Apart from their spherical structure, the properties of these polymers include abundant functional groups, intramolecular cavities, low viscosity, and high solubility. Dendritic polymers have been used in several drug delivery applications. See, for example, “Dendrimers as Drug Carriers: Applications in Different Routes of Drug Administration,” J Pharm Sci, VOL. 97, 2008, 123-143, which is incorporated herein by reference.

[0121] Dendritic polymers can have internal cavities capable of encapsulating drugs. The steric hindrance caused by high-density polymer chains can prevent drug crystallization. Therefore, branched polymers can offer the additional advantage of formulating crystalline drugs within a polymer matrix.

[0122] Examples of suitable 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(amino acid)-based dendrons, dendrimers, and highly branched polymers; poly(arylalkylene ether)-based dendrons, dendrimers, and highly branched polymers; poly(alkyleneimine)-based dendrons, dendrimers, and highly branched polymers; and poly(amidoamine)-based dendrons, dendrimers, or highly branched polymers.

[0123] Other examples of highly branched polymers include poly(amines), polycarbonates, poly(etherketones), polyurethanes, polycarbosilanes, polysiloxanes, poly(esteramines), poly(sulfonamines), poly(urethaneureas), and polyether polyols, such as polyglycerin.

[0124] The film can be prepared by a combination of at least one polymer and a solvent, optionally including other components. The solvent may be water, a polar organic solvent, or, but is not limited to, methanol, ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent may be a non-polar organic solvent such as methylene chloride. The film can be prepared by utilizing a selected casting or deposition method and a controlled drying process. For example, the film may be prepared through a controlled drying process that includes applying heat and / or radiation energy to a wet film matrix to form a viscoelastic structure, thereby controlling the uniformity of the film's contents. The controlled drying process may include contacting air alone, heat alone, or heat and air together, on the top or bottom of the film, or on a substrate supporting the cast, deposited, or extruded film, or on two or more surfaces simultaneously or at different points in time during the drying process. Some of these processes are described in more detail in U.S. Patent Nos. 8,765,167 and 8,652,378, which are incorporated herein by reference. Alternatively, the film may be extruded as described in U.S. Patent Application Publication No. 2005 / 0037055A1, which is incorporated herein by reference.

[0125] The polymers contained in the film may be water-soluble, water-swellable, water-insoluble, or a combination of one or more water-soluble, water-swellable, or water-insoluble polymers. The polymers may include cellulose, cellulose derivatives, or gums. Specific examples of usable water-soluble polymers, but are not limited to, polyethylene oxide, pullulan, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, and combinations thereof. Specific examples of usable water-insoluble polymers, but are not limited to, ethylcellulose, hydroxypropyl ethylcellulose, cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate, and combinations thereof. For higher doses, it may be desirable to incorporate polymers that provide a higher level of viscosity compared to lower doses.

[0126] As used herein, the terms “water-soluble polymer” and its variants refer to polymers that are at least partially soluble in water, preferably completely or largely soluble in water, or absorb water. Water-absorbing polymers are often referred to as water-swellable polymers. The materials usable in the present invention may be water-soluble or water-swellable at room temperature and other temperatures, for example, above room temperature. Furthermore, the materials may be water-soluble or water-swellable at pressures lower than atmospheric pressure. In some embodiments, films formed from such water-soluble polymers may be water-soluble to the extent that they are soluble upon contact with bodily fluids.

[0127] Other polymers that can be incorporated into the film include biodegradable polymers, copolymers, block polymers, or combinations thereof. The term “biodegradable” is understood to include substances that decompose chemically, as opposed to substances that are physically broken down (i.e., bioerodable materials). Polymers incorporated into the film may also include biodegradable materials or combinations of bioerodable materials. Known usable polymers or polymer species that meet the above criteria include: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxane, polyoxalate, poly(α-ester), polyacid anhydride, polyacetate, polycaprolactone, poly(orthoester), polyamino acid, polyamino carbonate, polyurethane, polycarbonate, polyamide, poly(alkylcyanoacrylate), and mixtures and copolymers thereof. Additional usable polymers include stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propanoic acid and sebacic acid, sebacic acid copolymers, caprolactone copolymers, poly(lactic acid) / poly(glycolic acid) / polyethylene glycol copolymers, polyurethane and (poly(lactic acid)) copolymers, α-amino acid copolymers, α-amino acid and caproic acid copolymers, α-benzyl glutamate and polyethylene glycol copolymers, succinate and poly(glycol) copolymers, polyphosphazenes, polyhydroxyalkanoates, or mixtures thereof. The polymer matrix may contain one, two, three, four, or more components.

[0128] While various different polymers may be used, it is desirable to select polymers that provide the film with mucosal adhesion properties, as well as the desired dissolution and / or disintegration rates. In particular, the time for which the film must maintain contact with mucosal tissue depends on the type of pharmaceutically active ingredient contained in the composition. Some pharmaceutically active ingredients may require only a few minutes for delivery through mucosal tissue, while others may require up to several hours or even longer. Therefore, in some embodiments, one or more water-soluble polymers may be used to form the film, as described above. However, in other embodiments, it may be desirable to use a combination of water-soluble polymers and water-swellable, water-insoluble, and / or biodegradable polymers as presented above. By including one or more water-swellable, water-insoluble, and / or biodegradable polymers, it is possible to provide a film with a slower dissolution or disintegration rate than a film formed solely of water-soluble polymers. Thus, this film can adhere to mucosal tissue for a longer time, for example, up to several hours, which would be desirable for the delivery of certain pharmaceutically active ingredients.

[0129] (Film characteristics) Preferably, individual film dosages of the pharmaceutical film may have a suitable thickness and small size, which is between approximately 0.0625 to 3 inches (1.5875 to 76.2 mm) × approximately 0.0625 to 3 inches. The film size may also be, in at least one embodiment, greater than 0.0625 inches, greater than 0.5 inches (12.7 mm), greater than 1 inch (25.4 mm), greater than 2 inches (50.8 mm), approximately 3 inches (76.2 mm), and greater than 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. In another embodiment, it may be greater than 0.0625 inches, greater than 0.5 inches, greater than 1 inch, greater than 2 inches, or greater 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, can be optimized by those skilled in the art based on the chemical and physical properties of the polymer matrix, the active pharmaceutical ingredient, dosage form, enhancer, and other additives included, as well as the dimensions of the desired dispensing unit. The film dosage form needs to have good adhesion when placed in the buccal or sublingual region of the user. Furthermore, the film dosage form must disperse and dissolve at a moderate rate, most preferably dispersing within about 1 minute and dissolving within about 3 minutes. In some embodiments, the film dosage form may disperse and dissolve in about 1 to about 30 minutes, for example, about 1 to about 20 minutes, or more than 1 minute, more than 5 minutes, more than 7 minutes, more than 10 minutes, more than 12 minutes, more than 15 minutes, more than 20 minutes, more than 30 minutes, about 30 minutes, or less than 30 minutes, 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. The dispersion rate sublingually may be lower than the dispersion rate on the buccal side of the oral cavity.

[0130] For example, in some embodiments, the film may contain polyethylene oxide alone or in combination with a second polymer component. The second polymer may be another water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer, or any combination thereof. Suitable water-soluble polymers include, but are not limited to, those presented above. In some embodiments, the water-soluble polymer may include hydrophilic cellulosic polymers, such as hydroxypropylcellulose and / or hydroxypropylmethylcellulose. In some embodiments, one or more water-swellable, water-insoluble, and / or biodegradable polymers may also be included in the polyethylene oxide-based film. Any of the water-swellable, water-insoluble, or biodegradable polymers presented above can be used. The second polymer component may be used in an amount of approximately 0% to approximately 80% by weight of the polymer component, more specifically approximately 30% to approximately 70% by weight, and even more specifically approximately 40% to approximately 60% by weight, which includes amounts of more than 5%, more than 10%, more than 15%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, and more than 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 less than 5% by weight.

[0131] (Additives) The film may contain additives. Examples of additives include preservatives, antimicrobial agents, excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, bulking agents, sweeteners, flavoring agents, aromas, release modifiers, adjuvants, plasticizers, flow enhancers, release agents, polyols, granulators, diluents, binders, buffers, absorbents, lubricants, adhesives, anti-adhesion agents, acidulants, softeners, resins, viscous lubricants, solvents, surfactants, emulsifiers, elastomers, anti-sticking agents, antistatic agents, and mixtures thereof. These additives may also be added together with the pharmaceutically active ingredient(s). As used herein, the term “stabilizer” means an excipient capable of preventing aggregation or other physical and chemical degradation of the active pharmaceutical ingredient, another excipient, or a combination thereof.

[0132] Stabilizers may also be classified as antioxidants, metal ion chelating agents, pH adjusters, emulsifiers and / or surfactants, or ultraviolet (UV) stabilizers.

[0133] Antioxidants (i.e., pharmaceutically acceptable compounds or compositions that slow, inhibit, interrupt and / or stop oxidation processes) include, in particular, the following substances: tocopherol and its esters, sesamol from sesame oil, coniferyl benzoic acid from benzoin resin, nordihydroguaietic resin and nordihydroguayaretinic acid (NDGA), gallic acid esters (especially methyl gallate, ethyl gallate, propyl gallate, amyl gallate, butyl gallate, lauryl gallate), butylated hydroxyanisole (BHA / BHT, also known as butyl-p-cresol); ascorbic acid and its salts and esters (e.g., acorbyl palmitate), erythorbic acid This includes isoascorbic acid (isoascorbic acid) and its salts and esters, monothioglycerol, sodium formaldehyde sulfoxylate, sodium disulfite, sodium bisulfite, sodium sulfite, potassium disulfite, butylated hydroxyanisole, butylated hydroxytoluene (BHT), and propionic acid. Typical antioxidants include tocopherols, e.g., α-tocopherol and its esters, butylated hydroxytoluene, and butylated hydroxyanisole. The term "tocopherol" also includes esters of tocopherol. A known tocopherol is α-tocopherol. The term "α-tocopherol" includes esters of α-tocopherol (e.g., α-tocopherol acetate).

[0134] Metal ion chelating agents (i.e., any compound that can participate in host-guest complex formation with another compound, such as an active ingredient or another excipient; also referred to as chelating agents) include calcium chloride, disodium calcium ethylenediaminetetraacetate, glucono delta-lactone, sodium gluconate, potassium gluconate, sodium tripolyphosphate, sodium hexametaphosphate, and combinations thereof. Metal ion chelating agents also include cyclic oligosaccharides, such as cyclodextrins, cyclomannins (five or more α-D-mannopyranose units linked at positions 1 and 4 by α-bonds), cyclogalactin (five or more β-D-galactopyranose units linked at positions 1 and 4 by β-bonds), cycloalthrins (five or more α-D-altropyranose units linked at positions 1 and 4 by α-bonds), 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 (e.g., glutamic acid, aspartic acid, etc.), inorganic salts of the above acidic substances (alkali metal salts, alkaline earth metal salts, ammonium salts, etc.), salts of the above acidic substances with organic bases (e.g., lysine, basic amino acids such as arginine, meglumine, etc.), and solvates thereof (e.g., hydrates). Other examples of pH adjusters include silicified microcrystalline cellulose, magnesium aluminometasilicate, calcium phosphates (e.g., anhydrous or hydrated calcium hydrogen phosphate, carbonates or bicarbonates of calcium, sodium or potassium, and calcium lactate, or mixtures thereof), sodium and / or calcium salts of carboxymethylcellulose or cross-linked carboxymethylcellulose (e.g., sodium and / or calcium salts of croscarmellose), potassium polaritrin, sodium alginate and / or calcium, sodium doxate, magnesium stearate, calcium, aluminum or zinc salts, magnesium palmitate, and magnesium oleate, sodium stearyl fumarate, and combinations thereof.

[0136] Examples of emulsifiers and / or surfactants include poloxamer or pluronic acid, polyethylene glycol, polyethylene glycol monostearate, polysorbate, sodium lauryl sulfate, polyethoxylated and hydrogenated castor oil, alkyl polyoside, water-soluble proteins grafted onto a hydrophobic main chain, lecithin, glyceryl monostearate, glyceryl monostearate / polyoxyethylene stearate, ketostearyl alcohol / sodium lauryl sulfate, carbomer, phospholipids, (C 10 ~C 20 ) Alkyl and alkylene carboxylates, alkyl ether carboxylates, aliphatic alcohol sulfates, aliphatic alcohol ether sulfates, alkylamide sulfates and sulfonates, fatty acid alkylamide polyglycol ether sulfates, alkanesulfonates and hydroxyalkanesulfonates, olefin sulfonates, acyl esters of isethionic acid, α-sulfo fatty acid esters, alkylbenzene sulfonates, alkylphenol glycol ether sulfonates, sulfosuccinates, monoesters and diesters of sulfosuccinates, aliphatic alcohol ether phosphates, protein / fatty acid condensation products, alkyl monoglyceride sulfates and sulfonates, alkylglyceride ether sulfonates, fatty acid methyl taurids, fatty acid sarcosinates, sulfolysine oleates and acyl glutamates, quaternary ammonium salts (e.g., di-(C) 10 ~C 24 )Alkyl-dimethylammonium chloride or bromide), (C 10 -C 24 ) Alkyl-dimethylethylammonium chloride or bromide, (C 10 -C 24 ) Alkyl-trimethylammonium chloride or bromide (e.g., cetyltrimethylammonium chloride or bromide), (C 10 -C 24 )Alkyl-dimethylbenzylammonium chloride or bromide (for example, (C 12 -C 18 )Alkyl-dimethylbenzylammonium chloride), N-(C10 -C 18 ) Alkyl-pyridinium chloride or bromide (e.g., N-(C 12 -C 16 )alkyl-pyridinium chloride or bromide), N-(C 10 -C 18 ) Alkyl-isoquinolinium chloride, bromide or monoalkyl sulfate, N-(C 12 -C 18 ) Alkyl-polyoylaminoformylmethylpyridinium chloride, N-(C 12 -C 18 ) Alkyl-N-methylmorpholinium chloride, bromide or monoalkyl sulfate, N-(C 12 -C 18 ) Alkyl-N-ethylmorpholinium chloride, bromide or monoalkyl sulfate, (C 16 -C 18 This includes alkyl-pentaoxetylammonium chloride, diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride, N,N-diethylaminoethyl-stearylamide, and salts of N,N-oleylamide with hydrochloride, acetic acid, lactic acid, citric acid, or phosphoric acid, N-acylaminoethyl-N,N-diethyl-N-methylammonium chloride, bromide, or monoalkyl sulfate, and N-acylaminoethyl-N,N-diethyl-N-benzylammonium chloride, bromide, or monoalkyl sulfate (wherein "acyl" represents, for example, stearyl or oleyl), and combinations thereof.

[0137] Examples of ultraviolet (UV) stabilizers include UV absorbers (e.g., benzophenone), UV quenchers (i.e., any compound that dissipates UV energy as heat without causing decomposition), scavengers (i.e., any compound that removes free radicals resulting from exposure to UV radiation), and combinations thereof.

[0138] In other embodiments, the stabilizers include ascorbyl palmitate, ascorbic acid, α-tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, cysteine ​​HCl, citric acid, ethylenediaminetetraacetic acid (EDTA), methionine, sodium citrate, sodium ascorbate, sodium thiosulfate, sodium disulfite, sodium bisulfite, propyl gallate, glutathione, thioglycerol, singlet oxygen quenchers, hydroxyl radical scavengers, hydroperoxide removers, reducing agents, metal chelating agents, detergents, chaotropes, and combinations thereof. "Singlet oxygen quenchers" include, but are not limited to, alkylimidazoles (e.g., histidine, L-camosine, histamine, imidazole-4-acetic acid), indoles (e.g., tryptophan and its derivatives, e.g., N-acetyl-5-methoxytryptamine, N-acetylserotonin, 6-methoxy-1,2,3,4-tetrahydro-β-carbolin), sulfur-containing amino acids (e.g., methionine, ethionine, gencolic acid, lanthionine, N-formylmethionine, felinine, S-allylcysteine, S-aminoethyl-L-cysteine), phenolic compounds (e.g., tyrosine and its derivatives), aromatic acids (e.g., ascorbic acids, salicylic acid, and their derivatives), azides (e.g., sodium azide), tocopherols and related vitamin E derivatives, and carotenes and related vitamin A derivatives. "Hydroxyl radical scavengers" include, but are not limited to, azides, dimethyl sulfoxides, histidine, mannitol, sucrose, glucose, salicylic acids, and L-cysteine. "Hydroperoxide removers" include, but are not limited to, catalase, pyruvates, glutathione, and glutathione peroxidase. "Reducing agents" include, but are not limited to, cysteine ​​and mercaptoethylene. "Metal chelating agents" include, but are not limited to, EDTA, EGTA, o-phenanthroline, and citrates. "Cleaning agents" include, but are not limited to, SDS and sodium lauroyl sarcosinate."Chaotrope" includes, but is not limited to, guanidine hydrochloride, isothiocyanates, urea, and formamide. As discussed herein, stabilizers can be present in amounts from 0.0001% to 50% by weight, which include, by weight, greater than 0.0001%, greater than 0.001%, greater than 0.01%, greater than 0.1%, greater than 1%, greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 1%, 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, plant proteins such as sunflower protein, soy protein, cottonseed protein, peanut protein, grapeseed protein, etc., whey protein, whey protein isolates, blood proteins, egg proteins, acrylic proteins, water-soluble polysaccharides such as alginate, carrageenan, guar gum, agar, xanthan gum, gellan gum, acacia gum and related gums (gutti gum, karaya gum, tragacanth gum), pectin, etc., water-soluble derivatives of cellulose: alkylcellulose, hydroxyalkylcellulose and hydroxyalkylalkylcellulose, for example, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxy This may include cellulose esters and hydroxyalkylcellulose esters such as ethylmethylcellulose, hydroxypropylmethylcellulose, and hydroxybutylmethylcellulose, for example cellulose phthalate acetate (CAP), hydroxypropylmethylcellulose (HPMC); carboxyalkylcellulose, carboxyalkylalkylcellulose, carboxyalkylcellulose esters, for example carboxymethylcellulose and their alkali metal salts; water-soluble synthetic polymers, for example polyacrylic acid and polyacrylic acid esters, polymethacrylic acid and polymethacrylic acid esters, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVA / vinyl acetate copolymer, or polycrotonic acid. Also preferred are phthalic acid-treated gelatin, succinic acid-treated gelatin, cross-linked gelatin, shellac, water-soluble chemical derivatives of starch, for example cationically modified acrylates and methacrylates having tertiary or quaternary amino groups such as diethylaminoethyl groups, which may be quaternized if necessary; or other similar polymers.

[0140] The stabilizer may include nanoparticle stabilizers such as a dispersant layer surrounding the surface of the nanoparticles. See, for example, Langmuir, 2007, (23)3, 1081-1090, December 20, 2006, doi.org / 10.1021 / la062042s. The stabilizer may include stabilizer ligands, such as monomers having functional groups that can be chemically adsorbed onto nanoparticles to form polymerizable monolayers. See, for example, Jadhav et al., https: / / doi.org / 10.1002 / ppsc.201400074. The stabilizer may also include surface stabilizers. See, for example, U.S. Patent No. 6,428,814 and Japanese Patent No. 4,598,399. Surface stabilizers may include tyroxapol (U.S. Patent No. 5,429,824), polyalkylene block copolymer (U.S. Patent No. 5,565,188), sulfate-modified nonionic block copolymer (U.S. Patent No. 5,569,448), high molecular weight linear poly(ethylene oxide) polymer (U.S. Patent No. 5,580,579), butylene oxide-ethylene oxide block copolymer (U.S. Patent No. 5,587,143), hydroxypropyl cellulose (U.S. Patent No. 5,591,456), and sugar-based surface stabilizers (U.S. Patent No. 5,622,938). Stabilizers may also include peptide stabilizers. See, for example, International Publication WO2006097748A2. Stabilizers may also include, for example, L-cysteine ​​hydrochloride, glycine hydrochloride, malic acid, sodium disulfite, citric acid, tartaric acid, and L-cystine dihydrochloride. See, for example, U.S. Patent No. 6,153,223. Stabilizers may include natural compounds. Stabilizers may include synthetic compounds. Stabilizers may include one or more of the aforementioned compounds or blends of the categories of compounds. Stabilizers may function to protect the metabolism of the prodrug until a desired time or until it reaches a specific target, tissue, or environment.

[0141] The additional components may be in the range of up to about 80% of the total weight of all composition components, preferably about 0.005% to 50%, and more preferably 1% to 20%, which includes over 1%, over 5%, over 10%, over 20%, over 30%, over 40%, over 50%, over 60%, over 70%, about 80%, over 80%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, about 3%, or less than 1%. Other additives may include anti-adhesion agents, fluidizing agents, and opacifying agents, such as magnesium, aluminum, silicon, and titanium oxides, preferably in concentrations of about 0.005% to about 5% and preferably about 0.02% to about 2% based on the weight of the total film components, which includes amounts greater than 0.02%, greater than 0.2%, greater than 0.5%, greater than 1%, greater than 1.5%, greater than 2%, greater than 4%, about 5%, greater than 5%, less than 4%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.02%.

[0142] In one embodiment, the composition may contain a plasticizer, which may be a polyalkylene oxide, such as polyethylene glycol, polypropylene glycol, polyethylene-propylene glycol, etc.; a low molecular weight organic plasticizer, such as glycerol, glycerol monoacetate, diacetate or triacetate, etc.; triacetin; polysorbate; cetyl alcohol; propylene glycol; sugar alcohol; sorbitol; sodium diethyl sulfosuccinate. The composition may contain triethyl citrate, tributyl citrate, plant extracts, fatty acid esters, fatty acids, oils, etc., and may be added at a concentration of about 0.1% to about 40% by weight of the composition, preferably in the range of about 0.5% to about 20%, including over 0.5%, over 1%, over 1.5%, over 2%, over 4%, over 5%, over 10%, over 15%, about 20%, over 20%, less than 20%, 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 the film material, such as animal or vegetable fats, preferably in their hydrogenated forms, may be added further. The composition may also contain compounds that improve the texture properties of the product. Other components may include binders that contribute to the ease of film formation and overall quality. Non-limiting examples of binders include starch, natural rubber, pregelatinized starch, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxazolidone, or polyvinyl alcohol.

[0143] Further potential additives include dissolution accelerators, such as substances that form encapsulation compounds with the active ingredient. Such agents would be useful in improving the properties of highly insoluble and / or highly unstable active substances. Generally, these substances are donut-shaped molecules with a hydrophobic internal cavity and a hydrophilic external cavity. The insoluble and / or unstable pharmaceutically active ingredient fits into the hydrophobic cavity, thereby creating a water-soluble encapsulation complex. Thus, the formation of the encapsulation complex enables the dissolution of highly insoluble and / or unstable pharmaceutically active ingredients in water. A particularly desirable example of such an agent is cyclodextrin, which is a cyclic carbohydrate derived from starch. However, other similar substances are also well within the scope of the present invention.

[0144] Suitable colorants include food, pharmaceutical and cosmetic (FD&C) colorants, pharmaceutical and cosmetic (D&C) colorants, or topical and cosmetic (Ext. D&C) colorants. These colorants are pigments, their corresponding lakes, and certain natural and naturally derived colorants. Lakes are pigments absorbed into aluminum hydroxide. Other examples of colorants include known azo dyes, organic or inorganic pigments, or naturally derived colorants. For example, oxides, or inorganic pigments such as iron or titanium are preferred, and these oxides are added at a concentration in the range of about 0.001 to about 10%, preferably about 0.5 to about 3%, based on the weight of the total components, which includes over 0.001%, over 0.01%, over 0.1%, over 0.5%, over 1%, over 2%, over 5%, about 10%, over 10%, less than 10%, 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%.

[0145] Flavors may be selected from liquids that emit natural and synthetic flavors. An exemplary list of such agents includes volatile oils, synthetic flavor oils, flavored aromatics, oils, liquids, oleopolymers, or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof. A non-limiting representative exemplary list includes mint oil, cocoa oil, and citrus oils such as lemon, orange, lime, and grapefruit, as well as fruit essences or other fruit flavors, including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, and apricot. Other usable flavorings include aldehydes and esters, such as benzaldehyde (cherry, almond), citral, i.e., α-citral (lemon, lime), neral, i.e., β-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruit), aldehyde C-9 (citrus fruit), aldehyde C-12 (citrus fruit), tollaldehyde (cherry, almond), 2,6-dimethyloctanol (green fruit), or 2-dodecenal (citrus fruits, mandarin), and combinations thereof.

[0146] Sweeteners can be selected from the following non-restrictive list: sugars, glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts, e.g., sodium salts; dipeptide-based sweeteners, e.g., aspartame, neotame, advantame; dihydrochalcone compounds, glycyrrhizin; stevia rebaudiana (stevioside); chlorine derivatives of sucrose, e.g., sucralose; sugar alcohols, e.g., sorbitol, mannitol, xylitol, etc. Also intended are hydrolyzed hydrogenated starch and synthetic sweeteners such as 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiadin-4-one-2,2-dioxide, especially potassium salts (acesulfame-K), and their sodium and calcium salts, as well as natural potent sweeteners, e.g., monk fruit (Luo Han Guo). Other sweeteners may also be used.

[0147] Defoaming and / or defoaming agents can also be used in films. These agents help remove air, such as trapped air, from the film-forming composition. Such trapped air can result in a non-uniform film. Simethicone is one particularly useful defoaming and / or defoaming agent. However, the present invention is not limited to this, and other suitable defoaming and / or defoaming agents can also be used. Simethicone and similar agents can also be used for densification purposes. More specifically, such agents can facilitate the removal of voids, air, moisture, and similar undesirable components, thereby providing a denser, and therefore more uniform, film. Agents or components that achieve such functions are referred to as densifying agents or density improvers. As mentioned above, trapped air or undesirable components can result in a non-uniform film.

[0148] Any other component described in U.S. Patents No. 7,425,292 and 8,765,167, as previously mentioned, may also be included in the films described herein.

[0149] The film composition may further preferably contain a buffer to control the pH of the film composition. Any desired level of buffer may be incorporated into the film composition to provide a desired pH level that the pharmaceutically active ingredient encounters when released from the composition. It is preferable that the buffer is provided in an amount sufficient to control the release of the pharmaceutically active ingredient from the film and / or its absorption into the body. In some embodiments, the buffer may include sodium citrate, citric acid, bicarbonate tartrate, and combinations thereof.

[0150] The pharmaceutical films described herein may be formed by any desired process. Preferred processes are described in U.S. Patents 8,652,378, 7,425,292 and 7,357,891, which are incorporated herein by reference. In one embodiment, a film dosage form composition is first formed by preparing a wet composition, which contains a polymer carrier matrix and a therapeutically effective amount of a pharmaceutically active ingredient. This wet composition is cast to form a film, which is then thoroughly dried to form a self-supporting film composition. This wet composition may be cast to form individual dosage forms, or it may be cast to form a sheet, which is then cut into individual dosage forms.

[0151] This pharmaceutical composition can adhere to mucosal surfaces. The present invention is particularly evident for use in the local treatment of body tissues, affected areas, or wounds that have moist surfaces and are susceptible to the effects of bodily fluids, such as the mouth, vagina, organs, or other types of mucosal surfaces. This composition delivers the pharmaceutical and provides a protective layer upon application and adhesion to mucosal surfaces, delivering the pharmaceutical to the treatment site, surrounding tissues, and other bodily fluids. Considering the control of film erosion in aqueous solutions or bodily fluids such as saliva, simultaneously with or after delivery, and the delay of natural film erosion, this composition provides a residence time suitable for effective drug delivery at the treatment site.

[0152] The residence time of this composition is determined by the decay rate of the water-disintegrable polymers used in the formulation and their respective concentrations. The decay rate can be adjusted, for example, by mixing components with different solubility properties or chemically different polymers, such as hydroxyethylcellulose and hydroxypropylcellulose; by using the same polymer in different molecular weight grades, such as mixing low and medium molecular weight hydroxyethylcellulose; by using excipients or plasticizers with various lipophilic values ​​or water solubility properties (including essentially insoluble components); by using water-soluble organic and inorganic salts; by using crosslinking agents such as glyoxal on polymers such as hydroxyethylcellulose for partial crosslinking; or by post-treatment irradiation or curing that can alter the physical state of the film, including the crystallinity or phase transition of the resulting film. These strategies can be used individually or in combination to modify the decay dynamics of the film. Upon application, the pharmaceutical composition film adheres to the mucosal surface and is retained in place. Water absorption softens the composition, thereby reducing the feeling of foreign body. Once the composition is placed on the mucosal surface, drug delivery occurs. The residence time can be adjusted over a wide range depending on the desired timing of drug delivery and the desired lifespan of the carrier. However, generally, the residence time is adjusted between about a few seconds and about a few days. Preferably, the residence time for most drugs is adjusted to about 5 seconds to about 24 hours. More preferably, the residence time is adjusted to about 5 seconds to about 30 minutes. In addition to providing drug delivery, once the composition adheres to the mucosal surface, it also provides protection of the treatment site and acts as a disintegrating bandage. Lipophilic drugs can be designed to delay disintegration in order to reduce disintegration and dissolution.

[0153] The disintegration dynamics of this composition can also be modified by adding highly water-soluble excipients that are sensitive to enzymes such as amylase, such as water-soluble organic and inorganic salts. Suitable excipients may include sodium and potassium hydrochlorides, carbonates, bicarbonates, citrates, trifluoroacetates, benzoates, phosphates, hydrofluorides, sulfates, or tartrates. The amount added may vary depending on the extent to which the disintegration dynamics are altered, as well as the amount and properties of other components in the composition.

[0154] The emulsifiers commonly used in the aforementioned water-based emulsions are preferably selected from linoleic acid, palmitic acid, myristoleic acid, lauric acid, stearic acid, cetoleic acid, or oleic acid and sodium hydroxide or potassium hydroxide when obtained in situ, or selected from sorbitol or polyoxyethylene derivatives including lauric acid esters, palmitic acid esters, stearic acid esters, or oleic acid esters of anhydrous sorbitol, monooleate, monostearate, monopalmitate, monolaurate, aliphatic alcohols, alkylphenols, allyl ethers, alkylaryl ethers, sorbitan monostearate, sorbitan monooleate and / or sorbitan monopalmitate.

[0155] The amount of pharmaceutically active ingredient used depends on the desired therapeutic strength and the composition of the layer, but preferably the pharmaceutically active ingredient constitutes about 0.001% to about 99%, more preferably about 0.003% to about 75%, and most preferably about 0.005% to about 50% of the composition weight, which includes amounts greater than 0.005%, greater than 0.05%, greater than 0.5%, greater than 1%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 30%, about 50%, greater than 50%, less than 50%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, less than 0.05%, or less than 0.005%. The amounts of other ingredients may vary depending on the drug or other ingredients, but typically these ingredients constitute not more than 50%, preferably not more than 30%, and most preferably not more than 15% of the total weight of the composition.

[0156] The thickness of the film may vary depending on the thickness of each layer and the number of layers. As mentioned above, both the thickness and number of layers can be adjusted to change the disintegration dynamics. Preferably, when the composition has only two layers, the thickness is in the range of 0.005 mm to 2 mm, preferably 0.01 to 1 mm, more preferably 0.1 to 0.5 mm, which includes greater than 0.1 mm, greater than 0.2 mm, about 0.5 mm, greater than 0.5 mm, less than 0.5 mm, less than 0.2 mm, or less than 0.1 mm. The thickness of each layer may vary from 10 to 90% of the total thickness of the layered composition, preferably from 30 to 60%, which includes greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 70%, greater than 90%, about 90%, less than 90%, less than 70%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%. Therefore, the preferred thickness of each layer can vary between 0.01 mm and 0.9 mm, or between 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 desired, the treatment site may include any area on which the film can deliver and / or maintain the desired level of pharmaceutical in the blood, lymph, or other bodily fluids. Typically, such treatment sites include the mucous membranes of the mouth, esophagus, ears, eyes, anus, nose, or vagina, as well as the skin. When the skin is used as the treatment site, a relatively large area of ​​skin, such as the upper arm or thigh, is usually preferred, as movement does not interfere with the film's adhesion.

[0158] This pharmaceutical composition can also be used as a wound dressing. By providing a physical, conformable, oxygen- and water-permeable, flexible barrier that can be washed away, the film can deliver the medicine not only to protect wounds but also to promote healing, sterilization, scarification, pain relief, or overall improvement of the affected person's symptoms. Some of the examples provided below are well suited for application to skin or wounds. As those skilled in the art will understand, the formulation may require the incorporation of special hydrophilic / hygroscopic excipients, which will help maintain good adhesion on dry skin over extended periods. Another advantage of the present invention when used in this form is that the use of dyes or colorants is unnecessary if the film is not to be conspicuous on the skin. On the other hand, if the film is to be conspicuous, dyes or colorants can be used.

[0159] This pharmaceutical composition can adhere to mucous membranes, which are naturally moist tissues, while also being usable on other surfaces such as skin or wounds. The pharmaceutical film can adhere to skin even when the skin is moistened with water-based fluids such as water, saliva, wound drainage, or sweat before application. The film can remain attached to the skin until it is eroded by contact with water, such as through rinsing, showering, bathing, or washing. The film can also be easily removed by peeling without causing significant tissue damage. [Examples]

[0160] (Examples) The proposed dosing regimen for diazepam buccal film (DBF) is designed to ensure that patients are exposed to diazepam at an level equivalent to that achieved when the reference agent, Diastat rectal gel (DRG), is administered according to the label of its approved product (Table 1 below). The Diastat label provides a weight-adjusted dosing regimen that first categorizes patients according to three age groups: 2–5 years, 6–11 years, and 12 years and older. The recommended doses in mg / kg are approximately 0.5 mg / kg, 0.3 mg / kg, and 0.2 mg / kg for each of the three age groups. Within each age group, the recommended dose for the individual patient is determined based on seven weight categories.

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

[0162] The invention of a suitable dosing regimen for DBF was equivalent to creating a mapping that could identify a suitable DBF dose (mg) for any patient based on the age group and weight category indicated on the label of Diastat. The suitable dose of DBF would be the dose that is expected to provide exposure to diazepam equivalent to the exposure provided by the labeled dose of Diastat. The first important point of this trial was to create this mapping for the adult age group (patients 12 years and older). This trial was complicated by two types of observations that distinguish DBF from DRG: (1) The pharmacokinetics of DBF were linear. In DBF, C max While both C and AUC were proportional to the dose, in DRG, max (2) DBF showed a food effect. C of DBF maxThe AUC 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, but the AUC was not affected. It was assumed that the DRG was not significantly affected by food because it is administered rectally. No food efficacy studies are reported on the approval label for DRG (Diastat Rectal Gel), and the Diastat label provides no information on food efficacy at all.

[0163] Example 1 - Two pilot study experiments in healthy volunteers As shown in Figure 1A, studies of two formulations were initially developed to cover the dose range shown in Table 1. For the low-dose formulation, size was used in a dose-proportional manner to create intensities of 5 mg, 7.5 mg, and 10 mg. Similarly, for the high-dose formulation, size was used in a dose-proportional manner to create intensities of 12.5 mg, 15 mg, 17.5 mg, and 20 mg. The high-dose and low-dose formulations were tested in two pilot clinical crossover studies against diastat rectal gel at doses of 5 mg and 20 mg.

[0164] The results showed that the PK parameter C was different between 5 mg of DBF and 5 mg of rectal gel. max The data showed excellent agreement regarding AUC. The data also supported dose proportionality in DRG over the 5–20 mg dose range, but suggested that DRG lacked dose proportionality. In DRG, the C between the 5 mg and 20 mg doses was observed. max The increase was lower than that proportional to the dose. The results of these pilot studies are summarized in Table 2.

[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 C after administration of 20 mg of DRG maxBased on this (which was approximately 58.7% higher), the formulation development plan was revised as shown in Table 3 below. From the data obtained, the DBF dose of approximately 12.5 mg was C from the 20 mg DRG dose (the highest dose). max It was suggested that this would be approximately equivalent to [the previous low-dose formulation]. Therefore, a high-dose formulation was not necessary. In this revised formulation development plan, all dosages will be derived from a single formulation (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 investigated in crossover trials with healthy volunteers at doses of 5 mg, 10 mg, and 15 mg. The 15 mg dose was included as the highest dose in the proportionality study experiment to establish linearity and provide flexibility in possible setting doses. This study experiment was conducted as shown in Figures 1A and 1B. max The dose-proportionality of both the saturation curve and AUC was demonstrated.

[0169] Based on these results, a crossover study was conducted to provide a direct comparison of the pharmacokinetics of DBF and DRG. In this four-treatment, four-period crossover study, one DBF dose (15 mg) was compared to three doses of rectal gel (5 mg, 12.5 mg, and 20 mg). Since DBF had been shown to be dose-proportional, one DBF dose level was sufficient. The purpose of this core comparative study was to compare DBF and DRG exposure (C) across the DRG dosing range (5–20 mg). max The objective was to investigate the relationship between both (and AUC). The design of the study experiment also allowed for a formal investigation of the dose-proportionality of DRG.

[0170] C max The results of this research experiment regarding this are shown in Figure 1C. The plasma concentration-time curves for all treatments for a typical target are shown in Figure 3. This research experiment was conducted on C after DRG administration. maxThis formally demonstrated that the AUC was lower than dose-proportional (Figure 4B), demonstrated that the AUC after DRG administration was approximately dose-proportional (Figure 4A), and demonstrated that the relative bioavailability of DBF was approximately 118% compared to DRG. This study also compared these parameters for the doses studied with DRG (5 mg, 12.5 mg, 20 mg) with any dose of DBF, showing the PK parameter C between these formulations. max This allowed for the estimation of the ratio of AUC. Since DBF was demonstrated to be proportional to the dose, these comparisons with the doses studied in DRG were immediately feasible. The comparison of all possible doses of DRG with all possible doses of DBF 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 studies using DBF, a two-group crossover study investigating the effects of a standard high-fat diet, and a four-group crossover study investigating the effects of body position (upright or reclined) in a fasting state, and the effects of a standard moderate-fat diet and a standard high-fat diet under reclined conditions. In the two food effect studies, consuming a high-fat diet within 30 minutes after administration resulted in C max It was shown that while C decreased by an average of approximately 45%, AUC was not affected. In the 4-group study, it was shown that body position (upright or reclined) did not affect diazepam PK. The effect of a high-fat diet (reclining position) in the 4-group study was almost consistent with the effect observed in the 2-group study. If a moderate-fat meal was consumed within 30 minutes of administration, C max While the average decreased by approximately 33%, AUC remained unaffected. Food also showed that T max It was associated with a delay during fasting. max The median was about 1 hour, but T under feeding conditions max The median was 2-3 hours. (For comparison, T after diastat administration as reported on the diastat label.) max (This is 1.5 hours.)

[0172] Figure 5 shows the mean plasma concentration-time curves in a two-group crossover study (N = 18). According to the label of barium, orally administered diazepam is decreased in exposure after a medium-fat meal. A 20% decrease in C max and a 27% decrease in AUC were reported, along with a maximum 2.5-hour shift in T max . Therefore, it was predicted that the ingested drug portion would be similarly affected by the food effect when conducting the food effect test of DBF. However, surprisingly, this research experiment showed that the unique properties of this formulation result in different food effects compared to orally administered barium. After administration of a high-fat meal, DBF showed a food effect where C max decreased by 47% but there was no decrease in AUC. This was clearly not expected and was a significantly greater effect than that reported in the literature for C max for orally administered barium, and was also different from that reported in the literature for the AUC of orally administered barium.

[0173] Figure 6 shows the mean plasma concentration-time curves in a four-group crossover (N = 24). This research experiment was conducted to determine the effect of a medium-fat meal on DBF absorption. Another objective of this research experiment was to determine whether the administration procedure could be changed to promote more transmucosal absorption. An increase in the initial part (transmucosal) of the profile might be sufficient to then decrease T max . To achieve this, a second fasting group was added.

[0174] In the above study experiment using DBF, DBF was administered by applying a film to the buccal mucosa of the oral cavity of subjects in an upright seated position for 5 minutes. At this time, the subjects swallowed all of the remaining medication. To further enhance absorption, DBF was administered with the subjects in a lateral reclining position, with the film positioned on the lower buccal mucosa of the oral cavity (so that all saliva would accumulate at the administration site). DBF was administered to subjects in this reclining position under conditions of fasting, moderate-fat diet, and high-fat diet in a cross-sectional manner. The time required for subjects to swallow was extended from 5 minutes to 15 minutes to prolong the residence time. (A fourth treatment—administration in an upright position under fasting conditions—was added as a control.) Residence time is routinely reported as one of the three main factors that promote transmucosal absorption (the other two being surface area and permeability kinetics). As shown in Figure 6, in the fasting state, posture (upright vs. reclining) did not have an effect. The effect of a high-fat diet in this study was almost the same as the effect of a high-fat diet observed in a two-group study in which DBF was administered to subjects in an upright position. Therefore, changing the administration method to increase residence time had no significant effect in either the fasted or fed state. A moderate-fat diet worked only to increase the height of the second portion of the bimodal profile compared to a high-fat diet. This was because the time separation between oral buccal absorption and transgastrointestinal absorption after feeding was slower than observed under feeding conditions. max Further evidence was provided that this explanation was given. After consuming a moderate-fat diet, C max It should be noted that the decrease was approximately 33%, which is significantly less than the approximately 45% decrease observed after consuming a high-fat diet.

[0175] (Population pharmacokinetic analysis modeling) Pharmacokinetic (PK) studies in healthy volunteers showed that DBF is not bioequivalent to DRG. DBF differed from DRG in the following ways: (1) DBF showed higher bioavailability than DRG. (2) The PK behavior of DBF was linear. Specifically, in the case of DBF, C max Both C and AUC increased proportionally with dose. In contrast, the PK behavior of DRG was not linear. Specifically, in the case of DRG, Cmax Although it was less than the dose ratio, it increased with the dose. On the other hand, the AUC increased proportionally to the dose. (3) DBF showed a food effect (after ingestion of a high-fat diet, the average of C 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 the AUC). In contrast, DRG is considered to be unaffected by food because it is administered via the rectal route.

[0176] Therefore, Aquestive selected a dosing regimen to correct the PK differences between DBF and DRG using population PK modeling (Table 4). Briefly, the recommended DBF doses corresponding to each adult weight class specified in the label of the Diastat Rectal Gel were adjusted to (1) provide a sufficiently high dose to ensure that the predicted median of diazepam C max after ingestion of a medium-fat diet is similar to the median of C max after administration of the dose described in the label of the Diastat Rectal Gel, and (2) provide a dose such that the predicted median of diazepam C max in the fasting state does not exceed the median of C max observed in the study of healthy volunteers in the first phase of DBF and proven to be safe. Simulations based on population PK modeling showed that, under medium-fat diet conditions, the proposed DBF dosing regimen resulted in C max similar to the predicted C max after administration of the dose described in the label of the Diastat Rectal Gel in each weight class.

[0177] (Table 4: DBF dosing algorithm)

Table 6

[0178] (Epilepsy Monitoring Unit (EMU) study experiment) A study was conducted on epilepsy patients to determine whether the pharmacokinetics of diazepam administered as DBF changed between patients in the interictal state (no seizures) and patients in the seizure / peri-seizure state (during a seizure or within 5 minutes after seizure discontinuation). This study was conducted with a predetermined dose of DBF (12.5 mg for all patients) regardless of body weight. The body weight-adjusted dose regimens shown in Table 5 were not used in this study.

[0179] The applicant measured pharmacokinetic parameters from a single-dose cross-matching study using plasma samples to determine diazepam concentration. See C below. max , AUC, and T max The values ​​were obtained after administering 12.5 mg of DBF to adults with epilepsy.

[0180] (Table 5) [Table 7]

[0181] As shown in the data above, pharmacokinetic parameters were derived from a single-dose crossover study in which 12.5 mg DBF was administered either when no seizure activity was observed in the preceding 3 hours (interictal period) or within 5 minutes of a seizure (peri-seizure period), and plasma samples were taken to determine diazepam concentrations at various time points up to 4 hours thereafter. The study included 35 adult men and women aged 17-65 years with uncontrolled tonic-clonic seizures or impaired-consciousness focused seizures. Both treatments were not completed (4 subjects), critical time points were missing (6 subjects), and pre-dose diazepam concentrations were lower than subsequent C max Patients exceeding 5% (2 subjects) or those for whom DBF was administered in a manner contrary to the instructions for use (5 subjects) were excluded from the analysis. max and AUC 0-4h The value is the geometric mean, T max The values ​​are medians. Geometric 90% confidence interval (CI) values ​​were determined using ln-transformed data. maxThe difference was not statistically significant, p = 0.5708 (Wilcoxon signed-rank test). The values ​​shown represent data from 18 evaluable subjects. AUC is the area under the plasma concentration-time curve 0–4 hours after drug administration. 0-4h , the maximum plasma drug concentration C max T is the time it takes to reach the maximum plasma concentration. max . From the literature of Rogawski et al. For example, see the entire paper by Rogawski MA, Gong H, Liow K, Aboumatar S, Klein P, Gelfand MA, Jung C, Wargacki S, Mehta R, and Heller AH, "Pharmacokinetics of diazepam buccal soluble film in adult patients with epilepsy: comparison of bioavailability with periictal and interictal administration," abstract 2.453, American Epilepsy Association Annual Meeting, www.aesnet.org, 2018, which is incorporated by citation.

[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-periseial crossover test are listed above. These values ​​represent the number obtained from 33 subjects. Percentages are shown in parentheses. From the literature by Jung et al. Jung C, Dubow J, Gong H, Liow K, Klein P, Gelfand MA, Wargacki S, Mehta R, Rogawski MA, Heller AH., "The usability of diazepam buccal soluble film as an oral treatment in adult patients with epilepsy," abstract 3.468, American Epilepsy Association Annual Meeting, www.aesnet.org, 2018.

[0184] This study demonstrated that diazepam exposure in patients after DBF administration was consistent regardless of whether the patient received the drug during a seizure. The subjects of this study (epilepsy patients) showed lower plasma concentrations than healthy volunteers after dose adjustments. Lower plasma concentrations in epilepsy patients associated with higher diazepam clearance are well-known from the literature, fully predictable, and attributable to the effect of hepatic enzyme induction from concomitant anticonvulsant medications taken by the patients (see Dhillon and Richens, 1981, which is incorporated in its entirety by citation). A subsequent study involving patients (described below) confirmed that the same magnitude and effect were observed in patients treated with DRG.

[0185] (Crossover trial of DBF with diastat (DRG) in epilepsy patients) The applicant tested the performance of the proposed DBF dosing regimen in patients in a one-to-one cross-comparison with diastat for two periods (Tables 7-8). The first objective was to compare the PK performance of DBF administered after a moderate-fat diet with that of diastat (DRG) administered after a moderate-fat diet. DBF was administered according to the proposed weight-adjusting dosing regimen described in Table 4, and diastat (DRG) was administered according to the FDA-approved dosing regimen for diastat. Furthermore, patients could register for an optional third period in which DBF was administered after a high-fat diet. The second objective of this study was to compare the PK performance of DBF administered after a high-fat diet with that of diastat (DRG) administered after a moderate-fat diet. The results of the first comparison are shown in Table 7 below.

[0186] C in this one-on-one research experiment max The ratio of the values ​​(geometric mean) [DBF / DRG] was 96.70%, and the 90% CI was 70.53–132.58% (Table 7 shows the results for diazepam C after consuming a moderate-fat diet). max C after administration of the labeled dose of DRG max We successfully demonstrated that it was similar to (results consistent with predictions from population PK modeling). This result is useful for validating the proposed DBF medication algorithm. Similarly, the AUC value (AUC (0-inf) It should also be noted that the geometric mean ratio [DBF / DRG] exceeded 100% despite equal or lower mg doses of DBF, which is consistent with population PK modeling results indicating that DBF has higher bioavailability than DRG.

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

[0188] The proposed DBF medication regimen also worked well within each weight category, and showed more consistent C across weight categories than after Diastat administration. 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 The ratio of the values ​​(geometric mean) [DBF (high-fat diet) / DRG] was 82.67%, and the 90% CI was 55.61–122.91%. This ratio (approximately 82.5%) is consistent with the predictions obtained from population PK modeling and is equally useful for validating the proposed DBF medication algorithm.

[0190] (Table 8: Pharmacokinetic parameters after administering DBF (diuretic fat) adjusted for weight after a high-fat diet, and DRG (diuretic gluten) adjusted for weight after a moderate-fat diet, to adults with epilepsy.) [Table 10]

[0191] The concentration profiles observed in DBF studies show that the onset of the absorption profile does not change significantly with food, 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, and T max Furthermore, the total dose is significantly shifted out compared to what would be predicted when higher concentrations are present and absorption is enhanced, given that the entire dose is administered orally. To test this hypothesis and to attempt to quantify the transmucosal delivery achieved during DBF administration, mathematical peak deconvolution was used to explain each mode of absorption in the observed profile. The profile can then be analyzed individually, and the contribution from each pathway can be estimated due to the high bioavailability resulting from both absorption pathways.

[0192] (Peak deconvolution) Several profiles were selected for peak deconvolution using the procedure described below. The resulting profiles were then analyzed for AUC 0-t using Prism software. Next, the percentage was assigned to the transdermal and oral absorption pathways using the ratio of AUC 0-t from each profile to the combined profile. The selected profiles were the mean profiles obtained from a four-group crossover study using the conditions of administering 15 mg of DBF upright in the fasting state, administering 15 mg of DBF after consuming a medium-fat meal, administering 15 mg of DBF after consuming a high-fat meal, and finally administering 5 mg of DBF from a dose-proportionality study. The plasma levels observed in the four mean profiles are shown in Table 9 below.

[0193] (Table 9: Diazepam plasma concentration after administration of DBF under various conditions)

Table 11

[0194] Summary of some of the experiments described in this specification: Rationale: Diazepam buccal film (DBF) is a novel dosage form of diazepam under development for the management of refractory epilepsy patients who require intermittent use of diazepam to control increasing seizure activity. The inventors evaluated the pharmacokinetic (PK) performance of DBF administered to epileptic adult patients according to a body weight-based regimen (dose range 12.5 - 17.5 mg) compared to diazepam rectal gel (DRG) administered according to the body weight-based regimen (dose range 12.5 - 20 mg) recommended in the FDA-approved label.

[0195] Methods: Adult men and women aged 18–65 years with epilepsy who had a stable regimen of one or more anticonvulsants (no change in the 30 days prior to administration of the investigational drug and no change expected throughout the study) were enrolled in a two-period crossover study (NCT03953820). They received a single dose of either DBF or DRG in a randomized order, with a 28-day rest period between each treatment period. The dose was administered within 30 minutes of consuming a standardized moderate-fat meal. Participants were kept in the clinic for 24 hours after administration. Diazepam plasma samples were taken before administration and at intervals of up to 10 days after administration to measure the maximum plasma concentration (C). max ), C max Time until (T max ), area under the curve (AUC) up to the last measurable concentration 0-T ), and the AUC(AUC) extrapolated to infinite time. 0-INF This enabled the analysis of adverse events (AEs) in the subjects through research experiments.

[0196] Results: Of the 31 enrolled subjects, PK profiles valid for both DBF and DRG analysis were available for 28 subjects (13 males, 15 females, mean [SD] body weight 84.6 ± 20.6 kg). Neither treatment was completed (n=2), or the pre-treatment diazepam concentration was C max Subjects exceeding 5% (n=1) were excluded from the analysis. The mean (SD) dose of diazepam was 15.4 ± 1.9 mg and 17.1 ± 3.0 mg for DBF and DRG, respectively. Table 7 shows the geometric mean and geometric mean ratio (DBF / DRG) of PK parameters for the entire study population (N=28), as well as C for each body weight category. max The geometric mean and corresponding proportions are shown. For the entire research experimental population, the geometric mean C of DBF and DRG is max The values ​​were 204.26 ng / mL (geometric SD [GSD] 136.12~306.49) and 211.22 ng / mL (GSD 87.71~508.63), respectively (see Figure 7), and C after DBF administration. max The values ​​were similar, but C after DRG administration maxThe variation was significantly less than the value (P<0.0001). The AUC value was higher for DBF than for DRG, and the T values ​​for DBF and DRG were different. max The median response times were 1.0 hour and 0.52 hours, respectively (P<0.05). Of the 28 subjects after DRG administration, 3 failed to achieve a plasma concentration of 70 ng / mL or higher. There were no serious adverse events (AEs) related to the investigational drug.

[0197] Conclusion: These results demonstrate that a single dose of DBF following a moderate-fat diet in adults with epilepsy, according to a weight-based regimen, provides diazepam exposure similar to that of recommended DRG doses, but with significantly less variability. max The geometric mean was consistently ≥ 150 ng / mL across all weight categories.

[0198] Another summary is as follows: (Introduction) Patients with refractory epilepsy may experience seizure exacerbations called "acute recurrent seizures" (ARS), which typically refer to a series of seizures that are grouped together and have short (or shorter than usual) inter-seizure intervals. -ARS is also commonly known as cluster seizures or consecutive seizures.

[0199] • ARS increases concerns about seizure-related risks, including post-seizure psychotic disorders, physical injury, frequent emergency room visits, hospitalization, or social and economic consequences due to missed school or work days, as well as concerns about status epilepticus, which can lead to persistent neurological damage or death (References 1-7). Despite these increased risks, many epileptic patients experiencing ARS do not have emergency medication prescriptions and / or seizure action plans in case of cluster seizures (References 1, 8-10).

[0200] • Diazepam buccal film (DBF) is a novel formulation of diazepam under development for the management of patients with refractory epilepsy who require intermittent use of diazepam to control increased seizure activity (References 11, 12). -DBF consists of a rectangular film smaller than the size of a postage stamp, which is applied to the oral buccal mucosa on the inside of the cheek. - Diazepam is transported within the soluble polymer matrix of the film, absorbed transmucosally, and then swallowed.

[0201] Currently, diazepam rectal gel (DRG; Diastat®, AcuDial® Rectal Gel, Valeant Pharmaceuticals, Bridgewater, NJ, USA) and midazolam nasal spray (Nidilam® Nasal Spray, UCB Biopharma, Smyrna, GA, USA) are the only treatments approved by the FDA for breakthrough or cluster attacks (References 2, 13-16). Current treatment with these medications has certain limitations. -Rectal administration can be difficult and time-consuming, and is also problematic for many patients and caregivers due to concerns about embarrassment and social acceptance (References 13, 17, 18). Intranasal administration is often unacceptable to patients and may negatively impact medication compliance.

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

[0203] (the purpose) This study was conducted to compare the pharmacokinetic (PK) performance of DBF in people with epilepsy with that of DRG, the only FDA-approved diazepam preparation currently used for the treatment of ARS.

[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 were randomized to receive a single dose of DBF and 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), and administer DBF, C max The drug was administered according to a body weight-based regimen (dose range 10-17.5 mg) that was predicted to be close to the PK performance of the DRG (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 (Reference 16).

[0206] For each administration of the investigational drug, patients were kept at the clinic from approximately 14 hours before administration until 24 hours after administration and after blood sampling. - Patients can either return to the clinical facility for a blood test 24 hours after medication administration, or have a home care nurse collect the sample. - While staying at the clinic, patients fasted overnight for at least 10 hours before being offered a standardized, moderate-fat diet.

[0207] (Evaluation of research experiments) • During each period, blood samples for PK analysis were collected before drug administration and at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 48, 72, 96, 120, 144, 192, and 240 hours after administration, enabling PK evaluation. - Blood samples taken within the first 8 hours after dosing were allowed a time window of ±1 minute, samples taken within 8 - 24 hours after dosing were allowed a time window of ±3 minutes, and all subsequent blood samples were allowed a time window of ±60 minutes. · The primary PK parameters of interest were C max , C max to the time (T max ), from time zero to the last non - zero concentration (AUC 0-t ), and the AUC extrapolated from time zero to infinite time (AUC 0-INF ). · Adverse events (AE) were monitored throughout the study.

[0208] (Data analysis) · The safety study population included all patients who received at least one dose of the investigational drug. This PK population included all patients who completed Period 1 and Period 2, had no major protocol violations, and whose PK profiles could be adequately characterized. · PK data were summarized using descriptive statistics for the entire study population and for each body weight category. · The ANOVA method was performed at α 0.05 on the log - transformed AUC 0-t , AUC 0-INF , and C max . The factors in the model were sequence, subject within sequence, period, and treatment. T max was analyzed using the non - parametric Wilcoxon signed - rank test. [[ID=​​​​​​​​​​​​​​Of the 31 registered patients, PK profiles valid for both DBF and DRG analysis were available for 28 subjects (13 males, 15 females, mean [SD] body 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.

[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 Table 11 shows the geometric mean and geometric mean ratio (DBF / DRG) of the PK parameters for N=27). -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 the estimated threshold plasma concentration of diazepam associated with seizure threshold elevation, as determined by pharmacodynamic PK studies in rats) (Reference 19).

[0211] (Table 11: Pharmacokinetic parameters after administration of DBF and DRG following a moderate-fat meal in the entire study population of adults with epilepsy (N=28)) [Table 13] a :expression e (difference) The calculation was performed using the least squares mean according to the multiplier of 100. b90% 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. -In the entire study population, the geometric mean C after DBF and DRG administration. max The values ​​were 204.26 ng / mL (Geometric SD [GSD]: 136.12-306.49) and 211.22 ng / mL (GSD 87.71-508.63), respectively, which represent the C levels after DBF administration. max The value is C after DRG. max The values ​​were similar, but significantly less varied (P<0.0001) (Table 11 and the inset in Figure 7). The graphed values ​​represent 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 Table 12 shows the geometric mean and the corresponding percentages within each weight category. -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. cThe maximum weight category includes four individuals weighing between 112 and 124.5 kg. CI, confidence interval; C max 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 demonstrate that, when administered to epileptic adults according to a weight-based regimen following a moderate-fat diet, a single dose of DBF provides similar exposure to diazepam as DRG, but with significantly less variability. • C after DBF administration max The geometric mean was consistently ≥ 150 ng / mL across all weight categories. These results support the further development of DBF as an easily administered alternative to DRG for epileptic patients who experience breakthrough or cluster seizures despite treatment with antiepileptic drugs.

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

[0216] Other embodiments are within the scope of the following claims. This application provides the invention in the following embodiments. (Aspect 1) A method for administering diazepam in a multimodal delivery profile, comprising delivering diazepam from a matrix and facilitating the permeation of at least some of the diazepam through mucosal tissue. (Aspect 2) The method according to embodiment 1, wherein the multimodal profile is a bimodal delivery profile. (Aspect 3) The method according to embodiment 1, further comprising delivering a permeable enhancer from the matrix. (Aspect 4) The method according to embodiment 1, wherein at least approximately 5-50% of diazepam is administered via the oral transmucosal route. (Aspect 5) The method according to embodiment 1, wherein at least about 5% of diazepam is administered via the gastrointestinal route. (Aspect 6) The method according to embodiment 1, wherein diazepam is administered as a prophylactic treatment. (Aspect 7) The method according to embodiment 1, wherein diazepam is administered as an emergency treatment drug. (Pattern 8) The method according to embodiment 1, wherein diazepam is administered to treat CNS disorders. (Aspect 9) The method according to embodiment 1, wherein diazepam is administered to treat seizures. (Aspect 10) The method according to embodiment 1, wherein diazepam is administered to treat generalized seizures. (Aspect 11) The method according to embodiment 1, wherein diazepam is administered to treat a focal seizure. (Aspect 12) The method according to embodiment 1, wherein diazepam is administered to treat a focal, pre-conscious seizure. (Aspect 13) The method according to embodiment 1, wherein diazepam is administered to treat a focal impairment of consciousness seizure. (Aspect 14) The method according to embodiment 1, wherein diazepam is administered to treat bilateral tonic seizures. (Aspect 15) The method according to embodiment 1, wherein diazepam is administered to treat absence seizures. (Aspect 16) The method according to embodiment 1, wherein diazepam is administered to treat atypical absence seizures. (Aspect 17) The method according to embodiment 1, wherein diazepam is administered to treat tonic-clonic seizures. (Aspect 18) The method according to embodiment 1, wherein diazepam is administered to treat cataplexy. (Aspect 19) The method according to embodiment 1, wherein diazepam is administered to treat clonic seizures. (Aspect 20) The method according to embodiment 1, wherein diazepam is administered to treat tonic seizures. (Aspect 21) The method according to embodiment 1, wherein diazepam is administered to treat myoclonic seizures. (Aspect 22) The method according to embodiment 1, wherein diazepam is administered to treat laughter and crying fits. (Aspect 23) The method according to embodiment 1, wherein diazepam is administered to treat febrile seizures. (Aspect 24) The method according to embodiment 1, wherein diazepam is administered to treat non-epileptic seizures. (Aspect 25) The method according to embodiment 1, wherein diazepam is administered to treat refractory seizures. (Aspect 26) The method according to embodiment 1, wherein diazepam is administered in a state of food ingestion. (Aspect 27) The method according to embodiment 1, further comprising adjusting the dose of diazepam to compensate for the food effect by increasing the dose to offset the food effect so that the subject achieves a safe and effective dose while ingesting food. (Aspect 28) The method according to embodiment 1, wherein diazepam is administered to a fasted state. (Aspect 29) The method according to embodiment 1, wherein approximately 2.5 to 30 mg of diazepam is delivered. (Aspect 30) The method according to embodiment 1, wherein approximately 2.5 mg of diazepam is delivered as a single dose. (Aspect 31) The method according to embodiment 1, wherein approximately 5 mg of diazepam is delivered as a single dose. (Aspect 32) The method according to embodiment 1, wherein approximately 7.5 mg of diazepam is delivered as a single dose. (Aspect 33) The method according to embodiment 1, wherein approximately 10 mg of diazepam is delivered as a single dose. (Aspect 34) The method according to embodiment 1, wherein approximately 12.5 mg of diazepam is delivered as a single dose. (Aspect 35) The method according to embodiment 1, wherein approximately 15 mg of diazepam is delivered as a single dose. (Aspect 36) The method according to embodiment 1, wherein approximately 17.5 mg of diazepam is delivered as a single dose. (Aspect 37) The method according to embodiment 1, wherein approximately 20 mg of diazepam is delivered as a single dose. (Aspect 38) The method according to embodiment 1, wherein approximately 25 mg of diazepam is delivered as a single dose. (Aspect 39) The method according to embodiment 1, wherein approximately 30 mg of diazepam is delivered as a single dose. (Pattern 40) The method according to embodiment 1, wherein the dose of diazepam is administered according to a regimen based on body weight. (Aspect 41) The method according to embodiment 1, wherein the matrix is ​​a mucosal adhesion matrix. (Aspect 42) The method according to embodiment 1, wherein diazepam is administered as a chewable tablet, gelatin, or lyophilized or inhalation-based dosage form, spray, gum, gel, cream, film, capsule, or tablet. (Aspect 43) The method according to embodiment 1, wherein the matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 30 minutes. (Aspect 44) The method according to embodiment 1, wherein the matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 15 minutes. (Aspect 45) The method according to embodiment 1, wherein the matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 10 minutes. (Aspect 46) The method according to embodiment 1, wherein the matrix is ​​a pharmaceutical film with an oral cavity retention time of less than 5 minutes. (Aspect 47) The method according to embodiment 1, wherein the permeation enhancer comprises a terpenoid. (Aspect 48) The method according to embodiment 1, wherein the permeation enhancer contains an aliphatic alcohol. (Aspect 49) The method according to embodiment 1, wherein the permeation enhancer contains an aromatic alcohol. (Appearance 50) The method according to embodiment 1, wherein the permeation enhancer contains benzyl alcohol. (Aspect 51) The method according to embodiment 1, wherein the permeation enhancer comprises a phenylpropanoid. (Appearance 52) The method according to embodiment 1, wherein the mucosal adhesion matrix comprises a water-soluble polymer. (Aspect 53) The method according to embodiment 1, wherein the permeation enhancer contains linoleic acid. (Aspect 54) A method for treating a medical condition, comprising administering diazepam in a multimodal profile, including delivering 2.5 to 30 mg of diazepam from an oral matrix within less than one hour. (Aspect 55) The method according to embodiment 54, wherein the multimodal profile is a bimodal profile. (Aspect 56) The method according to embodiment 54, wherein diazepam is delivered via at least a transmucosal route and a gastrointestinal route. (Aspect 57) The process involves delivering diazepam and a permeation enhancer from the matrix, with the diazepam delivered to achieve an effective linear AUC and a maximum of approximately 10 ml of C. max A method of treating the condition, including administering diazepam in a multimodal profile, to achieve the desired outcome. (Pattern 58) The method according to embodiment 57, wherein the multimodal profile is a bimodal profile. (Aspect 59) The method according to embodiment 57, wherein diazepam is delivered via at least a transmucosal route and a gastrointestinal route.

Claims

1. A pharmaceutical composition for orally administering diazepam with a multimodal delivery profile, wherein administration is performed To deliver a permeable enhancer containing diazepam and terpenoids to a mucosal adhesion matrix, and A pharmaceutical composition that provides a bimodal delivery profile to a subject by promoting the permeation of at least a portion of diazepam through mucosal tissue, wherein the diazepam is delivered via an oral transmucosal route and a gastrointestinal route, and the dose of diazepam is adjusted to compensate for the food effect by increasing the dose to offset the food effect so that the subject achieves a safe and effective dose in a food-ingested state, wherein at least about 5-50% of the diazepam is administered via the oral transmucosal route, or at least about 5% of the diazepam is administered via the gastrointestinal route.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to administer at least about 5-50% diazepam via an oral transmucosal route.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to administer at least about 5% diazepam via the gastrointestinal route.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to administer diazepam as a prophylactic treatment.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to administer diazepam as an emergency treatment drug.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to administer diazepam for the treatment of CNS disorders.

7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to administer diazepam for the treatment of acute seizures.

8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to administer diazepam to treat generalized seizures, focal seizures, focal seizures with impaired consciousness, focal seizures with impaired consciousness, bilateral tonic seizures, absence seizures, atypical absence seizures, tonic-clonic seizures, atonic seizures, clonic seizures, tonic seizures, myoclonic seizures, laughing seizures and crying seizures, febrile convulsions, non-epileptic seizures, or refractory seizures.

9. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to administer diazepam in a food-like manner.

10. The pharmaceutical composition according to claim 1, further comprising adjusting the dose of diazepam to compensate for the food effect by increasing the dose to offset the food effect, so that the subject achieves a safe and effective dose while in a food-ingested state.

11. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to administer diazepam in a fasted state.

12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to deliver about 2.5 to 30 mg of diazepam.

13. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to deliver approximately 2.5 mg of diazepam in a single dose, approximately 5 mg of diazepam in a single dose, approximately 7.5 mg of diazepam in a single dose, approximately 10 mg of diazepam in a single dose, approximately 12.5 mg of diazepam in a single dose, approximately 15 mg of diazepam in a single dose, approximately 17.5 mg of diazepam in a single dose, approximately 20 mg of diazepam in a single dose, approximately 25 mg of diazepam in a single dose, or approximately 30 mg of diazepam in a single dose.

14. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to administer a dose of diazepam according to a body weight-based regimen.

15. The pharmaceutical composition according to claim 1, wherein the matrix is ​​a mucosal adhesion matrix.

16. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to administer diazepam as a chewable, gelatin, lyophilized, or inhalation-based dosage form, spray, gum, gel, cream, film, capsule, or tablet.

17. The pharmaceutical composition according to claim 1, wherein the matrix is ​​a pharmaceutical film with an oral cavity residence time of less than 30 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes.

18. The pharmaceutical composition according to claim 15, wherein the mucosal adhesion matrix comprises a water-soluble polymer.

19. The pharmaceutical composition according to claim 1, wherein the permeation enhancer contains linoleic acid.

20. A pharmaceutical composition according to claim 1 for treating a medical condition, wherein the treatment comprises administering diazepam in a multimodal profile, and the administration comprises delivering 2.5 to 30 mg of diazepam from an oral matrix within 1 hour.

21. The pharmaceutical composition according to claim 20, wherein the multimodal profile is a bimodal profile.

22. The pharmaceutical composition according to claim 20, wherein the pharmaceutical composition is used to deliver diazepam via at least a transmucosal route and a gastrointestinal route.

23. A pharmaceutical composition according to claim 1 for treating a medical condition, comprising administering diazepam in a multimodal profile, wherein the administration is such that diazepam is delivered to an effective linear AUC and a maximum of approximately 10 ml of C max The pharmaceutical composition comprising delivering diazepam and a permeation enhancer from a matrix to achieve the above.

24. The pharmaceutical composition according to claim 23, wherein the multimodal profile is a bimodal profile.

25. The pharmaceutical composition according to claim 23, wherein the pharmaceutical composition is used to deliver diazepam via at least a transmucosal route and a gastrointestinal route.

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