Method of formulating injectable drug into film or sheet and system therefor

Abstract

The present disclosure relates to a method of formulating an injectable drug into a film or sheet. A method of formulating a drug into a film or sheet comprises: dissolving the drug in a premix and optionally in an aqueous medium to form a solution; and casting the solution into a mold in order to form the film or sheet. The medicament is formulated in its dosage form and is characterized by at least one of: a unit dose of less than about 200 mg; a volume of less than about 2 mL; chemical and / or physical stability at less than about 60 DEG C; and a solubility in a solvent medium of more than about 10 mg / mL.

Description

Technical Field

[0001] The present invention generally relates to a method for formulating an injectable drug into a film or sheet. The present invention also relates to a system for formulating an injectable drug into a film or sheet. Background Art

[0002] The parenteral route is the fastest and second most common way to administer a drug. In this method of administration, the drug enters the body via a route other than the gastrointestinal tract, typically using a needle and syringe to inject the drug in solution or suspension form into different parts and different depths in the body. Parenteral administration of a drug can be performed by injection (small volumes), infusion (large volumes) or implantation, and although its typical goal is to achieve a rapid systemic effect, it can also be applied locally to a specific area, tissue or organ by injecting the drug substance directly into the site of action, so as to achieve high drug concentrations and / or minimize systemic adverse effects at the site of action. Examples of parenteral administration are intravenous, intramuscular and subcutaneous routes.

[0003] Patients with clinical dysphagia or difficulty swallowing medications in solid dosage forms (such as tablets and capsules), gastrointestinal obstruction or resection, chronic neurological, psychiatric and other conditions, injection phobia and / or lack of intravenous access or requiring emergency or rescue medication may not be able to obtain optimal and convenient medication therapy via parenteral routes of administration. Other patients who are not suitable for parenteral routes include pediatric patients and neonates, overweight and obese patients, elderly and chronically ill patients, and emergency and acute care patients with, for example, skin burns, hematomas or dehydration.

[0004] Furthermore, patients with difficult intravenous access (DIVA) often present challenges for healthcare providers. Difficult peripheral intravenous (PIVC) access is generally understood to occur when two or more attempts to insert a puncture are unsuccessful, when a puncture support method is required, or when peripheral access is unavailable and a central venous catheter (CVC) must be inserted. It is estimated that more than 30% of adults and up to 50% of children requiring PIVC have challenging venous access.

[0005] Currently, to treat patients with difficult intravenous access, longer peripheral intravenous catheters and ultrasound-assisted catheterization are recommended. However, this remains painful and burdensome for patients, as they must be careful about the intravenous cannula site.

[0006] Other disadvantages of administering drugs by parenteral routes (including intravenous, subcutaneous, intramuscular, implants, and others) include the following:

[0007] It is irreversible and carries more risks than oral, buccal, and other routes;

[0008] It is invasive and can cause fear, pain, infection, and / or tissue damage such as phlebitis (inflammation of the veins, seen in 31% of patients), venous collapse, air embolism, or blood clots;

[0009] ● The preparation to be injected must be sterile and free of particles. The manufacturing and quality system of parenteral dosage forms requires strict environmental and microbiological monitoring, installation of pharmaceutical water systems, and particulate matter inspection;

[0010] ● Assistance from health personnel or other personnel trained in aseptic technique for preparing and administering injections is usually required;

[0011] Health care workers who use or may be exposed to needles are at increased risk for needlestick injuries. Needlestick injuries can lead to serious or fatal infection with blood-borne pathogens such as hepatitis B virus, hepatitis C virus, or HIV. More than 2 million people are injured each year from occupational needlestick injuries (NSIs);

[0012] It typically requires single-use (aka single-use) disposable injection supplies and devices, ranging from basic (such as sterile wipes, syringes, needles, cannulas, IV bags / bottles, tubing, etc.) to advanced devices, i.e., autoinjectors, patch injectors, continuous pumps, cartridges. These generate large amounts of biohazardous waste, some of which is sharp, requiring cumbersome safe handling and expensive disposal procedures.

[0013] • It may pose risks or hazards to patients who may resist injections or oral administration and / or patients who are not physically fit to receive injections, such as patients who are experiencing epileptic seizures or episodes of agitation.

[0014] It would be desirable to overcome or ameliorate at least one of the above problems. SUMMARY OF THE INVENTION

[0016] The present invention is based on the understanding that injectables and drugs that can be administered orally and / or parenterally can be replaced by other non-sterile oral dosage forms containing the same drug.

[0017] The present invention provides a method for preparing a drug into a film or sheet, the method comprising:

[0018] a) dissolving the drug in the premix and optionally in an aqueous medium to form a solution; and

[0019] b) casting the solution into a mold to form the film or sheet;

[0020] wherein said drug is formulated in its dosage form;

[0021] The drug is characterized by at least one of the following:

[0022] i) a unit dose of less than about 200 mg;

[0023] ii) a volume of less than about 2 mL;

[0024] iii) chemical and / or physical stability at less than about 60°C; and

[0025] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0026] In certain embodiments, the drug is selected from Biopharmaceutical Classification System (BCS) classes I, II, and III.

[0027] In certain embodiments, the medicament is characterized by at least two of the above criteria.

[0028] In certain embodiments, the drug is further characterized by a molecular weight of less than about 6000 Da.

[0029] In certain embodiments, the dosage form of the drug is selected from an injection solution, powder, tablet, capsule, swallowable liquid, inhalation liquid, nasal liquid, eye drops or ear drops.

[0030] In certain embodiments, the drug is selected from midazolam, ondansetron, dimenhydrinate, haloperidol, lidocaine, albuterol, levalbuterol, dexamethasone, prednisolone, prednisone, methylprednisolone, diazepam, lorazepam, clonazepam, diclofenac, ketoprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs), epinephrine, diphenhydramine, dopamine, adenosine, caffeine, naloxone, flumazenil, codeine, fentanyl, ketamine, others or combinations thereof.

[0031] In certain embodiments, the medicament is provided as a single unit dose.

[0032] In certain embodiments, the drug in the solution is from about 1 mg / mL to about 200 mg / mL.

[0033] In certain embodiments, the premix comprises an excipient selected from the group consisting of a film-forming polymer, a binder, a bioadhesive material, a coating agent, a controlled release agent, a dispersant, a solubility enhancer, an emulsifier, an emulsion stabilizer, a humectant, a modified release agent, a film former, a mucoadhesive agent, a plasticizer, a solubilizer, a stabilizer, a suspending agent, a thickener, a taste masking agent, a colorant, or a combination thereof.

[0034] In certain embodiments, the premix comprises a film-forming polymer selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl-cellulose, polyvinyl pyrrolidone, gelatin, pectin, xanthan gum, polyvinyl alcohol, trehalose, hydroxypropyl pea starch (Lycoat RS720), chitosan, pullulan, or a combination thereof.

[0035] In certain embodiments, the premix comprises at least two film-forming polymers.

[0036] In certain embodiments, the premix comprises one of the following:

[0037] a) xanthan gum and polyvinyl alcohol;

[0038] b) xanthan gum and pullulan;

[0039] c) xanthan gum and polyvinyl pyrrolidone;

[0040] d) xanthan gum and trehalose;

[0041] e) xanthan gum and Lycoat RS720;

[0042] f) xanthan gum and methylcellulose;

[0043] g) polyvinyl alcohol and hydroxypropyl methylcellulose;

[0044] h) hydroxypropyl methylcellulose and pullulan;

[0045] i) hydroxypropyl methylcellulose and polyvinylpyrrolidone;

[0046] j) hydroxypropyl methylcellulose and chitosan;

[0047] k) Hydroxypropyl methylcellulose and methylcellulose;

[0048] 1) pullulan and polyvinylpyrrolidone;

[0049] m) pullulan and trehalose;

[0050] n) pullulan and Lycoat RS720;

[0051] o) pullulan and methylcellulose;

[0052] p) polyvinylpyrrolidone and chitosan;

[0053] q) polyvinylpyrrolidone and methylcellulose;

[0054] r) trehalose and methylcellulose; and

[0055] s) Chitosan and methylcellulose.

[0056] In certain embodiments, the premix comprises at least three film-forming polymers.

[0057] In certain embodiments, the film-forming polymer is from about 0.1% w / v to about 20% w / v relative to the solution.

[0058] In certain embodiments, the premix comprises a binder. The binder may be polyvinyl pyrrolidone.

[0059] In certain embodiments, the binder is from about 0.1% w / v to about 20% w / v of the solution.

[0060] In certain embodiments, the premix comprises a humectant. The humectant may be glycerin or propylene glycol.

[0061] In certain embodiments, the humectant is from about 0.1% w / v to about 20% w / v of the solution.

[0062] In certain embodiments, the premix comprises a solubilizing agent. The solubilizing agent can be a co-solvent (such as propylene glycol), a complexing agent, or a surfactant.

[0063] In certain embodiments, the premix comprises a taste masking agent. The taste masking agent can be maltitol, sorbitol, xylitol, citric acid or sodium chloride.

[0064] In certain embodiments, the premix further comprises a pH adjuster.

[0065] In certain embodiments, the pH adjuster is about 0.1% w / v to about 20% w / v relative to the solution.

[0066] In certain embodiments, the premix further comprises a dental adhesive.

[0067] In certain embodiments, the dental adhesive powder or gel is about 0.1% w / v to about 10% w / v relative to the solution.

[0068] In certain embodiments, the step of casting the solution further comprises drying the solution.

[0069] In certain embodiments, the method further comprises the step of ultraviolet sterilizing the film or sheet.

[0070] In certain embodiments, the method further comprises the step of further dehydrating the film or sheet.

[0071] In certain embodiments, the film or sheet is characterized by a thickness of about 0.05 mm to about 1.0 mm.

[0072] In certain embodiments, the film or sheet is characterized by a disintegration time of about 10 s to about 60 min.

[0073] In certain embodiments, the film or sheet is characterized by a pH of about 2 to about 8.

[0074] In certain embodiments, the film or sheet is characterized by a folding endurance of greater than about 100 times.

[0075] In certain embodiments, the film or sheet is characterized by a flow rate of at least 50 N / cm 2 Young's modulus.

[0076] In certain embodiments, the film or wafer is for sublingual, buccal, and / or sublabial administration.

[0077] In certain embodiments, the drug is an injectable drug.

[0078] The present invention also provides a film or sheet for oral administration of a drug, comprising:

[0079] a) from about 1 mg / mL to about 200 mg / mL of the drug, relative to the film and / or sheet;

[0080] b) from about 0.1% w / v to about 20% w / v of a film-forming polymer, relative to the film and / or sheet;

[0081] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0082] The drug is characterized by at least one of the following:

[0083] i) a unit dose of less than about 200 mg;

[0084] ii) a volume of less than about 2 mL;

[0085] iii) chemical and / or physical stability at less than about 60°C; and

[0086] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0087] The present invention also provides a premix for forming a film or sheet for oral administration of a drug, the premix comprising:

[0088] a) from about 0.1% w / v to about 20% w / v of a film-forming polymer, relative to the premix; and

[0089] b) from about 0.1% w / v to about 20% w / v of a humectant, relative to the premix.

[0090] In certain embodiments, the premix comprises at least three film-forming polymers, each of the three film-forming polymers independently being present at about 0.1% w / v to about 20% w / v relative to the premix.

[0091] The present invention also provides a method of treating a disease or disorder treatable by a drug, the method comprising formulating the drug as a film or wafer as disclosed herein, and administering a therapeutically effective amount of the film and / or wafer to a subject in need thereof via sublingual, buccal and / or sublabial administration.

[0092] The present invention also provides a film or wafer for treating a disease or disorder treatable by a drug, wherein the film and / or wafer comprises the drug and is administrable sublingually, buccally and / or sublabially.

[0093] The present invention also provides the use of a film or wafer in the preparation of a medicament for treating a drug-treatable disease or disorder, wherein the film and / or wafer comprises the drug and is administrable sublingually, buccally and / or sublabially.

[0094] The present invention also provides a system for formulating a drug into a film or sheet, the system comprising:

[0095] a) a medicine receiving module for receiving medicine;

[0096] b) a premix module for containing a premix and introducing the premix into a medicine;

[0097] c) a mixing module for mixing the drug with the premix to form a solution;

[0098] d) a metering and dispensing module for dispensing the solution;

[0099] e) a mold for containing the dispensed solution; and

[0100] f) a curing module for curing the solution in the mold into a film or sheet. BRIEF DESCRIPTION OF THE DRAWINGS

[0102] Embodiments of the invention will now be described by way of non-limiting examples with reference to the accompanying drawings, in which:

[0103] Figure 1The apparatus used to study the initial disintegration time of thin films is shown. Each film is placed between two hollow columns. Afterwards, 1 ml of phosphate-buffered saline (pH 7.2) is gently added to the top column. The time required for the phosphate-buffered saline to permeate the film and collect in a petri dish is recorded as the initial disintegration time.

[0104] Detailed description

[0105] Often, when a drug is formulated, it may not have the same assurances of safety, quality, and efficacy as its corresponding marketed product.

[0106] Without wishing to be bound by theory, the inventors believe that injectable drug solutions, drug powders, tablets, capsules, swallowable / drinkable liquids, inhaled liquids, nasal liquids, eye drops, and / or ear drops can be selected and reused by extemporaneously formulating them into films and / or sheets. The films and / or sheets can deliver high-quality, safe, and effective doses of the drug via oral, sublingual, and / or buccal routes. The films and / or sheets can further be reconstituted by dissolving the film in a liquid medium (e.g., water, enteral nutrition solution) for nasogastric tube feeding while maintaining acceptable pharmacokinetic properties of the drug.

[0107] Drug compounding is the process of combining, mixing, or modifying ingredients to create a medication tailored to the needs of an individual patient. Specifically, formulating existing oral and parenteral drugs and other dosage forms into films and / or sheets can meet the pharmaceutical needs of patients with clinical dysphagia or difficulty swallowing medications for solid dosage forms (such as tablets and capsules), gastrointestinal obstruction or resection, chronic neurological, psychiatric, and other conditions, injection phobia, and / or lack of intravenous access. The films and / or sheets are classified as "US FDA 505(b)(2)" drug products, which means that the same drug ingredients are used in the product to create different physical forms of the drug.

[0108] The present invention allows medications to be prepared in medical institutions, nursing homes, and at home. This replaces the cumbersome practice of converting solid dosage forms (such as tablets and capsules) into powders, then adding the powder to syrups, beverages, or soft foods, and then measuring the required dosage volume for administration. In this regard, it provides greater convenience for medical staff and patients.

[0109] The drug can also be prepared at a dispensing pharmacy, clinic, or outsourcing agency. Films / sheets can be produced with low water activity and can reduce the possibility of microbial contamination, resulting in a longer shelf life compared to liquid instant formulations, which typically have a shelf life of 2 weeks, and a few can be as long as 6 weeks. This means that there is no need to frequently replenish the prepared liquid drug, thereby improving drug compliance and convenience, while reducing transportation / delivery costs.

[0110] The drug can also be formulated for clinical trials and drug research. This provides an alternative dosage form to tablets, capsules, injections, syrups, etc., as the manufacturing process allows for efficient production of small batches of different doses of active substances and placebos.

[0111] The medicaments can also be formulated for travel, military, and logistical purposes. Compared to tablets, capsules, and liquids, films / sheets are lighter and more compact, thus reducing baggage / luggage load. This also circumvents restrictions on liquids (although pharmaceuticals are excluded) in carry-on luggage on aircraft, airlines, or space vehicles. In addition, films / sheets can be self-administered, whereas injections are typically administered by trained personnel and require a syringe, needle, and / or intravenous infusion equipment.

[0112] Therefore, the present invention provides a method for formulating a drug into a film or sheet, the method comprising:

[0113] a) dissolving the drug in a premix and optionally using an aqueous medium to form a solution; and

[0114] b) casting the solution into a mold to form the film or sheet;

[0115] wherein said drug is formulated in its dosage form;

[0116] The drug is characterized by at least one of the following:

[0117] i) a unit dose of less than about 200 mg;

[0118] ii) a volume of less than about 2 mL;

[0119] iii) chemical and / or physical stability at less than about 60°C; and

[0120] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0121] Advantageously, the pharmaceutical composition (API and excipients in the parenteral solution) or other dosage forms can be formulated directly; that is, without first removing any components. Using commercial drug products that have been approved by regulatory agencies and meet manufacturing quality inspections to formulate into films / sheets can speed up manufacturing and patient access. It also ensures the sterility and accurate content of the API in the parenteral product. It also eliminates the need to purchase, stockpile, test, and store large quantities of pure API.

[0122] The film and / or sheet can be prepared using a unit dose method. In this way, accurate dosage administration is ensured. For example, the film and / or sheet can be cut into appropriate sizes to contain the desired dosage for administration.

[0123] As used herein, "drug" refers to a pharmaceutical product comprising an active ingredient and other excipients. The drug may be a commercially available drug product. In this regard, the drug product may be in its final dosage form, which is available for consumption by a patient. The drug product may be administered via any route, such as intravenous, intramuscular, subcutaneous, rectal, vaginal, inhalation, oral, or buccal administration. In this sense, the drug product may be in the form of, for example, a liquid formulation, a gel, a paste, a tablet, a capsule, or an insert.

[0124] As used herein, "compounding" means preparing a customized pharmaceutical formulation to meet a patient's unique needs that cannot be met with commercially available products. This can be for medical reasons, such as administering the drug in a different form (e.g., from a tablet to a liquid) to avoid inactive ingredients to which the patient is allergic, or to provide a precise dose that is not commercially available. It can also be for medically optional reasons, such as a preference for taste or texture, or dietary restrictions.

[0125] As used herein, "injectable medication" refers to a medication that is introduced into a subject's bloodstream via a hollow hypodermic needle or cannula. The needle / cannula is passed through the skin and into the body (usually intravenously, but also in an intramuscular or subcutaneous location). Thus, intravenous, intramuscular, and subcutaneous administration of medication are all included within the scope of injectable medication.

[0126] As used herein, a "dosage form" is the marketed form of a pharmaceutical drug product that contains a specific mixture of active ingredients and inactive components (excipients), has a specific configuration (such as a capsule shell), and is dispensed into a specific dose. For example, two products may both be loperamide 2 mg, but one is a capsule and the other is a tablet. This represents two dosage forms. There are several types of dosage forms based on the method / route of administration. These include many types of liquid, solid, and semisolid dosage forms. Common dosage forms include tablets or capsules, suspensions or syrups, etc. Parenteral dosage forms can include emulsions, liposomes, lipid complexes, powders, solutions, and suspensions.

[0127] In certain embodiments, the method is a method of formulating a pharmaceutical drug product into a film or sheet, the method comprising:

[0128] a) dissolving the pharmaceutical drug product in a premix and optionally using an aqueous medium to form a solution; and

[0129] b) casting the solution into a mold to form the film or sheet;

[0130] wherein the pharmaceutical drug product is characterized by at least one of the following:

[0131] i) a unit dose of the drug of less than about 200 mg;

[0132] ii) a volume of less than about 2 mL;

[0133] iii) chemical and / or physical stability at less than about 60°C; and

[0134] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0135] Oral administration of a drug is a route of administration in which the substance is taken in through the mouth. Oral administration also includes sublingual, buccal, and sublabial administration. Sublingual administration occurs when the drug is placed under the tongue, where it dissolves and is absorbed into the bloodstream through the tissues. Buccal administration involves placing the drug between the gums and cheek. As with sublingual administration, the drug dissolves and is absorbed into the bloodstream through the tissues. Sublabial administration involves placing the drug under the lips. Such modes of administration minimize the amount of active pharmaceutical ingredient lost due to digestion. Unlike injectables, they also do not require the product to be sterile.

[0136] In certain embodiments, the film and / or sheet is for oral administration. In certain embodiments, the film and / or sheet is for sublingual, buccal and / or sublabial administration. In certain embodiments, the film and / or sheet is for buccal administration.

[0137] As used herein, "film" refers to a thin, continuous sheet of material. The film may be air-dried or oven-dried. The film may comprise a polymer such as a water-soluble polymer. Examples of water-soluble polymers include, but are not limited to, polyethylene oxide, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl-cellulose, polyvinyl pyrrolidone, gelatin, pectin, and pullulan.

[0138] As used herein, "wafer" refers to a thin film made by a rapid drying method such as freeze drying. It is a low-temperature dehydration process that involves freezing the product, reducing the pressure, and then removing the ice by sublimation. This is in contrast to most conventional dehydration methods that use heat to evaporate water. Since low temperatures are used during processing, the original shape of the product is maintained. If the product to be dried is a liquid, the properties of the final product can be optimized by combining excipients (i.e., inactive ingredients). As the aqueous or solvent medium is quickly withdrawn from the solution, a porous internal structure may be created, which can regulate the disintegration rate of the wafer and thus lead to faster absorption.

[0139] In certain embodiments, the drug is selected from Biopharmaceutical Classification System (BCS) Class I, II, and III. BCS is a system that distinguishes drugs based on their solubility and permeability. The system uses parameters constraining predictions for drug solubility and intestinal permeability. Solubility classification is based on the United States Pharmacopoeia (USP) aperture. Intestinal permeability classification is based on comparison with intravenous injection. All of these factors are very important because 85% of the best-selling drugs in the United States and Europe are administered orally.

[0140] Solubility is the ability of a substance (the solute) to form a solution with another substance (the solvent). Solubility rating limits are based on the highest dose strength of an immediate-release product. A drug is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous medium with a pH range of 1 to 9.5. The volume estimate of 250 ml is derived from a typical bioequivalence study protocol, which specifies administering the drug product to fasting human volunteers with a glass of water.

[0141] Permeability ratings are based indirectly on the extent of absorption of a drug substance in humans and directly on measurements of the rate of mass transfer across the human intestinal membrane. Alternatively, non-human systems that are predictive of human drug absorption (such as in vitro culture methods) can be used. A drug substance is considered highly permeable if the extent of human absorption is determined to be 90% or more of the administered dose, either as determined by mass balance assays or compared to intravenous administration.

[0142] For dissolution grade limits, an immediate-release product is considered rapidly dissolving when not less than 85% of the labeled amount of drug substance dissolves within 15 minutes using USP Dissolution Apparatus 1 at 100 RPM or Apparatus 2 at 50 RPM in a volume of 900 ml or less in the following media: 0.1 M HCl or simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or simulated intestinal fluid.

[0143] According to the BCS, drug substances are divided into four categories based on their solubility and permeability:

[0144] Category I - High Permeability, High Solubility

[0145] These compounds (such as metoprolol, acetaminophen, ondansetron, diazepam, midazolam, albuterol) are well absorbed, and their rate of absorption is generally higher than their rate of excretion.

[0146] Class II - High permeability, low solubility

[0147] The bioavailability of these products (such as glyburide, ezetimibe, carbamazepine, cisapride) is limited by their solvation rate. A correlation between in vivo bioavailability and in vitro solvation can be found.

[0148] Class III - Low permeability, high solubility

[0149] Absorption of drugs such as atenolol, famotidine, enalapril is permeation rate limited, but the drug solvates very rapidly. If the formulation does not alter permeability or GI duration, then Class I criteria can be applied.

[0150] Category IV - Low permeability, low solubility

[0151] These compounds (such as chlorothiazide, furosemide) have poor bioavailability. They are generally not well absorbed by the intestinal mucosa and high variability is expected.

[0152] The drug is selected based on at least one criterion.

[0153] 1. Unit dose of 200 mg or less;

[0154] 2. be contained in a volume of 2 ml or less after reconstitution;

[0155] 3. Chemical and / or physical stability at temperatures not exceeding 60°C;

[0156] 4. Compatibility of the solution with the solvent medium. The solvent medium may contain alcohol, polymers and / or other excipients for taste masking, viscosity adjustment and pH adjustment of the casting solution.

[0157] In certain embodiments, the unit dose is less than about 180 mg, less than about 160 mg, less than about 140 mg, less than about 120 mg, less than about 100 mg, less than about 80 mg, less than about 60 mg, or less than about 50 mg.

[0158] Drugs with a water volume exceeding about 2 mL per dose are not considered for inclusion. In certain embodiments, the volume is less than about 1.8 mL, less than about 1.6 mL, less than about 1.4 mL, less than about 1.2 mL, less than about 1.0 mL, less than about 0.8 mL, or less than about 0.5 mL.

[0159] A drug is considered "chemically stable" if it is not particularly reactive in the environment or during normal use and retains its useful properties over the timeframe of its intended use. Specifically, its usefulness is retained in the presence of air, moisture, or heat, and under the conditions of its intended application. In other words, the drug does not chemically react and therefore degrade under specific conditions. This can be assessed by collecting drug samples and determining the amount of degradation and / or activity. Corollary, a drug is "physically stable" if it does not change its physical state under specific conditions.

[0160] For example, the drug can resist degradation such as hydrolysis and / or oxidation at temperatures less than about 60° C. In certain embodiments, the drug is characterized by the absence of ester and / or amide moieties. In certain embodiments, the drug is characterized by sterically hindered ester and / or amide moieties such that it resists degradation at temperatures less than about 60° C.

[0161] The physical stability of a drug may be affected by temperature, ionic strength, acid-base catalysis, solvents, light and radiation, oxygen, particle size distribution and moisture. Physical instability includes precipitation, crystallization, aggregation, phase transition, polymorphism and solubility change. When a drug undergoes physical deterioration, its physical appearance may change, and its efficacy may optionally change. Generally speaking, the physical stability of a drug can be controlled to a certain extent by excipients. The physical stability of a drug can be further enhanced by the excipients in the premix.

[0162] The drug can substantially retain its activity or efficacy after formulation. In certain embodiments, the formulated drug retains at least about 90% of its activity, at least about 91% of its activity, at least about 92% of its activity, at least about 93% of its activity, at least about 94% of its activity, at least about 95% of its activity, at least about 96% of its activity, at least about 97% of its activity, at least about 98% of its activity, or at least about 99% of its activity.

[0163] The drug product's solution compatibility with the solvent medium and / or aqueous medium can be assessed first by listing the excipients or ingredients in the drug product. The drug product with ingredients compatible with the solvent medium can then be mixed with the solvent medium to confirm solution compatibility. This two-step process is necessary to confirm solution compatibility because the composition or concentration of the listed ingredients may not be specified, and some excipients or ingredients may be incompatible with the solvent medium above a certain concentration.

[0164] In certain embodiments, the drug is characterized by at least two of the above criteria. In certain embodiments, the drug is characterized by three of the above criteria. In certain embodiments, the drug is characterized by four of the above criteria.

[0165] In certain embodiments, the drug is further characterized by a molecular weight of less than about 6000 Da.In certain embodiments, the drug is characterized by five of the above criteria.

[0166] As used herein, the term "solvent medium" refers to a solvent system that can be aqueous or organic. Such solvents can be polar or non-polar, and / or protic or aprotic. A solvent system refers to a combination of solvents that produces a final single phase. "Solvent" and "solvent system" can include, but are not limited to, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, dioxane, chloroform, ether, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, nitromethane, propylene carbonate, formic acid, alcohol, butanol, isopropyl alcohol, propanol, ethanol, methanol, acetic acid, ethylene glycol, diethylene glycol, or water.

[0167] The term "aqueous medium" as used herein refers to a water-based solvent or solvent system, and is primarily composed of water. Such a solvent can be polar or non-polar, and / or protic or aprotic. A solvent system refers to a combination of solvents that produces a final single phase. "Solvent" and "solvent system" can include, but are not limited to, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, dioxane, chloroform, ether, methylene chloride, tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, nitromethane, propylene carbonate, formic acid, butanol, isopropyl alcohol, propanol, ethanol, methanol, acetic acid, ethylene glycol, diethylene glycol or water. A water-based solvent or solvent system can also include dissolved ions, salts and molecules such as amino acids, proteins, sugars and phospholipids. Such salts may be, but are not limited to, sodium chloride, potassium chloride, ammonium acetate, magnesium acetate, magnesium chloride, magnesium sulfate, potassium acetate, potassium chloride, sodium acetate, sodium citrate, zinc chloride, sodium HEPES, calcium chloride, ferric nitrate, sodium bicarbonate, potassium phosphate, and sodium phosphate. Thus, biological fluids, physiological solutions, and culture media are also within the scope of this definition.

[0168] In certain embodiments, the solubility in a solvent medium is solubility in an aqueous medium.

[0169] In certain embodiments, the drug is characterized by a solubility in an aqueous or solvent medium of about 1 mg / mL to about 1000 mg / mL, In other embodiments, the solubility is about 10 mg / mL to about 1000 mg / mL, about 20 mg / mL to about 1000 mg / mL, about 30 mg / mL to about 1000 mg / mL, about 40 mg / mL to about 1000 mg / mL, about 50 mg / mL to about 1000 mg / mL, about 100 mg / mL to about 1000 mg / mL, about 200 mg / mL to about 1000 mg / mL, about 300 mg / mL to about 1000 mg / mL, about 400 mg / mL to about 1000 mg / mL, about 500 mg / mL to about 1000 mg / mL, about 600 mg / mL to about 1000 mg / mL, about 700 mg / mL to about 1000 mg / mL, or about 800 mg / mL to about 1000 mg / mL. In other embodiments, the solubility is greater than about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 150 mg / mL, about 200 mg / mL, or about 250 mg / mL.

[0170] The drug is provided in its original dosage form and is formulated as is. In other words, the pharmaceutical drug product is used as is. In certain embodiments, the drug is provided in an aqueous or solvent medium or as a powder. The powder is soluble in an aqueous or solvent medium. In other embodiments, the drug is provided in an aqueous or solvent medium. In certain embodiments, the dosage form of the drug is selected from an injection, a powder, a tablet, a capsule, a swallowable liquid, an inhaled liquid, a nasal liquid, an eye drop, or an ear drop. When the drug is in tablet form, it can be crushed to facilitate preparation. When the drug is a capsule, the microparticles in the capsule can be further processed into a powder. In certain embodiments, the drug is an injectable drug.

[0171] Thus, in certain embodiments, the method is a method of formulating an injectable drug into a film or sheet, the method comprising:

[0172] a) dissolving the injectable drug in a premix and optionally using an aqueous medium to form a solution; and

[0173] b) casting the solution into a mold to form the film or sheet;

[0174] wherein said injectable drug is formulated in its dosage form;

[0175] The injectable drug is characterized by at least one of the following:

[0176] i) a unit dose of less than about 200 mg;

[0177] ii) a volume of less than about 2 mL;

[0178] iii) chemical and / or physical stability at less than about 60°C; and

[0179] iv) Solubility in solvent media.

[0180] In certain embodiments, the solubility in the solvent medium exceeds about 10 mg / mL.

[0181] In certain embodiments, the method is a method of formulating an injectable drug into a film or sheet, the method comprising:

[0182] a) dissolving the injectable drug in a premix and optionally using an aqueous medium to form a solution; and

[0183] b) casting the solution into a mold to form the film or sheet;

[0184] wherein said injectable drug is formulated in its dosage form;

[0185] The injectable drug is characterized by at least one of the following:

[0186] i) a unit dose of less than about 200 mg;

[0187] ii) a volume of less than about 2 mL;

[0188] iii) chemical and / or physical stability at less than about 60°C;

[0189] iv) a solubility in the solvent medium exceeding about 10 mg / mL; and

[0190] v) a molecular weight of less than about 6000 Da.

[0191] In certain embodiments, the drug is a BCS class I drug. For example, the BCS class I drug can be acetylsalicylic acid, allopurinol, amantadine hydrochloride, amitriptyline hydrochloride, amlodipine, amoxicillin, ascorbic acid, aspirin, berothiazine, caffeine, clindamycin, diazepam, diltiazem, doxycycline hydrochloride, ertugliflozin, escitalopram oxalate, fluconazole, fluoxetine, gliclazide, imatinib, itopride hydrochloride, ketorolac tromethamine, levetiracetam, levofloxacin ... Ofloxacin, levodopa, levonorgestrel, methimazole, metoprolol, metronidazole, mobotinib, norethindrone, ofloxacin, oseltamivir, phenobarbital, prednisolone, pregabalin, promethazine hydrochloride, propranolol hydrochloride, pyridoxine hydrochloride, quetiapine fumarate, riboflavin, ruxolitinib, albuterol sulfate, theophylline, timolol, tramadol, vildagliptin, voriconazole, zidovudine, ketamine, or dexmedetomidine hydrochloride. In certain embodiments, the drug is amitriptyline hydrochloride, amlodipine, berothiazine, caffeine, diazepam, doxycycline hydrochloride, ertugliflozin, escitalopram oxalate, fluoxetine, itopride hydrochloride, ketorolac tromethamine, levodopa, levonorgestrel, methimazole, metoprolol, norethisterone, ositol, phenobarbital, prednisolone, pregabalin, promethazine hydrochloride, propranolol hydrochloride, pyridoxine hydrochloride, quetiapine fumarate, riboflavin, ruxolitinib, albuterol sulfate, theophylline, timolol, tramadol, vildagliptin, ketamine or dexmedetomidine hydrochloride. In certain embodiments, the drug is ketamine or dexmedetomidine hydrochloride.

[0192] In certain embodiments, the drug is a BCS class II drug. For example, the BCS class II drug can be aceclofenac, acimenid, atorvastatin calcium, budesonide, cefuroxime, chlorzoxazone, clonazepam, clopidogrel, clozapine, daclatasvir, danazol, dexlansoprazole, dextromethorphan hydrobromide, diacerein (diacerien), diclofenac sodium, enzalutamide, eplerenone, etoricoxib, felodipine, fenofibrate, gefitinib, ibrutinib, ibuprofen, indinavir sulfate, ketoprofen, ivermectin, lansoprazole, Mebendazole, montelukast sodium, naproxen, nicardipine, nifedipine, nitrofurantoin, obeticholic acid, olanzapine, omeprazole, oxcarbazepine, ozanimod, palbociclib isethionate, paliperidone palmitate, pemitinib, phenytoin sodium, posaconazole, pralsetinib, racecadotril, rifampin, risperidone, rosuvastatin, sertraline hydrochloride, sulfamethoxazole, tamoxifen citrate, telmisartan, terbinafine hydrochloride, trimethoprim, valsartan, venetoclax, vericizumab, or dexamethasone. In certain embodiments, the drug is aceclofenac, acimenid, atorvastatin calcium, budesonide, cefuroxime, chlorzoxazone, clonazepam, clopidogrel, clozapine, daclatasvir, danazol, dexlansoprazole, dextromethorphan hydrobromide, diacerein, diclofenac sodium, enzalutamide, eplerenone, etoricoxib, felodipine, fenofibrate, gefitinib, ibrutinib, ibuprofen, indinavir sulfate, ketoprofen, ivermectin, lansoprazole, mebendazole, montelukin, In some embodiments, the drug is dexamethasone.

[0193] In certain embodiments, the drug is a BCS class III drug. For example, the BCS class III drug can be abacavir, acyclovir, atenolol, baclofen, benznidazole, chloramphenicol, cimetidine, dapagliflozin, empagliflozin, glucosamine sulfate potassium, lamivudine, levothyroxine sodium, linagliptin, lisinopril, metformin hydrochloride, methotrexate sodium, methyldopa, mirabegron, neostigmine bromide, olopatadine hydrochloride, pantoprazole sodium, pentosan polysulfate sodium, proguanil hydrochloride, rabeprazole sodium, ranitidine hydrochloride, ribavirin, rizatriptan benzoate, saxagliptin, sitagliptin, sofosbuvir, tenofovir disoproxil, thiamine hydrochloride, valacyclovir, vilbergron, vortioxetine hydrobromide, or zinc sulfate.

[0194] In certain embodiments, the drug is selected from midazolam, ondansetron, dimenhydrinate, haloperidol, lidocaine, salbutamol, levosalbutamol, prednisolone, prednisone, methylprednisolone, diazepam, lorazepam, clonazepam, diclofenac, ketoprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs), epinephrine, diphenhydramine, dopamine, amiodarone, adenosine, magnesium sulfate, furosemide, sodium bicarbonate, naloxone or flumazenil. In certain embodiments, the drug is selected from midazolam, ondansetron, dimenhydrinate, haloperidol or lidocaine. In certain embodiments, the drug is selected from midazolam, ondansetron, dimenhydrinate, haloperidol, lidocaine, salbutamol, levosalbutamol, dexamethasone, prednisolone, prednisone, methylprednisolone, diazepam, lorazepam, clonazepam, diclofenac, ketoprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs), epinephrine, diphenhydramine, dopamine, adenosine, caffeine, naloxone, flumazenil, codeine, fentanyl, ketamine, other or their combinations. In other embodiments, the drug is midazolam.

[0195] In certain embodiments, the drug is provided as a single unit dose. A single unit dose is an amount or unit of a compound, mixture, or formulation containing a controlled substance that is individually identifiable and in a form indicating that it is an amount or unit of a controlled substance to be administered or used by an individual.

[0196] In certain embodiments, the medicine in the solution is about 1mg / mL to about 200mg / mL.In certain embodiments, the concentration of the medicine in the solution is about 1mg / mL to about 180mg / mL, about 1mg / mL to about 160mg / mL, about 1mg / mL to about 150mg / mL, about 1mg / mL to about 140mg / mL, about 1mg / mL to about 120mg / mL, about 1mg / mL to about 100mg / mL, about 1mg / mL to about 80mg / mL, about 1mg / mL to about 60mg / mL, about 1mg / mL to about 50mg / mL, about 1mg / mL to about 40mg / mL, about 1mg / mL to about 20mg / mL, about 1mg / mL to about 10mg / mL or about 1mg / mL to about 5mg / mL.In certain embodiments, the medicine in the solution is about 2.5mg / mL.

[0197] The premix can be provided as a powder, solution, or suspension. When the premix is provided as a powder or suspension, an aqueous medium can be added to form a solution with the drug. When the premix is provided as a solution, an aqueous or solvent medium can be added to bring the drug and excipient to an appropriate concentration to form a film and / or sheet.

[0198] In certain embodiments, the premix comprises an excipient selected from the group consisting of a film-forming polymer, a binder, a bioadhesive material, a coating agent, a controlled-release agent, a dispersant, a solubility enhancer, an emulsifier, an emulsion stabilizer, a humectant, a modified-release agent, a film former, a mucoadhesive agent, a plasticizer, a solubilizer, a stabilizer, a suspending agent, a thickener, a sweetener, a taste-masking agent, a colorant, or a combination thereof. In certain embodiments, the premix comprises at least one excipient.

[0199] An "excipient" is a pharmaceutically inactive substance that acts as a carrier or vehicle for a drug or other active substance.

[0200] In certain embodiments, the premix comprises the polymer for forming a film.The polymer for forming a film can be a water-soluble polymer.Water-soluble polymers include, but are not limited to polyethylene oxide, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl-cellulose, polyvinyl pyrrolidone, gelatin, pectin, xanthan gum, polyvinyl alcohol, trehalose, hydroxypropyl pea starch (Lycoat RS720), chitosan and pullulan (pullulan). In other embodiments, the polymer for forming a film is selected from xanthan gum, polyvinyl alcohol, hydroxypropyl methylcellulose, pullulan, trehalose, methylcellulose, hydroxypropyl pea starch (Lycoat RS720) or its combination. In certain embodiments, the polymer for forming a film is selected from polyethylene oxide, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl-cellulose, polyvinyl pyrrolidone, gelatin, pectin, xanthan gum, polyvinyl alcohol, trehalose, hydroxypropyl pea starch (Lycoat RS720), chitosan, pullulan or its combination.

[0201] It was found that by using the aforementioned water-soluble polymers, it was possible to produce transparent, smooth films with acceptable mechanical properties. This indicates that the active pharmaceutical ingredient is at least dissolved within the film and / or sheet. This also ensures that the pharmacokinetic properties of the drug can be reliably reproduced, such that they are similar to or at least acceptable to those of the dosage form.

[0202] In certain embodiments, the premix comprises the following combination of film-forming polymers (wherein X indicates the presence of the film-forming polymer):

[0203]

[0204]

[0205] In certain embodiments, the premix comprises at least two film-forming polymers. In certain embodiments, the premix comprises one of:

[0206] a) xanthan gum and polyvinyl alcohol;

[0207] b) xanthan gum and pullulan;

[0208] c) xanthan gum and polyvinyl pyrrolidone;

[0209] d) xanthan gum and trehalose;

[0210] e) xanthan gum and Lycoat RS720;

[0211] f) xanthan gum and methylcellulose;

[0212] g) polyvinyl alcohol and hydroxypropyl methylcellulose;

[0213] h) hydroxypropyl methylcellulose and pullulan;

[0214] i) hydroxypropyl methylcellulose and polyvinylpyrrolidone;

[0215] j) hydroxypropyl methylcellulose and chitosan;

[0216] k) Hydroxypropyl methylcellulose and methylcellulose;

[0217] 1) pullulan and polyvinylpyrrolidone;

[0218] m) pullulan and trehalose;

[0219] n) pullulan and Lycoat RS720;

[0220] o) pullulan and methylcellulose;

[0221] p) polyvinylpyrrolidone and chitosan;

[0222] q) polyvinylpyrrolidone and methylcellulose;

[0223] r) trehalose and methylcellulose; and

[0224] s) Chitosan and methylcellulose.

[0225] In certain embodiments, the premix comprises at least three film-forming polymers. In certain embodiments, the premix comprises a combination of the following film-forming polymers (wherein X indicates the presence of the film-forming polymer):

[0226]

[0227]

[0228]

[0229] In certain embodiments, the premix comprises at least four film-forming polymers. In certain embodiments, the premix comprises the following combination of film-forming polymers (wherein X indicates the presence of the film-forming polymer):

[0230]

[0231]

[0232]

[0233]

[0234] In certain embodiments, the film-forming polymer is present in an amount of about 0.1% w / v to about 20% w / v relative to the solution. When more than one film-forming polymer is present, the total amount of film-forming polymer is present in an amount of about 0.1% w / v to about 20% w / v relative to the solution.

[0235] The various polymers that form films can give different properties to the film, such as thickness, elasticity or disintegration rate. The composition of the polymer that forms films in the solution can be adjusted to obtain required drug release characteristics. Finding that by at least 2 kinds of polymers that form films or preferably at least 3 kinds of combinations of polymers that form films, synergistic (or at least addition) effect can be obtained, to form uniform film or thin slice. This can improve (or at least maintain) the delivery of medicine to the patient.

[0236] In certain embodiments, the premix comprises a binder. The binder may be polyvinyl pyrrolidone.

[0237] In certain embodiments, the binder is from about 0.1% w / v to about 20% w / v of the solution.

[0238] In certain embodiments, the premix comprises a humectant. The humectant may be glycerin or propylene glycol.

[0239] In certain embodiments, the humectant is from about 0.1% w / v to about 20% w / v of the solution.

[0240] In certain embodiments, the premix comprises a solubilizing agent. The solubilizing agent can be a cyclodextrin. In certain embodiments, the solubilizing agent is a cosolvent (such as propylene glycol), a complexing agent, or a surfactant.

[0241] In certain embodiments, the solubilizing agent is from about 0.1% w / v to about 20% w / v relative to the solution.

[0242] In certain embodiments, the premix comprises a sweetener. In certain embodiments, the premix comprises a taste masking agent. The sweetener or taste masking agent can be maltitol, sorbitol, xylitol, citric acid or sodium chloride.

[0243] In certain embodiments, the sweetener or taste-masking agent is from about 0.1% w / v to about 20% w / v of the solution.

[0244] In certain embodiments, the premix comprises a plasticizer. The plasticizer makes the film and / or sheet flexible and soft, and can enhance the flexibility and plasticity of the film. The plasticizer can be ethylene glycol, citric acid (tributyl citrate, triethyl citrate) or glycerol (triacetin, tributyrin).

[0245] In certain embodiments, the plasticizer is from about 0.1% w / v to about 20% w / v of the solution.

[0246] In certain embodiments, the premix further comprises a pH adjusting agent. The pH adjusting agent is a pH controlling agent and is used to change or maintain pH (acidity or alkalinity). They can be organic or inorganic acids, alkalis, neutralizing agents or buffers. Typical reagents include the following acids and their sodium salts: sorbic acid, acetic acid, benzoic acid and propionic acid. Acidity regulators can be represented by their E numbering, such as E260 (acetic acid).

[0247] In certain embodiments, the pH adjuster is about 0.1% w / v to about 20% w / v relative to the solution.

[0248] In certain embodiments, the premix further comprises a dental adhesive. The dental adhesive can be provided as a powder or a gel. Dental adhesives are adhesives used to adhere films and / or sheets to teeth. Dental adhesives can be self-curing, light-curing, or dual-curing, with curing times varying for different products but typically within 30 seconds. The addition of a dental adhesive imparts additional mucoadhesive properties to the film and / or sheet.

[0249] In certain embodiments, the dental adhesive powder or gel is about 0.1% w / v to about 10% w / v relative to the solution.

[0250] After selecting a film-forming polymer and other excipients and mixing them to form a premix, the drug is dissolved in the premix to form a solution. The solution is then cast into a mold to form a film and / or sheet. Therefore, the mold is appropriately sized to form the film and / or sheet. For example, the mold can have a depth (or height) of about 10 μm to about 1 cm. Alternatively, a tray can be used as the mold. If a tray is used, the formed film and / or sheet can undergo a subsequent cutting step so that the appropriate dose can be administered to the patient.

[0251] In certain embodiments, the solution is characterized by a viscosity of less than about 800 cP. In other embodiments, the viscosity is less than about 700 cP, about 600 cP, about 500 cP, about 400 cP, or about 300 cP.

[0252] In certain embodiments, the step of casting the solution further comprises drying the solution.

[0253] To form the film, the solution can be dried, for example, using evaporation. For example, the solution can be dried at room temperature or ambient temperature or in an oven. For example, a microwave oven, an incubator, a fan, and / or a dessicator chamber can be used to dry the solution. Depending on the drying duration, residual aqueous medium may still remain in the film.

[0254] In certain embodiments, the solution is dried at a temperature of about 10° C. to about 80° C. In other embodiments, the temperature is about 10° C. to about 70° C., about 10° C. to about 60° C., or about 20° C. to about 60° C.

[0255] To form the flakes, the solution can be dried, for example, using freeze-drying techniques. The solution may need to undergo several cycles of heating and cooling to form the flakes. This may help expand the internal structure of the flakes to alter the dissolution rate.

[0256] In certain embodiments, the method further comprises the step of ultraviolet sterilization of the film and / or sheet. By subjecting the surface of the film and / or sheet to UV-C radiation, the microbial stability of the film and / or sheet can be achieved. This further step ensures the sterility of the final product.

[0257] In certain embodiments, the method further comprises the step of further dehydrating the film and / or sheet. For example, the film and / or sheet may be subjected to a further heating cycle. The elimination of water may result in a low water activity of less than about 0.8. w) is the partial vapor pressure of water in the film and / or sheet divided by the partial vapor pressure of water at standard state. Standard state is most commonly defined as pure water at the same temperature. Using this specific definition, pure distilled water has a water activity of exactly 1. Water activity is the thermodynamic activity of water as a solvent in equilibrium with the relative humidity of the surrounding air. As temperature increases, a w Usually increases. Lower a w Materials tend to support fewer microorganisms as these dry out due to water migration.

[0258] In certain embodiments, the method further comprises the step of removing the film from the mold after step b).

[0259] In certain embodiments, the film and / or sheet is monolayer. In other embodiments, the film and / or sheet is multilayer. The drug in the film and / or sheet can be uniformly dissolved.

[0260] The film and / or sheet can be characterized by an immediate release characteristic or a modified release characteristic. A modified release dose is a mechanism that delays the release of a drug (delayed release dose) or extends the release time (extended release [ER, XR, XL] dose) after its administration. For example, a sustained release dosage form is a dosage form designed to release (release) a drug at a predetermined rate in order to maintain a constant drug concentration over a specific time period and to minimize side effects. This can be achieved through a variety of formulations, including liposomes and drug-polymer conjugates (e.g., hydrogels). The purpose of an extended release dosage is to release the drug over an extended time period and can include sustained release (SR) and / or controlled release (CR) dosages. SR maintains drug release over a sustained time period, but not at a constant rate. CR maintains drug release over a sustained time period at an almost constant rate. Other forms of modified release include time-dependent release such as pulsed release and delayed release.

[0261] In certain embodiments, the films and / or sheets are characterized by a thickness of about 0.05 mm to about 1.0 mm.

[0262] In certain embodiments, the films and / or wafers are characterized by a disintegration time of about 10 s to about 60 min.

[0263] In certain embodiments, the film and / or sheet is characterized by a pH of about 3 to about 7. In certain embodiments, the film and / or sheet is characterized by a pH of about 2 to about 8. Studies have found that certain formulations require the addition of acid to promote solubility of the drug in the premix.

[0264] In certain embodiments, the film and / or sheet is characterized by a folding endurance of greater than about 100. Folding endurance is defined as the logarithm (base 10) of the number of double folds required to cause a test piece to break under standard conditions.

[0265] In certain embodiments, the film and / or sheet is characterized by a flow rate of at least 50 N / cm 2 Young's modulus.

[0266] The film and / or sheet is intended to be administered orally to a subject in need thereof. In other embodiments, the film and / or sheet is for sublingual, buccal, and / or sublabial administration. Although the onset of action may be slightly delayed and the bioavailability may be slightly reduced compared to intravenous administration, other pharmacokinetic properties of the film and / or sheet are expected to be similar.

[0267] In certain embodiments, the drug is an injectable drug.

[0268] The present invention also provides a film or sheet for oral administration of a drug, comprising:

[0269] a) from about 1 mg / mL to about 200 mg / mL of the drug, relative to the film and / or sheet;

[0270] b) from about 0.1% w / v to about 20% w / v of a film-forming polymer, relative to the film and / or sheet;

[0271] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0272] The drug is characterized by at least one of the following:

[0273] i) a unit dose of less than about 200 mg;

[0274] ii) a volume of less than about 2 mL;

[0275] iii) chemical and / or physical stability at less than about 60°C; and

[0276] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0277] In certain embodiments, the solubility in the solvent medium exceeds about 10 mg / mL.

[0278] In certain embodiments, the film or sheet for oral administration of a drug comprises:

[0279] a) from about 1 mg / mL to about 200 mg / mL of the drug, relative to the film and / or sheet;

[0280] b) from about 0.1% w / v to about 20% w / v of a film-forming polymer, relative to the film and / or sheet;

[0281] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0282] d) from about 0.1% w / v to about 10% w / v of a dental adhesive relative to the film and / or sheet;

[0283] The drug is characterized by at least one of the following:

[0284] i) a unit dose of less than about 200 mg;

[0285] ii) a volume of less than about 2 mL;

[0286] iii) chemical and / or physical stability at less than about 60°C; and

[0287] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0288] In certain embodiments, the film or sheet for oral administration of an injectable drug comprises:

[0289] a) about 1 mg / mL to about 200 mg / mL of an injectable drug relative to the film and / or sheet;

[0290] b) from about 0.1% w / v to about 20% w / v of a film-forming polymer, relative to the film and / or sheet;

[0291] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0292] The injectable drug is characterized by at least one of the following:

[0293] i) a unit dose of less than about 200 mg;

[0294] ii) a volume of less than about 2 mL;

[0295] iii) chemical and / or physical stability at less than about 60°C;

[0296] iv) a solubility in aqueous or solvent media exceeding about 10 mg / mL; and

[0297] i) a molecular weight of less than about 6000 Da.

[0298] In certain embodiments, the film or sheet for oral administration of an injectable drug comprises:

[0299] a) about 1 mg / mL to about 200 mg / mL of an injectable drug relative to the film and / or sheet;

[0300] b) from about 0.1% w / v to about 20% w / v of a film-forming polymer, relative to the film and / or sheet;

[0301] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0302] d) from about 0.1% w / v to about 10% w / v of a dental adhesive relative to the film and / or sheet;

[0303] The injectable drug is characterized by at least one of the following:

[0304] i) a unit dose of less than about 200 mg;

[0305] ii) a volume of less than about 2 mL;

[0306] iii) chemical and / or physical stability at less than about 60°C;

[0307] iv) a solubility in aqueous or solvent media exceeding about 10 mg / mL; and

[0308] v) a molecular weight of less than about 6000 Da.

[0309] The present invention also provides a film or sheet for oral administration of a drug, comprising:

[0310] a) from about 1 mg / mL to about 200 mg / mL of the drug, relative to the film and / or sheet;

[0311] b) at least two film-forming polymers, each of said two film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0312] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0313] The drug is characterized by at least one of the following:

[0314] ii) a unit dose of less than about 200 mg;

[0315] iii) a volume of less than about 2 mL;

[0316] iv) chemical and / or physical stability at less than about 60°C; and

[0317] v) a solubility in the solvent medium exceeding about 10 mg / mL.

[0318] In certain embodiments, the film or sheet for oral administration of a drug comprises:

[0319] a) from about 1 mg / mL to about 200 mg / mL of the drug, relative to the film and / or sheet;

[0320] b) at least two film-forming polymers, each of said two film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0321] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0322] d) from about 0.1% w / v to about 10% w / v of a dental adhesive relative to the film and / or sheet;

[0323] The drug is characterized by at least one of the following:

[0324] i) a unit dose of less than about 200 mg;

[0325] ii) a volume of less than about 2 mL;

[0326] iii) chemical and / or physical stability at less than about 60°C; and

[0327] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0328] In certain embodiments, the film or sheet for oral administration of an injectable drug comprises:

[0329] a) about 1 mg / mL to about 200 mg / mL of an injectable drug relative to the film and / or sheet;

[0330] b) at least two film-forming polymers, each of said two film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0331] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0332] The injectable drug is characterized by at least one of the following:

[0333] i) a unit dose of less than about 200 mg;

[0334] ii) a volume of less than about 2 mL;

[0335] iii) chemical and / or physical stability at less than about 60°C;

[0336] iv) a solubility in aqueous or solvent media exceeding about 10 mg / mL; and

[0337] v) a molecular weight of less than about 6000 Da.

[0338] In certain embodiments, the film or sheet for oral administration of an injectable drug comprises:

[0339] a) about 1 mg / mL to about 200 mg / mL of an injectable drug relative to the film and / or sheet;

[0340] b) at least two film-forming polymers, each of said two film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0341] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0342] d) from about 0.1% w / v to about 10% w / v of a dental adhesive relative to the film and / or sheet;

[0343] The injectable drug is characterized by at least one of the following:

[0344] i) a unit dose of less than about 200 mg;

[0345] ii) a volume of less than about 2 mL;

[0346] iii) chemical and / or physical stability at less than about 60°C;

[0347] iv) a solubility in aqueous or solvent media exceeding about 10 mg / mL; and

[0348] v) a molecular weight of less than about 6000 Da.

[0349] The present invention also provides a film or sheet for oral administration of a drug, comprising:

[0350] a) from about 1 mg / mL to about 200 mg / mL of the drug, relative to the film and / or sheet;

[0351] b) at least three film-forming polymers, each of said three film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0352] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0353] The drug is characterized by at least one of the following:

[0354] i) a unit dose of less than about 200 mg;

[0355] ii) a volume of less than about 2 mL;

[0356] iii) chemical and / or physical stability at less than about 60°C; and

[0357] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0358] In certain embodiments, the film or sheet for oral administration of a drug comprises:

[0359] a) from about 1 mg / mL to about 200 mg / mL of the drug, relative to the film and / or sheet;

[0360] b) at least three film-forming polymers, each of said three film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0361] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0362] d) from about 0.1% w / v to about 10% w / v of a dental adhesive relative to the film and / or sheet;

[0363] The drug is characterized by at least one of the following:

[0364] i) a unit dose of less than about 200 mg;

[0365] ii) a volume of less than about 2 mL;

[0366] iii) chemical and / or physical stability at less than about 60°C; and

[0367] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0368] In certain embodiments, the film or sheet for oral administration of an injectable drug comprises:

[0369] a) about 1 mg / mL to about 200 mg / mL of an injectable drug relative to the film and / or sheet;

[0370] b) at least three film-forming polymers, each of said three film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0371] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0372] The injectable drug is characterized by at least one of the following:

[0373] i) a unit dose of less than about 200 mg;

[0374] ii) a volume of less than about 2 mL;

[0375] iii) chemical and / or physical stability at less than about 60°C;

[0376] iv) a solubility in aqueous or solvent media exceeding about 10 mg / mL; and

[0377] v) a molecular weight of less than about 6000 Da.

[0378] In certain embodiments, the film or sheet for oral administration of an injectable drug comprises:

[0379] a) about 1 mg / mL to about 200 mg / mL of an injectable drug relative to the film and / or sheet;

[0380] b) at least three film-forming polymers, each of said three film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0381] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0382] d) from about 0.1% w / v to about 10% w / v of a dental adhesive relative to the film and / or sheet;

[0383] The injectable drug is characterized by at least one of the following:

[0384] i) a unit dose of less than about 200 mg;

[0385] ii) a volume of less than about 2 mL;

[0386] iii) chemical and / or physical stability at less than about 60°C;

[0387] iv) a solubility in aqueous or solvent media exceeding about 10 mg / mL; and

[0388] v) a molecular weight of less than about 6000 Da.

[0389] The present invention also provides a film or sheet for oral administration of a drug, comprising:

[0390] a) from about 1 mg / mL to about 200 mg / mL of the drug, relative to the film and / or sheet;

[0391] b) at least four film-forming polymers, each of said four film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0392] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0393] The drug is characterized by at least one of the following:

[0394] i) a unit dose of less than about 200 mg;

[0395] ii) a volume of less than about 2 mL;

[0396] iii) chemical and / or physical stability at less than about 60°C; and

[0397] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0398] In certain embodiments, the film or sheet for oral administration of a drug comprises:

[0399] a) from about 1 mg / mL to about 200 mg / mL of the drug, relative to the film and / or sheet;

[0400] b) at least four film-forming polymers, each of said four film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0401] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0402] d) from about 0.1% w / v to about 10% w / v of a dental adhesive relative to the film and / or sheet;

[0403] The drug is characterized by at least one of the following:

[0404] i) a unit dose of less than about 200 mg;

[0405] ii) a volume of less than about 2 mL;

[0406] iii) chemical and / or physical stability at less than about 60°C; and

[0407] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0408] In certain embodiments, the film or sheet for oral administration of an injectable drug comprises:

[0409] a) about 1 mg / mL to about 200 mg / mL of an injectable drug relative to the film and / or sheet;

[0410] b) at least four film-forming polymers, each of said four film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0411] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0412] The injectable drug is characterized by at least one of the following:

[0413] i) a unit dose of less than about 200 mg;

[0414] ii) a volume of less than about 2 mL;

[0415] iii) chemical and / or physical stability at less than about 60°C;

[0416] iv) a solubility in aqueous or solvent media exceeding about 10 mg / mL; and

[0417] v) a molecular weight of less than about 6000 Da.

[0418] In certain embodiments, the film or sheet for oral administration of an injectable drug comprises:

[0419] a) about 1 mg / mL to about 200 mg / mL of an injectable drug relative to the film and / or sheet;

[0420] b) at least four film-forming polymers, each of said four film-forming polymers independently being from about 0.1% w / v to about 20% w / v, relative to said film and / or sheet;

[0421] c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet;

[0422] d) from about 0.1% w / v to about 10% w / v of a dental adhesive relative to the film and / or sheet;

[0423] The injectable drug is characterized by at least one of the following:

[0424] i) a unit dose of less than about 200 mg;

[0425] ii) a volume of less than about 2 mL;

[0426] iii) chemical and / or physical stability at less than about 60°C;

[0427] iv) a solubility in aqueous or solvent media exceeding about 10 mg / mL; and

[0428] v) a molecular weight of less than about 6000 Da.

[0429] In certain embodiments, the oral administration is by sublingual, buccal, and / or sublabial administration.

[0430] The present invention also provides a premix for forming a film or sheet for oral administration of a drug, the premix comprising:

[0431] a) from about 0.1% w / v to about 20% w / v of a film-forming polymer, relative to the premix; and

[0432] b) from about 0.1% w / v to about 20% w / v of a humectant, relative to the premix.

[0433] The present invention also provides a premix for forming a film or sheet for oral administration of a drug, the premix comprising:

[0434] a) at least two film-forming polymers, each of said two film-forming polymers independently being from about 0.1% w / v to about 20% w / v relative to said premix; and

[0435] b) from about 0.1% w / v to about 20% w / v of a humectant, relative to the premix.

[0436] The present invention also provides a premix for forming a film or sheet for oral administration of a drug, the premix comprising:

[0437] a) at least three film-forming polymers, each of said three film-forming polymers independently being from about 0.1% w / v to about 20% w / v relative to said premix; and

[0438] b) from about 0.1% w / v to about 20% w / v of a humectant, relative to the premix.

[0439] The present invention also provides a premix for forming a film or sheet for oral administration of a drug, the premix comprising:

[0440] a) at least four film-forming polymers, each of said four film-forming polymers independently being from about 0.1% w / v to about 20% w / v relative to said premix; and

[0441] b) from about 0.1% w / v to about 20% w / v of a humectant, relative to the premix.

[0442] The polymer may be selected from the table disclosed herein.

[0443] In this way, medical institutions can reconstitute the film or sheet as needed. In addition, because the premix is compatible with multiple APIs, the same formulation platform can be used to incorporate and deliver different APIs separately or in combination to benefit patients with various conditions.

[0444] In certain embodiments, the premix comprises:

[0445] a) from about 0.1% w / v to about 20% w / v of a film-forming polymer, relative to the premix; and

[0446] b) from about 0.1% w / v to about 20% w / v of glycerol, relative to the premix.

[0447] In certain embodiments, the premix comprises:

[0448] a) at least two film-forming polymers, each of said two film-forming polymers independently being from about 0.1% w / v to about 20% w / v relative to said premix; and

[0449] b) from about 0.1% w / v to about 20% w / v of glycerol, relative to the premix.

[0450] In certain embodiments, the premix comprises:

[0451] a) at least three film-forming polymers, each of said three film-forming polymers independently being from about 0.1% w / v to about 20% w / v relative to said premix; and

[0452] b) from about 0.1% w / v to about 20% w / v of glycerol, relative to the premix.

[0453] In certain embodiments, the premix comprises:

[0454] a) at least four film-forming polymers, each of said four film-forming polymers independently being from about 0.1% w / v to about 20% w / v relative to said premix; and

[0455] b) from about 0.1% w / v to about 20% w / v of glycerol, relative to the premix.

[0456] In certain embodiments, the premix further comprises from about 0.1% w / v to about 10% w / v of a dental adhesive relative to the premix.

[0457] The present invention also provides a method of treating a disease or disorder treatable by a drug, the method comprising formulating the drug as disclosed herein into a film and / or wafer, and administering a therapeutically effective amount of the film and / or wafer to a subject in need thereof by sublingual, buccal and / or sublabial administration.

[0458] The present invention also provides a film and / or wafer for treating a disease or disorder treatable by a drug, wherein the film and / or wafer comprises the drug and is administrable sublingually, buccally and / or sublabially.

[0459] The present invention also provides the use of a film and / or wafer in the preparation of a medicament for treating a drug-treatable disease or disorder, wherein the film and / or wafer comprises the drug and is administrable sublingually, buccally and / or sublabially.

[0460] The drug can be used to treat diseases or disorders such as migraines, epilepsy and asthma attacks. Compared to injection, sublingual administration, buccal administration and / or sublabial administration of the drug may be less dangerous. The formulation to be injected must be sterile and free of particulates, and there may be a risk of infection at the injection site. Administration of the drug in film and / or sheet form can eliminate the need for injection, thereby reducing the risk of infection.

[0461] The present invention also provides a system for formulating a drug into a film or sheet, the system comprising:

[0462] a) a medicine receiving module for receiving medicine;

[0463] b) a premix module for containing a premix and introducing the premix into a medicine;

[0464] c) a mixing module for mixing the drug with the premix to form a solution;

[0465] d) a metering and dispensing module for dispensing the solution;

[0466] e) a mold for containing the dispensed solution; and

[0467] f) a curing module for curing the solution in the mold into a film or sheet.

[0468] In certain embodiments, the system for formulating an injectable drug into a film or sheet comprises:

[0469] a) a drug receiving module for receiving the injectable drug;

[0470] b) a premix module for containing a premix and introducing the premix into an injectable drug;

[0471] c) a mixing module for mixing the injectable drug with the premix to form a solution;

[0472] d) a metering and dispensing module for dispensing the solution;

[0473] e) a mold for containing the dispensed solution; and

[0474] f) a curing module for curing the solution in the mold into a film or sheet.

[0475] As used herein, "system" refers to one or more devices that configure or interact with each other based on a set of rules. This set of rules can be provided by software and / or process protocols. In this sense, a system is a group of interacting or interrelated elements or components that operate according to a set of rules to form a unified whole. A system, surrounded by and influenced by its environment, is described by its boundaries, structure, and purpose, and expressed by its functionality.

[0476] A system can be modular because its components can be separated and reassembled as needed. This provides the benefits of flexibility and versatility in use. The following describes the various components of a modular system. These components can be used individually or in any combination.

[0477] The module for premixes accommodates and introduces premixes for making films or sheets. Depending on the desired product, different amounts of premixes can be added. For example, a premix sufficient for a single dosage form or for multiple dosage forms can be added.

[0478] The module for receiving medication is used to receive medication. The medication can be received according to the original formulation. In this regard, the medication is received as a pharmaceutical composition. For example, the medication can be in liquid form, aliquoted from an ampoule, or combined from several ampoules. Alternatively, the medication can be in the form of a powder or solution.

[0479] The mixing module allows the drug to be combined with the premix. Aqueous media can be added as needed.

[0480] The metering and dispensing module allows for dispensing of all or part of the solution. Dispensing can be into a mold. Dispensing can be quantified by weight and / or volume. Other methods, such as conductivity, can also be used.

[0481] The mold contains a solution in a suitable mold to form a film or sheet. The module can be configured to produce one or more films and sheets. For example, the module can be a tray with 10-50 molds, so that each mold will receive a set volume / weight equivalent to one film / sheet from the module for metering and dispensing.

[0482] The module for curing the film or sheet converts the liquid or gel-like solution in the mold into a solid. If the viscosity of the solution is high, a press can also be included to suppress and control the thickness of the film / sheet. The curing may involve a photoactivation process, such as cross-linking by light of a specific wavelength or by mixing with an activator, and removing the liquid content by evaporation, such as thermal heating, freeze drying, or diffusion through a controlled pore membrane.

[0483] The system may optionally comprise a module for surface sterilization of the film or sheet. For example, the module may be an ultraviolet light source.

[0484] The system may optionally include a module for packaging films or sheets. This allows for safe transport between formulated medication and application to the patient.

[0485] The system may optionally include a module for cleaning the system. The module can clean and rinse away any residue on the system components.

[0486] The system may optionally include a sensing and data collection module. The module can record each step of the process for logging and analysis. Such information can be used for troubleshooting.

[0487] The system can optionally include a control system. The control system can be a computer-implemented system. This can involve a computer program that regulates the control of the premix, medicine, mixing, sterilization, packaging and / or cleaning. The program can also be configured to enable (such as opening or closing) a detection device and / or a quantifying device to detect and / or quantify the amount of the medicine in each film or sheet. The control system can also be configured with data related to the control (calibration diagram). The control system can be configured to be connected to a network for remote and / or automatic management of the system.

[0488] This lightweight, energy-efficient, bench-portable device is designed to use aseptic (contactless) technology to formulate and deliver the desired quality and quantity in a film / tablet format containing a precise and accurate dose.

[0489] It offers the possibility of films / sheets that formulate drugs (and injectable drugs) at the point of distribution / use and addresses a key capability gap that hinders the efficient formulation of safe, high-quality, personalized and environmentally friendly drugs for patients and other applications (such as clinical development, military, etc.). Example

[0490] General approach

[0491] The method has the following steps:

[0492] 1. Screen injectable drug formulations (e.g., ASHP injectable drug information) and select those with the following characteristics for film / sheet formulation development:

[0493] (a) a unit dose of 200 mg or less,

[0494] (b) a dose that, after reconstitution, is contained in a volume of 2 ml or less,

[0495] (c) be chemically and physically stable over a temperature range not exceeding 60°C, and

[0496] (d) Have solution compatibility with aqueous solutions containing alcohols, polymers and / or other excipients for taste masking, viscosity adjustment and pH adjustment of casting solutions.

[0497] 2. Formulate injectable drugs or other dosage forms into films / sheets by:

[0498] (a) Prepare a solution containing the drug at the desired dosage strength using a specified amount of a specific excipient

[0499] (b) Casting a precise volume of solution into a mold

[0500] (c) Drying the solution to obtain a film / sheet and sterilizing it under ultraviolet light

[0501] (d) Removing the film / sheet from the mold and packaging the film or sheet

[0502] Premixes, films and sheets

[0503] Premixed packages of polymers and solid excipients for film formulations of injectable BCS Class I, II, and III drugs are available as follows. The polymer premix is available in powder, suspension, and / or solution form and comes with detailed step-by-step instructions on how to add, mix, dispense, and process to obtain the final film / sheet. No injection essentials are provided. Alternatively, single-layer and multilayer films / sheets are available for rapid and slow-release formulations of the same or combined APIs, manufactured using recycled injectable BCS Class I, II, and III drug solutions or powders.

[0504] The formulations listed in the table below are encompassed by premixed powders of polymers and solid excipients or their respective suspensions and / or solutions. Studies have shown that using combinations of polymers can also complement the characteristics of different polymers. This improves the rubbery texture of the resulting film and also results in faster film disintegration. To produce a film or sheet, first, prepare an aqueous polymer solution having the following composition:

[0505]

[0506] Next, an equal volume of the injection drug solution is added to the premix. The mixture is thoroughly mixed by acoustic / ultrasound, dielectrophoresis, electrokinetic time pulses, electrohydrodynamics, thermal actuation, magnetohydrodynamic flow, electrodynamic instability, or passive microfluidic mixers (such as 2-D serpentine structures, twisted channels, zigzag channels, or embedded barriers), or stirred using a glass rod, a magnetic stirrer, or a vortex mixer until homogeneous.

[0507] The mixture may require pre-treatment to remove air bubbles that were created during the mixing process. If so, place it in an ultrasonic bath at 25°C and 50% to 150% power until no air bubbles are present in the mixture (now called the casting solution). Bubbles can also be removed by applying a low pressure to the mixture.

[0508] The mixture can be measured by weight, volume, or it can be dosed as a whole and the dose of the mixture transferred to the mold or tray. In one embodiment, if by volume, 0.5 to 2 ml of the casting solution is drawn up using a volumetric pipette and deposited onto the mold. Dental adhesive powder / gel can be added to increase the adhesion of the film / sheet to the mucosal tissue. The water content of the mixture on the mold or tray is then reduced. The reduction in water content can be achieved by air drying at ambient temperature or drying in a convection oven below 60°C. The dried film can be collected from the mold or tray by vacuum, robotic arm, or simply peeling by hand or any manual tool and sterilized (one of which is UVC sterilization) and then individually packaged in light-proof, waterproof, resealable bags.

[0509] The center thickness of the formed film is evaluated using a thickness gauge, optical method, acoustic method, micrometer or other method. Figure 1 The initial disintegration time was evaluated using an apparatus in , the folding endurance was evaluated using repeated manual folding along the same plane on the film, and the surface pH was evaluated using a pH meter.

[0510] Results (range) for monolayer films obtained using midazolam 5 mg / ml injectable drug solution:

[0511]

[0512] Midazolam is characterized by at least one of the following:

[0513] i) a unit dose of less than about 200 mg;

[0514] ii) a unit dose volume of less than about 2 mL;

[0515] iii) chemical and / or physical stability at less than about 60°C; and

[0516] iv) a solubility in the solvent medium exceeding about 10 mg / mL.

[0517] in conclusion

[0518] Formulations F1 to F10 are suitable for incorporation into injectable pharmaceutical solutions to produce medicated films or sheets. The films or sheets can be used for oral administration. For example, and in addition to midazolam, other drugs such as ondansetron hydrochloride, scopolamine bromide, chlorpheniramine maleate, caffeine hydrochloride, and combinations thereof have been tested.

[0519] The effectiveness was also tested in relation to the drug content detected in the film. Based on pharmaceutical standards, if each individual drug content was between 85% and 115% of the average content, the formulation met the test requirements (European Pharmacopoeia). All formulations had drug content within this range.

[0520] By repurposing injectable drugs and administering them buccally, the drug can be delivered to the patient in / through the buccal mucosa for local or systemic effects. Through this route, the drug bypasses enzymatic degradation in the gastrointestinal tract and first-pass effects in the liver, thereby achieving the same effect as injection.

[0521] It will be understood that many further modifications and permutations of various aspects of the described embodiments are possible. Accordingly, the described aspects are intended to embrace all such alterations, modifications and variations that fall within the spirit and scope of the appended claims.

[0522] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0523] Throughout this specification and the claims that follow, unless the context requires otherwise, the phrase "consisting essentially of" and variations such as "consisting essentially of" should be understood to indicate that the recited elements are required, i.e., essential elements of the invention. The phrase allows for the presence of other unrecited elements that do not materially affect the characteristics of the invention, but excludes other unspecified elements that affect the basic and novel characteristics of the defined method.

[0524] Reference in this specification to any previous publication (or information derived from such publication) or any known matter does not constitute and should not be taken as an acknowledgment or endorsement or as any form of suggestion that such previous publication (or information derived from such publication) or known matter forms part of the common general knowledge in the field to which this specification relates.

Claims

1. A method for preparing a drug into a film or sheet, the method comprising: a) dissolving the drug in the premix and optionally in an aqueous medium to form a solution; and b) casting the solution into a mold to form the film or sheet; wherein said drug is formulated in its dosage form; The drug is characterized by at least one of the following: i) a unit dose of less than about 200 mg; ii) a volume of less than about 2 mL; iii) chemical and / or physical stability at less than about 60°C; and iv) a solubility in the solvent medium exceeding about 10 mg / mL.

2. The method of claim 1, wherein the drug is selected from the group consisting of Biopharmaceutical Classification System (BCS) classes I, II, and III.

3. The method of claim 1 or 2, wherein the drug is characterized by at least two of the above criteria.

4. The method of any one of claims 1 to 3, wherein the drug is further characterized by a molecular weight of less than about 6000 Da.

5. The method according to any one of claims 1 to 4, wherein the dosage form of the drug is selected from injection, powder, tablet, capsule, swallowable liquid, inhalation liquid, nasal liquid, eye drops or ear drops.

6. The method according to any one of claims 1 to 5, wherein the drug is selected from midazolam, ondansetron, dimenhydrinate, haloperidol, lidocaine, salbutamol, levalbuterol, dexamethasone, prednisolone, prednisone, methylprednisolone, diazepam, lorazepam, clonazepam, diclofenac, ketoprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs), epinephrine, diphenhydramine, dopamine, adenosine, caffeine, naloxone, flumazenil, codeine, fentanyl, ketamine, or a combination thereof.

7. The method according to any one of claims 1 to 6, wherein the drug is provided as a single unit dose.

8. The method of any one of claims 1 to 7, wherein the drug in the solution is from about 1 mg / mL to about 200 mg / mL.

9. The method of any one of claims 1 to 8, wherein the premix comprises an excipient selected from the group consisting of a film-forming polymer, a binder, a bioadhesive material, a coating agent, a controlled release agent, a dispersant, a solubility enhancer, an emulsifier, an emulsion stabilizer, a humectant, a modified release agent, a film former, a mucoadhesive agent, a plasticizer, a solubilizer, a stabilizer, a suspending agent, a thickener, a taste masking agent, a colorant, or a combination thereof.

10. The method of any one of claims 1 to 9, wherein the premix comprises a film-forming polymer selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl-cellulose, polyvinyl pyrrolidone, gelatin, pectin, xanthan gum, polyvinyl alcohol, trehalose, hydroxypropyl pea starch (Lycoat RS720), chitosan, pullulan, or a combination thereof.

11. The method according to any one of claims 1 to 10, wherein the premix comprises at least two film-forming polymers.

12. The method according to any one of claims 1 to 11, wherein the premix comprises one of the following: a) xanthan gum and polyvinyl alcohol; b) xanthan gum and pullulan; c) xanthan gum and polyvinyl pyrrolidone; d) xanthan gum and trehalose; e) xanthan gum and Lycoat RS720; f) xanthan gum and methylcellulose; g) polyvinyl alcohol and hydroxypropyl methylcellulose; h) hydroxypropyl methylcellulose and pullulan; i) hydroxypropyl methylcellulose and polyvinylpyrrolidone; j) hydroxypropyl methylcellulose and chitosan; k) Hydroxypropyl methylcellulose and methylcellulose; l) pullulan and polyvinylpyrrolidone; m) pullulan and trehalose; n) pullulan and Lycoat RS720; o) pullulan and methylcellulose; p) polyvinylpyrrolidone and chitosan; q) polyvinylpyrrolidone and methylcellulose; r) trehalose and methylcellulose; and s) Chitosan and methylcellulose.

13. The method according to any one of claims 1 to 12, wherein the premix comprises at least three film-forming polymers.

14. The method of any one of claims 10 to 13, wherein the film-forming polymer is about 0.1% w / v to about 20% w / v relative to the solution.

15. The method according to any one of claims 1 to 14, wherein the premix comprises a binder.

16. The method of claim 15, wherein the binder is about 0.1% w / v to about 20% w / v relative to the solution.

17. The method of any one of claims 1 to 16, wherein the premix comprises a humectant.

18. The method of claim 17, wherein the humectant is from about 0.1% w / v to about 20% w / v relative to the solution.

19. The method of any one of claims 1 to 18, wherein the premix comprises a solubilizer.

20. The method of any one of claims 1 to 19, wherein the premix comprises a taste masking agent.

21. The method of any one of claims 1 to 20, wherein the premix further comprises a pH adjuster.

22. The method of claim 21, wherein the pH adjuster is about 0.1% w / v to about 20% w / v relative to the solution.

23. The method of any one of claims 1 to 22, wherein the premix further comprises a dental adhesive.

24. The method of claim 23, wherein the dental adhesive powder or gel is about 0.1% w / v to about 10% w / v relative to the solution.

25. The method of any one of claims 1 to 24, wherein the step of casting a solution further comprises drying the solution.

26. The method according to any one of claims 1 to 25, wherein the method further comprises the step of ultraviolet sterilizing the film or sheet.

27. The method according to any one of claims 1 to 26, wherein the method further comprises the step of further dehydrating the film or sheet.

28. The method of any one of claims 1 to 27, wherein the film or sheet is characterized by a thickness of about 0.05 mm to about 1.0 mm.

29. The method of any one of claims 1 to 28, wherein the film or sheet is characterized by a disintegration time of about 10 seconds to about 15 minutes.

30. The method of any one of claims 1 to 29, wherein the film or sheet is characterized by a pH of about 2 to about 8.

31. The method of any one of claims 1 to 30, wherein the film or sheet is characterized by an endurance of greater than about 100 folds.

32. The method of any one of claims 1 to 31, wherein the film or sheet is characterized by a strength of at least 50 N / cm 2 Young's modulus.

33. The method of any one of claims 1 to 32, wherein the film or wafer is for sublingual, buccal and / or sublabial administration.

34. The method of any one of claims 1 to 33, wherein the drug is an injectable drug.

35. A film or sheet for oral administration of a drug, comprising: a) from about 1 mg / mL to about 200 mg / mL of the drug, relative to the film and / or sheet; b) from about 0.1% w / v to about 20% w / v of a film-forming polymer, relative to the film and / or sheet; c) from about 0.1% w / v to about 20% w / v of a humectant, relative to the film and / or sheet; The drug is characterized by at least one of the following: i) a unit dose of less than about 200 mg; ii) a volume of less than about 2 mL; iii) chemical and / or physical stability at less than about 60°C; and iv) a solubility in the solvent medium exceeding about 10 mg / mL.

36. A premix for forming a film or sheet for oral administration of a drug, the premix comprising: a) from about 0.1% w / v to about 20% w / v of a film-forming polymer, relative to the premix; and b) from about 0.1% w / v to about 20% w / v of a humectant, relative to the premix.

37. The premix of claim 36, comprising at least three film-forming polymers, each of the three film-forming polymers independently being present at about 0.1% w / v to about 20% w / v relative to the premix.

38. A method of treating a disease or disorder treatable by a drug, said method comprising formulating said drug as a film or wafer as disclosed herein, and administering a therapeutically effective amount of said film and / or wafer to a subject in need thereof by sublingual, buccal and / or sublabial administration.

39. A film or wafer for use in treating a disease or disorder treatable by a drug, wherein the film and / or wafer comprises the drug and is administrable sublingually, buccally and / or sublabially.

40. Use of a film or wafer in the preparation of a medicament for treating a disease or disorder treatable by a pharmaceutical, wherein the film and / or wafer comprises the medicament and is administrable sublingually, buccally and / or sublabially.

41. A system for formulating a drug into a film or sheet, the system comprising: a) a medicine receiving module for receiving medicine; b) a premix module for containing a premix and introducing the premix into a medicine; c) a mixing module for mixing the drug with the premix to form a solution; d) a metering and dispensing module for dispensing the solution; e) a mold for containing the dispensed solution; and f) a curing module for curing the solution in the mold into a film or sheet.

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