DE202019005745U1 - Orodispersible tablets comprising glycopyrrolate with increased bioavailability - Google Patents

Abstract

Porous orodispersible tablet with microscopic pores comprising a therapeutically effective amount of glycopyrrolate,
the porous orodispersible tablet with microscopic pores in the mouth disintegrates in less than 60 seconds,
wherein the porous orodispersible tablet with microscopic pores is produced by freeze-drying a liquid formulation with a pH in the range from 4.0 to 6.5, preferably in the range from 4.0 to 5.0, the liquid formulation having at least one filler , at least one binder, at least one emulsifier, at least one disintegrant and water; and
wherein the porous orodispersible tablet with microscopic pores preferably has an increased bioavailability compared to a reference tablet which comprises the same amount of glycopyrrolate.

Description

TECHNICAL AREA

This disclosure relates to porous orodispersible glycopyrrolate tablets with increased bioavailability for administration to a patient.

BACKGROUND

Glycopyrrolate is a quaternary ammonium compound with the following chemical name: 3 - [(Cyclopentylhydroxyphenylacetyl) oxy] -1,1-dimethylpyrrolidinium bromide. The molecular formula is C ₁₉ H ₂₈ BrNO ₃ , the molecular weight is 398.33. Glycopyrrolate is an active component of the drug ROBINUL ^R.

Glycopyrrolate is an anticholinergic drug and is known to antagonize muscarinic symptoms. Hence, it can be used to control the volume and free acidity of gastric secretions. Glycopyrrolate can also be used to control excessive pharyngeal, tracheal, or bronchial secretions. Glycopyrrolate is used in the preoperative phase or during sedation as a complementary therapy to anesthesia. Glycopyrrolate can also be used to counteract some of the post-operative effects.

However, not all patients tolerate an oral glycopyrrolate formulation that does not easily dissolve in the patient's saliva and may need to be swollen as an intact tablet with water. In pharmacokinetic studies carried out in children and adults, it has been shown that glycopyrrolate is poorly absorbed after oral administration, with a bioavailability between 1 and 20%. In addition, the absorption varies considerably from one patient to another. ( Buck et al. 2010 ).

Some patients, including those with swallowing problems, may not be able to swallow a glycopyrrolate tablet. Oral glycopyrrolate is not recommended for these patients, but it is difficult to administer glycopyrrolate systemically several times a day. In addition, glycopyrrolate must be used with caution in patients with liver or kidney disease. The injectable form of glycopyrrolate usually contains 0.9% benzyl alcohol as a preservative. (Buck et al. 2010). However, excessive amounts of benzyl alcohol can lead to hypotension and metabolic acidosis. Accordingly, injectable forms of glycopyrrolate may not be suitable for newborns and should be used with caution in older infants. (Buck et al. 2010).

Therefore, there is a need for glycopyrrolate orodispersible tablets with increased bioavailability, since such formulations can be taken without water and these formulations with lower glycopyrrolate dosages can be therapeutically effective which would reduce the burden on the liver and / or kidneys of the patient.

U.S. 7,091,236 discloses that the bioavailability of glycopyrrolate can be increased when a liquid formulation of glycopyrrolate is administered without food. However, these liquid formulations are intended for patients who have difficulty swallowing, e.g. B. pediatric or geriatric patients may not be suitable. Some orodispersible glycopyrrolate tablets used to treat sialorrhea are out PCT / US2008 / 061025 and US 2008/0260823 known, but there is a need for glycopyrrolate orodispersible tablets with an increased bioavailability, especially for geriatric patients, pediatric patients or patients with neurological disorders.

U.S. 5,298,261 provides methods for making vacuum dried tablets, but there are in U.S. 5,298,261 there is no indication that this method can be used with a quaternary amine compound without compromising the bioavailability of the compound.

SUMMARY

In one aspect, the present disclosure provides a porous orodispersible tablet having microscopic pores and containing a therapeutically effective amount of glycopyrrolate. The porous orodispersible tablets disintegrate in the mouth in less than 60 seconds and are produced by freeze-drying a liquid suspension with a pH in the range from 4.0 to 6.5, the liquid suspension having at least one filler, at least one binder and at least one emulsifier , at least one disintegrant and water contains. The porous orodispersible tablet has an increased bioavailability compared to a reference tablet that contains the same amount of glycopyrrolate. The therapeutically effective amount of glycopyrrolate can range from 0.5 mg to 5 mg per tablet. In the porous orodispersible tablet of this disclosure, the disintegrant can include citric acid, succinic acid, tartaric acid, or any combination thereof. In the porous orodispersible tablet of this disclosure, the filler may comprise mannitol and the disintegrant may comprise citric acid. In the porous orodispersible tablet of this disclosure, the disintegrant can comprise citric acid and the pH of the liquid suspension is in the range of 4.0 to 5.0. In the porous orodispersible tablet of this disclosure, the filler may comprise mannitol, starch, modified starch, microcrystalline cellulose, xylitol, or any mixtures thereof. In the porous orodispersible tablet of this disclosure, the binder can comprise gelatin, natural gum, synthetic gum, xanthan gum, gum acacia, pregelatinized starch, starch, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyacrylamide, or any mixtures thereof. In the porous orodispersible tablet of this disclosure, the emulsifier Gelucire 44/14; Gelucire 50/13; Imwitor 91; Imwitor 308; Imwitor 380; Imwitor 742; Imwitor 780K; Imwitor 928; Imwitor 988; Poloxamer 124; Poloxamer 188 or any mixtures thereof. The porous orodispersible tablet of this disclosure may further comprise one or more of the following ingredients: a sweetener, a flavor, a color, an antibacterial agent, an antifungal agent, an absorption enhancer, a taste masking agent, a lubricant, and / or a wetting agent. In one embodiment, the porous orodispersible tablet of this disclosure can further comprise sucralose and at least one flavor enhancer. In another embodiment, the porous orodispersible tablet of this disclosure can further comprise one or more of the following substances: sucralose, sucrose, glucose, aspartame, fructose, sorbitol, saccharin, cyclamate or any mixtures thereof.

The porous orodispersible tablets of this disclosure can be used to treat sialorrhea, control the excessive production of gastric acid, control excessive sweating, and / or treat stomach and / or abdominal pain. The porous orodispersible tablets of this disclosure can be used as a medicament for a patient suffering from at least one of the following diseases: stroke, facial paralysis, facial cancer, throat cancer, esophageal cancer, mental retardation, Alzheimer's disease, Parkinson's disease, cerebral palsy, amyotrophic lateral sclerosis, Gastric ulcer, intestinal ulcer, thyroid disease, or neuromuscular disease.

In another aspect, this disclosure provides porous orodispersible tablets with microscopic pores for use in the treatment of sialorrhea, controlling excessive production of gastric acid, controlling excessive sweating, and / or treating stomach and / or abdominal pain. This medical use includes administering to the patient the porous orodispersible tablet of this disclosure, the porous orodispersible tablet comprising a therapeutically effective amount of glycopyrrolate. The patient may have at least one of the following diseases: stroke, facial paralysis, facial cancer, throat cancer, esophageal cancer, mental retardation, Alzheimer's disease, Parkinson's disease, cerebral palsy, amyotrophic lateral sclerosis, gastric ulcer, colon ulcer, thyroid disease, or neuromuscular disease. The porous orodispersible tablet of this disclosure can be administered without water. The patient can be a pediatric or geriatric patient and / or the patient has difficulty swallowing. The porous orodispersible tablet can be administered in conjunction with an anesthetic.

Other aspects of this disclosure include microscopic pore porous orodispersible tablets of this disclosure for use in treating a patient comprising administering the porous orodispersible tablet to the patient during induction of anesthesia, intubation, or after surgery.

Other aspects of this disclosure include microscopic pore porous orodispersible tablets of this disclosure for use in treating a patient for surgical or drug induced arrhythmia comprising administering to the patient the porous orodispersible tablet of this disclosure. The patient may be in treatment for drug addiction.

• - Mischen einer Suspension auf Wasserbasis von Glycopyrrolat in einer Menge von 0,5 mg bis 5 mg pro Dosis mit mindestens einem Füllstoff, mindestens einem Bindemittel, mindestens einem Emulgator und mindestens einem Sprengmittel;
• - Einstellen eines pH-Wertes der Suspension auf einen Wert im Bereich von etwa 4,0 bis etwa 6,5;
• - Dosieren der Suspension nach Gewicht in Blisterformen;
• - Gefrieren der Suspension in den Formen; und
• - Trocknen der gefrorenen Suspension unter Vakuum und Sublimieren von Wasser, um so die poröse Schmelztablette gemäß dieser Offenbarung zu erhalten.

In a further aspect, a possibility for producing the porous orodispersible tablet with microscopic pores is also described, which contains a therapeutically effective amount of glycopyrrolate, comprising:

• - Mixing a water-based suspension of glycopyrrolate in an amount of 0.5 mg to 5 mg per dose with at least one filler, at least one binder, at least one emulsifier and at least one disintegrant;
• Adjusting a pH of the suspension to a value in the range from about 4.0 to about 6.5;
• - Dosing the suspension by weight in blister forms;
• - Freezing the suspension in the molds; and
• Drying the frozen suspension under vacuum and subliming water so as to obtain the porous orodispersible tablet according to this disclosure.

In the above procedure, the disintegrant can include citric acid, succinic acid, tartaric acid, or any combination thereof; the filler can comprise mannitol and the disintegrant citric acid; the disintegrant can comprise citric acid and the pH of the liquid suspension can range from 4.0 to 5.0. The filler can comprise mannitol, starch, modified starch, microcrystalline cellulose, xylitol, or any mixtures thereof. The binder can include gelatin, natural gum, synthetic gum, xanthan gum, acacia gum, pregelatinized starch, starch, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyacrylamide, or any mixtures thereof. The emulsifier can be Gelucire 44/14; Gelucire 50/13; Imwitor 91; Imwitor 308; Imwitor 380; Imwitor 742; Imwitor 780K; Imwitor 928; Imwitor 988; Poloxamer 124; Poloxamer 188 or any mixtures thereof. The suspension can also be mixed with one or more of the following substances: a sweetener, a flavor, a color, an antibacterial agent, an antifungal agent, an absorption enhancer, a taste masking agent, a lubricant and / or a wetting agent. The suspension The suspension can also be mixed with one or more of the following substances: sucralose, sucrose, glucose, aspartame, fructose, sorbitol, saccharin, cyclamate or any mixtures thereof.

DETAILED DESCRIPTION

This disclosure provides a porous orodispersible tablet containing a therapeutically effective amount of glycopyrrolate. The tablet will be referred to as a glycopyrrolate orodispersible tablet in the remainder of this disclosure. The glycopyrrolate orodispersible tablets of this disclosure have increased bioavailability compared to other oral glycopyrrolate tablets comprising the same amount of glycopyrrolate. The glycopyrrolate orodispersible tablets of this disclosure disintegrate in the mouth into a suspension in less than 60 seconds, so that these tablets can be taken without water, even by patients with swallowing disorders or facial paralysis. Therefore, the glycopyrrolate orodispersible tablets of this disclosure are particularly beneficial to pediatric patients, geriatric patients, and other patients who may otherwise not be able to swallow their medication with water.

Because the glycopyrrolate orodispersible tablets of this disclosure have increased bioavailability, patients can take glycopyrrolate in lower dosages. For example, a patient may take 0.5 mg, 1 mg, 1.5 mg, or 1.75 mg glycopyrrolate instead of 2 mg glycopyrrolate per dose. Because of the increased bioavailability, the glycopyrrolate orodispersible tablets may be therapeutically effective at lower glycopyrrolate dosages, and therefore these tablets may help avoid or minimize at least some of the undesirable effects of glycopyrrolate, including xerostomia, decreased sweating, urinary retention and urgency, blurred vision, tachycardia, palpitations, headache, dizziness, nausea, vomiting, nervousness and other reactions.

The glycopyrrolate orodispersible tablet of this disclosure is a solid dosage form. The glycopyrrolate orodispersible tablet of this disclosure is porous and its surface includes microscopic pores. The glycopyrrolate orodispersible tablet of this disclosure disintegrates rapidly in the mouth, creating a suspension that can be easily swallowed by a patient without water. The glycopyrrolate orodispersible tablet is especially beneficial for people who may have difficulty swallowing their medication. These include patients with swallowing disorders, pediatric patients, geriatric patients, stroke patients, patients with brain injuries, patients with a thyroid disease or a neurological disorder.

The glycopyrrolate orodispersible tablet of the present disclosure can be administered to any patient whose condition or symptom is treated with a glycopyrrolate-containing formulation can be improved. These patients include cancer patients, especially cancer patients who have cancer of the face, throat, or esophagus. Other patients include patients with neurological disorders or neurological dysfunction, including mental retardation, facial paralysis, excessive salivation (sialorrhea), Alzheimer's disease, Parkinson's disease, cerebral palsy, or amyotrophic lateral sclerosis. The glycopyrrolate orodispersible tablet of this disclosure can be used for patients with gastrointestinal disorders, including gastrointestinal ulcers or other gastrointestinal disorders in which excessive production of gastric acid and / or abnormal bowel contractions are controlled and / or gastric / Abdominal pain needs to be treated to be of benefit.

In this disclosure, the term "treating or controlling a symptom" is understood to mean providing treatment that minimizes or eliminates the symptom at least for a period of time, e.g. B. until the next dose of glycopyrrolate has to be taken to control / treat the symptom. The level of treatment can be determined by the patient or the caregiver, e.g. B. when the patient and / or the caregiver report less salivation or less pain.

Intravenous injection or intramuscular administration with a syringe is typically used for patients unable to swallow their medication, but it may be desirable to administer glycopyrrolate orally. In addition, certain side effects can be avoided when glycopyrrolate is administered orally. The glycopyrrolate orodispersible tablets of the present disclosure meet these and other needs.

The glycopyrrolate orodispersible tablets of this disclosure have increased bioavailability compared to other oral tablets comprising glycopyrrolate. Glycopyrrolate must be used with caution in patients with liver or kidney disease. Because the glycopyrrolate orodispersible tablets of this disclosure have increased bioavailability, the glycopyrrolate orodispersible tablets with lower glycopyrrolate dosages can be therapeutically effective, which can reduce stress on the liver and / or kidneys.

The increased bioavailability of the glycopyrrolate orodispersible tablets of this disclosure includes both a statistically significant increase in the rate of glycopyrrolate absorption and a statistically significant increase in the extent of glycopyrrolate absorption. The glycopyrrolate orodispersible tablet of this disclosure can increase the amount of glycopyrrolate absorption by at least 10%, preferably by at least 20%, compared to an oral glycopyrrolate reference tablet that contains the same amount of glycopyrrolate but is not a porous orodispersible tablet. In addition, the glycopyrrolate orodispersible tablet of this disclosure can be taken without water, while other oral glycopyrrolate tablets are taken with substantial amounts of water, e.g. B. with a glass of water (about 240 ml of water).

Glycopyrrolate exists in four different stereoisomeric forms: (R, R) -glycopyrrolate and (S, S) -glycopyrrolate, (R, S) -glycopyrrolate and (S, R) -glycopyrrolate. In some embodiments, a glycopyrrolate formulation of this disclosure comprises a mixture of at least two of four stereoisomers: at least one mixture of (R, R) -glycopyrrolate and (S, S) -glycopyrrolate; at least one mixture of (R, R) -glycopyrrolate and (R, S) -glycopyrrolate or at least one mixture of (R, R) -glycopyrrolate and (S, R) -glycopyrrolate. In some embodiments, a glycopyrrolate formulation of this disclosure comprises a mixture of any three of the four stereoisomers. In some embodiments, a glycopyrrolate formulation comprises a mixture of all four stereoisomers. In other embodiments, the formulation comprises only one stereoisomer: (R, R) -glycopyrrolate, (S, S) -glycopyrrolate, (R, S) -glycopyrrolate or (S, R) -glycopyrrolate.

The term “therapeutically effective amount of glycopyrrolate” is to be understood broadly and means a dosage of glycopyrrolate that is effective to treat, alleviate and / or at least partially ameliorate at least some of the patient's symptoms. The therapeutically effective amount of glycopyrrolate can be adjusted by a doctor based on the patient's age, weight, severity of symptoms, glycopyrrolate tolerance, and other factors.

The therapeutically effective amount of glycopyrrolate can range from 0.1 mg to 10 mg per oral tablet. Preferably, the therapeutically effective amount of glycopyrrolate can range from 0.5 mg to 5 mg per oral tablet. The glycopyrrolate orodispersible tablets of this disclosure particularly preferably comprise 0.5 mg to 3 mg glycopyrrolate per tablet. Preferred formulations can be 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 2.75 mg or 3 mg glycopyrrolate per tablet include. The glycopyrrolate orodispersible tablets of this disclosure can be taken one to four times daily, e.g. Two or three times a day, and the dosage and schedule of administration can be further adjusted by a doctor as needed. The effective dosage of glycopyrrolate is based on body weight, among other factors. In children, the dose and schedule of administration should be determined by a doctor. The dose can range from 0.01 mg glycopyrrolate to 0.05 mg glycopyrrolate per kilogram of body weight three times a day. A doctor can adjust this dosage and the administration schedule individually for each patient.

The glycopyrrolate tablet formulations of this disclosure dissolve orally. These tablets disintegrate or dissolve quickly in the patient's mouth in less than 60 seconds. The patient does not have to swallow an intact tablet or chew it. Instead, the tablet disintegrates quickly in the mouth. In addition, glycopyrrolate orodispersible tablets of this disclosure can be made without water or with only a minimal amount of water, e.g. B. a sip of water.

Rapid oral disintegration means that a tablet breaks up into smaller pieces and / or the tablet is at least partially dissolved and / or forms a suspension shortly after the tablet has been placed in the mouth. In a preferred embodiment, the glycopyrrolate orodispersible tablet formulations of the present disclosure are taken orally and disintegrate in the mouth in less than 1 minute, less than 50 seconds, less than 40 seconds, less than 30 seconds, less than 20 seconds, or less than 10 seconds after putting them in the mouth. Preferably, the orodispersible glycopyrrolate tablets of this disclosure disintegrate in the mouth within 20 to 50 seconds. The glycopyrrolate orodispersible tablets of this disclosure do not require water to be swallowed. Thus, the present glycopyrrolate orodispersible tablets make oral glycopyrrolate formulations available to patients who have difficulty swallowing and / or who cannot swallow water. These patients can include pediatric patients, patients with neurological disorders, geriatric patients, and other patients who cannot swallow water and / or fluids.

The glycopyrrolate orodispersible tablets of this disclosure are porous. The glycopyrrolate orodispersible tablet of this disclosure is interspersed with microscopic pores. The pore diameter can range from 5 to 20 micrometers. In some tablets according to this disclosure, the mean pore diameter can range from 10 µm to 15 µm.

The glycopyrrolate orodispersible tablets of this disclosure comprise several ingredients, each of which will now be described. All percentages of the ingredients in the glycopyrrolate orodispersible tablets described in this disclosure are calculated as percentages by weight, unless otherwise stated.

The glycopyrrolate orodispersible tablets of this disclosure are prepared as liquid formulations (suspensions) with water as the main solvent, which can be used in combination with other co-solvents. The liquid formulations for the glycopyrrolate orodispersible tablets of this disclosure can contain between 40 and 90% by weight of water. The liquid formulations are subjected to freeze drying, in which the water is sublimed, and the glycopyrrolate orodispersible tablets are produced.

The glycopyrrolate orodispersible tablets of this disclosure can comprise between 0.1 mg and 10 mg glycopyrrolate per oral tablet. Preferably, the orodispersible glycopyrrolate tablets of this disclosure comprise 0.5 mg to 5 mg glycopyrrolate per oral tablet. Most preferably, the orodispersible glycopyrrolate tablets of this disclosure comprise 0.5 mg to 3 mg glycopyrrolate per tablet.

The glycopyrrolate orodispersible tablets of the present disclosure can further contain one or more excipients, which are composed of a filler (filler), a binder (gelling agent), a dispersant (emulsifier), a sweetener, a flavor, a disintegrant, a lubricant, a color, a preservative and / or a wetting agent are selected.

Suitable fillers include mannitol, various starches, microcrystalline cellulose, xylitol or any mixtures thereof. Preferably, the orodispersible glycopyrrolate tablets of this disclosure comprise mannitol. Typically, the filler, such as mannitol, is used in the glycopyrrolate orodispersible tablets of this disclosure in an amount of 1 to 20% by weight of the liquid formulation prior to freeze drying, including water. Preferably, the filler, such as. B. mannitol, in an amount from 1 to 10% by weight of the liquid formulation, including water, used prior to freeze drying. Most preferably the filler, such as mannitol, is used in an amount of 1 to 5% by weight of the liquid formulation prior to freeze drying, including water.

Suitable binders (gelling agents) include gelatin, natural gum, synthetic gum, xanthan gum, acacia gum, pregelatinized starch, starch, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyacrylamide or any mixtures thereof. Preferably, glycopyrrolate orodispersible tablets of this disclosure comprise gelatin. Typically, the binder, such as gelatin, is used in an amount of 1 to 20% by weight of the liquid formulation prior to freeze drying, including water, for the orodispersible glycopyrrolate tablets of this disclosure. Preferably, the binder, such as. B. gelatin, in an amount of 1 to 10% by weight of the liquid formulation prior to freeze drying, including water.

Suitable emulsifiers include Gelucire 44/14; Gelucire 50/13; Imwitor 91; Imwitor 308; Imwitor 380; Imwitor 742; Imwitor 780K; Imwitor 928; Imwitor 988; Poloxamer 124; Poloxamer 188 or any mixtures thereof. Other suitable emulsifiers are from the U.S. Patent 9,345,771 known and can also be used. Preferably, the orodispersible glycopyrrolate tablets of this disclosure contain poloxamer 188. Typically, the emulsifier, such as poloxamer 188, is used in an amount of 0.001 to 1% by weight of the liquid formulation prior to freeze drying, including water, for the orodispersible glycopyrrolate tablets of this disclosure . Preferably, the emulsifier, such as. B. Poloxamer 188, in an amount from 0.01 to 0.10% by weight of the liquid formulation prior to freeze drying, including water.

Suitable sweeteners include sucralose, sucrose, glucose, aspartame, fructose, sorbitol, saccharin and its salts, cyclamate and its salts, or any mixtures thereof. Preferably, the orodispersible glycopyrrolate tablets of this disclosure contain sucralose. Typically, the sweetener, such as sucralose, is used in an amount of from 0.001 to 1% by weight of the liquid formulation prior to freeze drying, including water, for the orodispersible glycopyrrolate tablets of this disclosure. Preferably the sweetener such as sucralose is used in an amount of 0.1 to 1.00% by weight of the liquid formulation prior to freeze drying, including water.

Suitable flavors include cherry, black cherry, mint, vanilla, strawberry, grape, cotton candy or other flavors or any mixtures thereof. Typically, the flavor will be used in an amount of from 0.001 to 5% by weight of the total formulation prior to freeze drying, including water. Preferably the flavor is used in an amount of from 0.01% to 1% by weight of the total formulation, including water.

Disintegrants include citric acid, succinic acid and tartaric acid. Other disintegrants can also be used. Preferably, the orodispersible glycopyrrolate tablets of this disclosure contain citric acid. Typically, the disintegrant, such as. B. citric acid, used in an amount sufficient to adjust the pH of the liquid formulation for glycopyrrolate orodispersible tablets to slightly acidic. The pH of the liquid formulation for the glycopyrrolate orodispersible tablets can be in the range from 4.0 to 6.5 and preferably in the range from 4.0 to 5.0. Typically from 0.01 to 1% by weight of the disintegrant, such as citric acid, can be used to adjust the pH of the liquid formulation as needed.

The glycopyrrolate orodispersible tablets of this disclosure may contain some other ingredients such as one or more of the following: a coloring agent, an antibacterial agent, an antifungal agent, an absorption enhancer, a taste masking agent such as e.g. B. sodium bicarbonate, a lubricant and / or a wetting agent.

The glycopyrrolate orodispersible tablets according to this disclosure can comprise ingredients as shown in Table 1. Table 1. Glycopyrrolate orodispersible tablets with improved bioavailability ingredient Amount (% by weight, including water) per tablet Preferred fabric Preferred amount (% by weight, including water) per tablet Glycopyrrolates from 0.1 mg to 10 mg Glycopyrrolates 1.5 mg to 2 mg filler from 1% by weight to 20% by weight Mannitol 1 wt% to 10 wt% binder from 1% by weight to 20% by weight gelatin 1 wt% to 10 wt% Emulsifier from 0.001% by weight to 1% by weight Poloxamer 188 0.01 wt% to 0.10 wt% Sweeteners from 0.001% by weight to 1% by weight Sucralose 0.01 wt% to 1 wt% Flavor from 0.001% by weight to 5% by weight Black cherry flavor 0.01 wt% to 1 wt% Explosives from 0.01 wt% to 1 wt% as needed to adjust to pH 4.0 to 6.5 Citric acid as needed to adjust to pH 4.0 to 6.5 0.01 wt% to 1 wt% Water (sublimed by freeze drying, the finished tablet is dried) from 40% by weight to 95% by weight Water (sublimed by freeze drying, the finished tablet is dried) 50 wt% to 90 wt%

Another aspect of the present disclosure is the glycopyrrolate orodispersible tablet, which comprises further active ingredients in addition to glycopyrrolate. These other agents may include an anti-inflammatory drug and / or an analgesic, among others.

In further aspects, a possibility for producing the glycopyrrolate orodispersible tablet of this disclosure is also described. The glycopyrrolate orodispersible tablet according to this disclosure is produced by lyophilization (freeze drying). In some freeze drying approaches, the liquid formulation containing a therapeutically effective amount of glycopyrrolate is prepared with suitable excipients and water. In some embodiments, the liquid formulation comprises an effective amount of glycopyrrolate, at least one filler, at least one binder, at least one emulsifier, at least one sweetener, at least one flavor and at least one disintegrant. These liquid formulations can be prepared using water as the solvent. In further embodiments, the liquid formulation comprises the ingredients listed in Table 1. In at least some embodiments, the pH of the liquid formulation is adjusted and is in the range of about 4.0 to about 6.5. In some embodiments, the pH of the suspension is adjusted and ranges from about 4.0 to about 5.0.

Preferred liquid formulations contain glycopyrrolate in an amount of 0.5 mg to 2 mg per tablet, mannitol, gelatin, poloxamer 188, sucralose, at least one flavoring agent, citric acid and water. The pH of the liquid formulation is adjusted and is in the range from 4.0 to 5.0.

The resulting liquid formulation, which is a suspension, can be dosed according to weight into individual pre-formed blister forms in a fully automatic, continuous filling process. It is important that the suspension remains homogeneous during dosing. This process is regulated and monitored to ensure that each dose contains the exact amount of the active ingredient - glycopyrrolate.

After filling, the blister forms are passed through a freezer tunnel cooled with liquid nitrogen. A freezing step can be carried out at a temperature in the range of -40 ° C to -80 ° C. This freezes the water in the glycopyrrolate suspension and it is ready for storage at low temperatures before the freeze-drying process. As soon as a sufficient number of blister forms have been filled and frozen, water sublimation can begin by drying the blister forms. the Blister forms are placed in a freeze dryer. As a result of drying, the frozen water evaporates from the solid phase into the gas phase and creates microscopic pores in the tablet formulation. During the primary drying, the temperature is kept below freezing point. As a rule, the temperature of the primary drying is in the range from -10 ° C to -20 ° C. This step is carried out in a vacuum, e.g. B. at a pressure of about 0.1 mbar or less. In a subsequent secondary drying step, the temperature can be increased to room temperature (usually 20 ° C). This secondary drying step can also be carried out in a vacuum.

When the freeze drying is complete and the water has sublimed, the blister forms are passed through a blister sealing machine where they are sealed with aluminum foil or a suitable paper laminate. The sheets of the blister forms are cut to the correct size and the foil is perforated to facilitate opening by the patient.

In further aspects, this disclosure provides a kit that includes the glycopyrrolate porous orodispersible tablets of this disclosure, prescribing information, and a container such as. B. a plastic bottle, a box and / or a sheet with blister forms comprises. The container can be a sheet of blister forms. The prescribing information can be printed on the sheet of blister molds.

In further aspects, this disclosure relates to porous orodispersible tablets with microscopic pores according to the present disclosure for use in a treatment which comprises the administration of the porous glycopyrrolate orodispersible tablet of this disclosure to a patient, which can be administered without water and which can also be used as adjunctive therapy other drugs and treatments. Patients include those on treatment for sialorrhea (excessive salivation), treatment for excessive sweating, prevention of vomiting, treatment for excessive gastric acid secretion, treatment for excessive bowel contractions, and / or treatment for stomach and / or abdominal pain require. Patients include patients with any of the following diseases or conditions: neurological disorders, motor deficits, cerebral palsy, facial paralysis, mental retardation, Parkinson's disease, Alzheimer's disease, stroke, cancer, thyroid disease, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease , Gastric ulcer, or a neuromuscular disorder. Patients include any other patient in whom an anticholinergic may be of benefit. Patients also include patients with swallowing disorders (dysphagia). Patients also include pediatric and geriatric patients.

In another aspect, the present disclosure provides ways of administering the glycopyrrolate orodispersible tablet of this disclosure in conjunction with a variety of anesthetics, including sedatives and barbiturates. The glycopyrrolate orodispersible tablet of this disclosure may be useful for patients during a preoperative procedure to reduce salivary, tracheobronchial, and pharyngeal secretions.

In another aspect, this disclosure provides ways in which the porous glycopyrrolate orodispersible tablet of this disclosure is administered to a patient without water during induction of anesthesia and / or intubation.

In another aspect, this disclosure provides a porous orodispersible tablet having microscopic pores for use in a treatment wherein the glycopyrrolate porous orodispersible tablet of this disclosure is administered to a patient without water during surgery.

In a further aspect, this disclosure provides a porous orodispersible tablet with microscopic pores for use in a treatment wherein a patient is administered the glycopyrrolate porous orodispersible tablet of this disclosure without water to counteract surgical and / or drug-induced arrhythmias.

The drug-induced arrhythmia can be triggered by narcotics (opioids) or other controlled substances. A patient may be in need of treatment for a drug overdose or in treatment for drug addiction.

Example 1: Comparative analysis of pharmacokinetics and bioavailability

The glycopyrrolate porous orodispersible tablet with 2 mg glycopyrrolate per tablet was prepared by mixing a liquid formulation comprising glycopyrrolate, mannitol, gelatin, poloxamer 188, sucralose, a flavor, citric acid and water as indicated in Table 1. The pH of the liquid formulation was adjusted to 4.0-5.0. This suspension was then freeze-dried and tablets were made. The tablets so produced were used as test glycopyrrolate orodispersible tablets (test ODT) in an analysis of pharmacokinetics and bioavailability, as reported below.

An analysis of the pharmacokinetics and bioavailability was carried out for the glycopyrrolate orodispersible tablet with 2 mg glycopyrrolate (the test ODT). The analysis was performed against an oral reference tablet from Par Pharmaceutical Inc., which also comprised 2 mg of glycopyrrolate, which is referred to as the reference tablet.

The analysis included creating pharmacokinetic (PK) profiles of the test ODT tablet, glycopyrrolate 2 mg, and the reference tablet, glycopyrrolate 2 mg, Par Pharmaceuticals Inc. to assess the potential for local irritation in subjects using the test ODT product were given an appropriate rating, safety included a specific assessment of local (in the mouth) safety, with local irritation and tolerability in the oral cavity (rough visual assessment of redness, pain, and tenderness) rated as adverse events (AE) of particular concern became. The PK profiles of glycopyrrolate were examined after administration of a single dose of 2 mg of each of the two formulations under fasting conditions.

It was an open, laboratory-blinded, randomized, two-phase crossover study with a single dose of 2 mg orally administered glycopyrrolate, which was carried out on up to 16 healthy male and female volunteers in a single study center under fasting conditions. All study participants signed a declaration of consent before participating in the study.

The subjects received either the test ODT tablet or the reference tablet according to a randomization scheme under fasting conditions. The subjects received each tablet once.

In accordance with the bioavailability / bioequivalence guidelines, the dosage in this study comprised a single oral dose of 2 mg glycopyrrolate (as tablets) at two separate time points under fasting conditions. The administered dose is recommended in adults (18 years of age and older) for the treatment of chronic heavy salivation. After an overnight fasting period of at least 10 hours, the subjects received either the reference tablet or the test ODT tablet (according to the randomization scheme). The reference tablet was swallowed whole with 240 mL water. The test ODT tablet was placed on the tongue until it disintegrated and then swallowed without water.

Safety variables included adverse event reporting, vital signs, physical examination, oral tolerability assessment including oral mucosal assessment, a 12-lead EKG, and laboratory tests (hematology, clinical chemistry, urinalysis, and pregnancy tests). The previous and accompanying medication was also recorded. Each subject was carefully monitored for adverse events by the investigator. In addition, information about adverse events was obtained from the subjects by questioning them regularly, but no leading questions were asked. The data from 15 subjects who completed the study were included in the pharmacokinetic analysis.

• ■ Primäre PK-Parameter für Glycopyrrolat:
  • • Maximale beobachtete Plasmakonzentration (Cmax);
  • • Fläche unter der Kurve der Plasmakonzentration über der Zeit, vom Zeitpunkt Null bis t, wobei t der Zeitpunkt der letzten quantifizierbaren Konzentration ist (AUC(o-t)); und
  • • Fläche unter der Kurve der Plasmakonzentration über der Zeit mit Extrapolation ins Unendliche (AUC(o-∞)).
• ■ Sekundäre PK-Parameter für Glycopyrrolat:
  • • Zeit bis zur maximalen beobachteten Plasmakonzentration (t_max);
  • • terminale Eliminationsratenkonstante (λz); und
  • • apparente terminale Eliminationshalbwertszeit (t½z).

The following pharmacokinetic parameters (PK) have been studied:

• ■ Primary PK parameters for glycopyrrolate:
  • • Maximum observed plasma concentration (Cmax);
  • • Area under the curve of plasma concentration versus time, from time zero to t, where t is the time of the last quantifiable concentration (AUC (ot)); and
  • • Area under the curve of the plasma concentration over time with extrapolation to infinity (AUC (o-∞)).
• ■ Secondary PK parameters for glycopyrrolate:
  • • Time to maximum observed plasma concentration (t _max );
  • • Terminal elimination rate constant (λz); and
  • • apparent terminal elimination half-life (t½z).

Safety variables included adverse event reporting, vital signs, physical examination, oral tolerability assessment including oral mucosal assessment, a 12-lead EKG, and laboratory tests (hematology, clinical chemistry, urinalysis, and pregnancy tests). The previous and accompanying medication was also recorded.

Table 2 summarizes the descriptive statistics of the PK parameters. Table 2. Plasma pharmacokinetic parameters of glycopyrrolate (pg / ml) (pharmacokinetic population) Reference tablet statistics Cmax (pg / mL) AUC (0-t) (h • pg / mL) AUC (0-∞) (h • pg / mL) tmax (h) λ _z (1 / h) t _½.z (h) n 15th 15th 15th 15th 15th 15th Average 490.1 2513 2681 - 0.3088 2,365 SD 410.7 1484 1567 - 0.06808 0.6166 CV% 83.8 59.1 58.5 - 22.0 26.1 Median 433.7 2127 2213 3,501 0.3074 2.255 minimum 83.40 645.1 669.6 1.51 0.1699 1,591 maximum 1829 6724 7029 6.01 0.4357 4.079 geometric mean 390.1 2180 2324 - 0.3013 2.301 geometric CV% 77.9 60.2 60.6 - 24.0 24.0 Test ODT tablet statistics Cmax (pg / mL) AUC _(0-t) (h • pg / mL) AUC _(0-∞) (h • pg / mL) t _max (h) λ _z (1 / h) t _½.z (h) n 15th 15th 15th 15th 15th 15th Average 619.4 3165 3386 - 0.2980 2,494 SD 490.4 2349 2451 - 0.06550 0.8903 CV% 79.2 74.2 72.4 - 22.0 35.7 Median 426.0 2305 2452 3.010 0.2980 2,326 minimum 150.0 1030 1089 1.01 0.1260 1.710 maximum 2017 9178 9503 6.00 0.4054 5.502 geometric mean 499.0 2631 2818 - 0.2894 2,395 geometric CV% 72.7 64.2 64.9 - 27.5 27.5
CV = coefficient of variation; n = number of people examined; SD = standard deviation. Reference product (A): Glycopyrrolate 2 mg tablet, Par Pharmaceutical Inc., USA, administered under fasting conditions.
Test product (B): glycopyrrolate 2 mg orodispersible tablet according to the present disclosure, administered under fasting conditions.

The test ODT product was compared with the reference product with regard to the PK parameters for glycopyrrolate, an analysis of variance with sequence, test subject (test subject sequence), product and period effects after logarithmic transformation of the data was carried out. Point estimates and 90% CI were calculated for the geometric mean values of the “test / reference” ratio of these parameters in relation to the acceptance range of 80.00% to 125.00%.

Table 3 is a summary of the statistical analyzes of the pharmacokinetic parameters of glycopyrrolate in plasma. Table 3. Summary of statistical analyzes of plasma glycopyrrolate pharmacokinetic parameters Parameter (unit) LS % Ratio (test / reference) 90% confidence interval of the ratio Intra CV (%) Test ODT product Reference product AUC _(0-∞) (h • pg / mL) 2823.18 2332.10 121.06 102.26; 143.31 26.49 AUC _(0-t) (h • pg / mL) 2638.22 2187.94 120.58 101.45; 143.32 27.14 C _max (pg / mL) 501.41 393.21 127.52 103.67; 156.86 32.78 t _max (h) (median) 3.01 3.50 p-value: 0.7101
CV = coefficient of variation; LS = least square mean; n: number of subjects evaluated (n = 15)
Reference product (A): Glycopyrrolate 2 mg tablet, Par Pharmaceutical Inc., USA, administered under fasting conditions.
Test product (B): Glycopyrrolate 2 mg, orodispersible tablet according to this disclosure, administered under fasting conditions.

After administration of a single dose of the test product and the reference product, the median maximum plasma concentrations of glycopyrrolate were 3.50 hours for the reference product and 3.01 hours for the test product after administration (p-value = 0.7101).

The point estimates of the mean test / reference ratios of the primary parameters Cmax, AUC _(0-t) , and AUC _(0-∞) for glycopyrrolate are 127.52%, 120.58% and 121.06%, respectively.

The term “confidence interval” is abbreviated as KI. The 90% CI for the mean "test / reference" ratios of the primary parameters Cmax, AUC _(0-t) , and AUC _(0-∞) for glycopyrrolate are 103.67% to 156.86%, 101.45% up to 143.32% or 102.26% to 143.31%.

The pharmacokinetic results and conclusions from this study are as follows. The bioavailability study was carried out to compare the plasma concentrations of the test ODT product with those of the reference product, glycopyrrolate 2 mg tablets. The study design was a randomized two-phase crossover study with a single dose and a washout phase of 3 to 14 calendar days between glycopyrrolate doses. The data of 15 evaluable test subjects were analyzed. There was no carry-over of glycopyrrolate between the two treatment periods and all values prior to administration in treatment period 2 were recorded as zero.

The dissolution time of the test ODT product was between 11 and 50 seconds with an arithmetic mean dissolution time of 28 seconds.

The bioavailability was compared using the primary PK parameters of glycopyrrolate. For Cmax, the mean ratio was 127.52% with a 90% CI between 103.67% and 156.86%. The mean ratio of AUC _(0-t) was 120.58% with a CI between 101.45% and 143.32%. The mean ratio of AUC _(0-∞) was 121.06% with a CI between 102.26% and 143.31%. The tmax was respectively 3.50 hours and 3.01 hours for the reference tablet and the test ODT tablet and did not differ statistically between the two products. The upper limit of the 90% CI for all primary PK parameters was outside the predefined acceptance limits of 80.00% to 125.00%.

Based on the above results, it was concluded that the reference product, glycopyrrolate 2 mg tablets, and the test ODT product, glycopyrrolate 2 mg in orodispersible tablet according to this disclosure are not equivalent in terms of both rate and extent of absorption . The test ODT product has a higher rate of absorption and a higher extent of absorption, leading to the conclusion that the bioavailability in the glycopyrrolate orodispersible tablets according to the present disclosure is increased compared to an oral glycopyrrolate reference tablet.

The test ODT drug was well tolerated by all subjects (5 subjects had 8 AEs) during treatment with 2 mg glycopyrrolate per treatment period. The most common AE was dry throat, which occurred in 2 subjects. All dry throat events were considered by the investigator to be related to the investigational drug and of low intensity. No redness, swelling or erosion / ulceration occurred in any of the test subjects after administration of the test product. The results of the laboratory tests, vital signs assessment, EKGs, and physical exam were as expected for a healthy male and female population.

The results of this study suggest that the test ODT drug is not equivalent to the reference tablet in terms of the rate and extent of absorption of glycopyrrolate. The test ODT tablet has increased bioavailability including an increase in the rate and extent of absorption of glycopyrrolate.

QUOTES INCLUDED IN THE DESCRIPTION

This list of the documents listed by the applicant was generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Patent literature cited

• US 7091236 [0007]
• US 2008061025 PCT [0007]
• US 2008/0260823 [0007]
• US 5298261 [0008]
• US 9345771 [0036]

Non-patent literature cited

• Buck et al. 2010 [0004]

Claims (9)

Porous orodispersible tablet with microscopic pores comprising a therapeutically effective amount of glycopyrrolate, the porous orodispersible tablet with microscopic pores in the mouth disintegrates in less than 60 seconds, wherein the porous orodispersible tablet with microscopic pores is produced by freeze-drying a liquid formulation with a pH in the range from 4.0 to 6.5, preferably in the range from 4.0 to 5.0, the liquid formulation having at least one filler , at least one binder, at least one emulsifier, at least one disintegrant and water; and wherein the porous orodispersible tablet with microscopic pores preferably has an increased bioavailability compared to a reference tablet which comprises the same amount of glycopyrrolate. Porous orodispersible tablet with microscopic pores after Claim 1 wherein the therapeutically effective amount of glycopyrrolate is in the range from 0.5 mg to 5 mg per tablet, preferably in the range from 0.5 mg to 3 mg, more preferably in the range from 0.5 mg to 2 mg, and most preferably ranges from 1.5 mg to 2 mg. Porous orodispersible tablet with microscopic pores after Claim 1 or 2 wherein the disintegrant comprises citric acid, succinic acid, tartaric acid, or any combination thereof, preferably wherein the disintegrant comprises citric acid and the pH of the liquid formulation is in the range from 4.0 to 5.0. Porous orodispersible tablet with microscopic pores according to one of the Claims 1 until 3 , wherein the filler comprises mannitol, starch, modified starch, microcrystalline cellulose, xylitol or any mixtures thereof, wherein preferably the filler comprises mannitol and the disintegrant comprises citric acid. Porous orodispersible tablet with microscopic pores according to one of the Claims 1 until 4th wherein the binder comprises gelatin, natural gum, synthetic gum, xanthan gum, acacia gum, pregelatinized starch, starch, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyacrylamide or any mixtures thereof and / or where the emulsifier Gelucire 44/14; Gelucire 50/13; Imwitor 91; Imwitor 308; Imwitor 380; Imwitor 742; Imwitor 780K; Imwitor 928; Imwitor 988; Poloxamer 124; Poloxamer 188 or any mixtures thereof and / or wherein the porous orodispersible tablet with microscopic pores further comprises one or more of the following substances: a sweetener, wherein the sweetener is independently selected from sucralose, sucrose, glucose, aspartame, fructose, sorbitol, saccharin, cyclamate or any mixtures thereof, a flavor, a color, an antibacterial agent, an antifungal agent, an absorption enhancer, a taste masking agent, a lubricant and / or a wetting agent, preferably wherein the porous orodispersible tablet with microscopic pores further comprises sucralose as a sweetener and at least one flavor . Porous orodispersible tablet with microscopic pores according to one of the Claims 1 until 5 for use in the treatment of sialorrhea, for controlling excessive production of gastric acid, for controlling excessive sweating and / or for treating stomach and / or abdominal pain, wherein the porous orodispersible tablet with microscopic pores is preferably administered without water. Porous orodispersible tablet with microscopic pores according to one of the Claims 1 until 5 for use in treatment after Claim 6 , the patient has at least one of the following diseases: stroke, facial paralysis, facial cancer, throat cancer, esophageal cancer, mental retardation, Alzheimer's disease, Parkinson's disease, cerebral palsy, amyotrophic lateral sclerosis, gastric ulcer, colon ulcer, thyroid disease or neuromuscular disease. Porous orodispersible tablet with microscopic pores according to one of the Claims 1 until 5 for use in treatment after Claim 6 or 7th , wherein the patient is a pediatric patient, is a geriatric patient and / or the patient has dysphagia. Porous orodispersible tablet with microscopic pores according to one of the Claims 1 until 5 , the porous orodispersible tablet with microscopic pores having an increased bioavailability compared to a Having reference tablet which contains the same amount of glycopyrrolate, wherein the therapeutically effective amount of glycopyrrolate in the reference tablet is preferably in the range from 0.5 mg to 2 mg per tablet.