ORAL FILM FOR SAFE ADMINISTRATION OF API

Abstract

The present invention relates to dosage units of oral films for the administration of active pharmaceutical ingredients (API), such as analgesics, relaxants, anxiolytics, sedatives, hypnotics, narcotics, anesthetics and/or other API with peripheral and/or central nervous effects, in particular for use in the treatment of pain, metabolic disorders and diseases of the central nervous system (CNS). More particular the invention relates to dosage units of oral films comprising relaxants, anxiolytics, sedatives, hypnotics, narcotics, anesthetics and/or analgesics prone to misuse and abuse, such as overdosing. More particular, the invention relates to dosage units of oral films comprising propofol. In a further aspect, the invention relates to dosage units of oral films comprising propofol for use in the treatment of a subject suffering from migraine.

Claims

1. A dosage unit of a mucoadhesive oral film for use in the treatment of a disease in a subject, preferably a human subject, comprising an active pharmaceutical ingredient (API) characterized in that the dose of said API is selected in such a way that in case of covering all non-keratinized parts of the mouth of said subject by multiple said dosage units, a toxic effect of said API is prevented.

2. The dosage unit according to claim 1 characterized in that the subject is selected from the group of full-grown human subjects and not full-grown human subjects, whereby a. in full-grown human subjects the non-keratinized parts of the mouth have an area of about 150 cm.sup.2, about 130 cm.sup.2, about 110 cm.sup.2; or b. in not full-grown human subjects the non-keratinized parts of the mouth have an area of up to 150 cm.sup.2, up to 130 cm.sup.2, up to 110 cm.sup.2, preferably an area of 45-150 cm.sup.2, of 45-130 cm.sup.2, of 45-110 cm.sup.2.

3. The dosage unit according to claim 1 characterized in that the API is selected from the group of hormones, particular proteohormones, metabolic modulators, growth factors, endogenous peptide analogues, psychiatric medication, anabolic agents, beta2 agonists, hallucinogens, muscle relaxants, analgesics, anxiolytics, sedatives, hypnotics and/or anesthetics.

4. The dosage unit according to claim 1 characterized in that an analgesic, anxiolytic, sedative, hypnotic and/or anesthetic is selected from the group of triptans, ditans such as lasmiditan, NSAIDs, glucocorticoid steroids, salicylates and derivatives, phenylacetic acid derivatives, 2-phenylpropionic acid derivatives, 4-aminophenol derivatives, pyrazolones, selective COX2 inhibitors, anti-depressants, anti-convulsant drugs, opioids, muscle relaxants, barbiturates, benzodiazepines, etomidates, ketamine, propofol, anti-histamines or local anesthetics.

5. The dosage unit according to claim 3 for use in the treatment of a metabolic disorder in a subject in the need thereof, preferably a human subject, characterized in that a hormone, particularly a proteohormone, is selected and the metabolic disorder is selected from the groups of acid-base imbalances, metabolic brain diseases, disorders of calcium metabolism, DNA repair-deficiency disorder, glucose metabolism disorders, hyperlactatemia, iron metabolism disorders, lipid metabolism disorders, malabsorption syndromes, metabolic syndrome X, inborn error of metabolism, mitochondrial diseases, phosphorus metabolism disorders, porphyrias, proteostasis deficiencies, metabolic skin diseases, wasting syndrome and water-electrolyte imbalances.

6. The dosage unit according to claim 5 characterized in that the API is a proteohormon, particularly insulin, and the disease is selected as a glucose metabolism disorder, in particular diabetes.

7. The dosage unit according to claim 1 for use in the treatment of a nervous system disease in a subject in the need thereof, preferably a human subject.

8. The dosage unit according to claim 7 characterized in that the nervous system disease is a primary headache, preferably a migraine.

9. The dosage unit according to claim 7 characterized in that the primary headache is selected as migraine selected from migraine without aura, migraine with aura, migraine with aura without headache, migraine with aura with headache, migraine with brainstem aura, hemiplegic migraine, retinal migraine, chronic migraine, pediatric migraine, menstrual migraine, refractory migraine, intractable migraine or acute confusional migraine (ACM).

10. The dosage unit according to claim 1 characterized in that the dosage unit has an area selected from the ranges of at least 1 cm.sup.2, at least 2 cm.sup.2, at least 3 cm.sup.2, at least 4 cm.sup.2, at least 5 cm.sup.2, at least 6 cm.sup.2, at least 7 cm.sup.2, at least 8 cm.sup.2, at least 9 cm.sup.2, at least 10 cm.sup.2, at least 11 cm.sup.2 or at least 12 cm.sup.2, preferably at least 6 cm.sup.2.

11. The dosage unit according to claim 1 characterized in that the dose of the API is selected as a subtherapeutic dose, preferably selected as not more than 1/10, more preferably not more than 1/35, of a therapeutic dose.

12. The dosage unit according to claim 1 characterized in that the dosage unit has a residence time, wherein the residence time is selected to be at least as long as the systemic half-life of the API.

13. The dosage unit according to claim 1 characterized in that the organoleptic features of the composition for producing the dosage unit do not mask the taste of the dosage unit.

14. The dosage unit according to claim 1 characterized in that the composition for producing the dosage unit is essentially free of flavoring agents and/or sweetening agents.

15. The dosage unit according to claim 1 characterized in that the composition for producing the film of the dosage unit comprises a. solvent up to 95% by weight, up to 90% by weight, up to 80% by weight, up to 70% by, or up to 60% by weight; and b. polymer up to 35% by weight, up to 30% by weight, up to 25% by weight, or up to 25% by weight; and c. API up to 30% by weight, up to 20% by weight, up to 10% by weight, or up to 5% by weight; and d. optionally a plasticizer of up to 15% by weight, up to 10% by weight or up to 5% by weight; whereby preferably the polymer is a hydrophilic polymer.

16. The dosage unit according to claim 1 for use in the treatment of migraine characterized in that the composition for producing the film of the dosage unit comprises a. polymer at least 60%, preferably at least 70% and more preferably at least 80% (w/w) of the solid content; and b. plasticizer up to 30%, preferably up to 25% and more preferably up to 20% (w/w) of the solid content; and c. propofol as API up to 25%, preferably 22.5% and more preferably up to 20% (w/w) of the solid content whereby preferably the polymer is a hydrophilic polymer.

17. The dosage unit according to claim 1 for use in the treatment of migraine characterized in that the API is selected as propofol, the dosage is selected as not more than 1/10 of a therapeutic sedative dose, residence time is at least 1 min, the area of the dosage unit is at least 6 cm.sup.2 and the composition for producing the dosage unit is essentially free of flavoring agents and sweetening agents.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0228] FIG. 1 Cumulative permeation data of formulation F6 compared to a satuarated solution of propofol in an ex-vivo permetation test on porcine buccal mucosa in vertical Franz-cells.

[0229] FIG. 2 Flux data of formulation F6 compared to a satuarated solution of propofol in an ex-vivo permetation test on porcine buccal mucosa in vertical Franz-cells.

SPECIFIC EMBODIMENTS

[0230] 1. A dosage unit of a mucoadhesive oral film for use in the treatment of a disease in a subject, preferably a human subject, comprising an active pharmaceutical ingredient (API) characterized in that the dose of said API is selected in such a way that in case of covering all non-keratinized parts of the mouth of said subject by multiple said dosage units, a toxic effect of said API is prevented. [0231] 2. The dosage unit according to embodiment 1 characterized in that the subject is selected from the group of full-grown human subjects and not full-grown human subjects, whereby [0232] a. in full-grown human subjects the non-keratinized parts of the mouth have an area of about 150 cm.sup.2, about 130 cm.sup.2, about 110 cm.sup.2; or [0233] b. in not full-grown human subjects the non-keratinized parts of the mouth have an area of up to 150 cm.sup.2, up to 130 cm.sup.2, up to 110 cm.sup.2, preferably an area of 45-150 cm.sup.2, of 45-130 cm.sup.2, of 45-110 cm.sup.2. [0234] 3. The dosage unit according to any one or more of embodiment 1 and 2 characterized in that the API is selected from the group of hormones, particular proteohormones, metabolic modulators, growth factors, endogenous peptide analogues, psychiatric medication, anabolic agents, beta2 agonists, hallucinogens, muscle relaxants, analgesics, anxiolytics, sedatives, hypnotics and/or anesthetics. [0235] 4. The dosage unit according to any one or more of claims 1 to 3 characterized in that an analgesic, anxiolytic, sedative, hypnotic and/or anesthetic is selected from the group of triptans, ditans such as lasmiditan, NSAIDs, glucocorticoid steroids, salicylates and derivatives, phenylacetic acid derivatives, 2-phenylpropionic acid derivatives, 4-aminophenol derivatives, pyrazolones, selective COX2 inhibitors, anti-depressants, anti-convulsant drugs, opioids, muscle relaxants, barbiturates, benzodiazepines, etomidates, ketamine, propofol, anti-histamines or local anesthetics. [0236] 5. The dosage unit according to embodiment 3 for use in the treatment of a metabolic disorder in a subject in the need thereof, preferably a human subject, characterized in that a hormone, particularly a proteohormone, is selected and the metabolic disorder is selected from the groups of acid-base imbalances, metabolic brain diseases, disorders of calcium metabolism, DNA repair-deficiency disorder, glucose metabolism disorders, hyperlactatemia, iron metabolism disorders, lipid metabolism disorders, malabsorption syndromes, metabolic syndrome X, inborn error of metabolism, mitochondrial diseases, phosphorus metabolism disorders, porphyrias, proteostasis deficiencies, metabolic skin diseases, wasting syndrome and water-electrolyte imbalances. [0237] 6. The dosage unit according to embodiment 5 characterized in that the API is a proteohormon, particularly insulin, and the disease is selected as a glucose metabolism disorder, in particular diabetes. [0238] 7. The dosage unit according to any one or more of embodiment 1 to 4 for use in the treatment of a nervous system disease in a subject in the need thereof, preferably a human subject. [0239] 8. The dosage unit according to embodiment 7 characterized in that the nervous system disease is a primary headache, preferably a migraine. [0240] 9. The dosage unit according to any one or more of embodiment 7 to 8 characterized in that the primary headache is selected as migraine selected from migraine without aura, migraine with aura, migraine with aura without headache, migraine with aura with headache, migraine with brainstem aura, hemiplegic migraine, retinal migraine, chronic migraine, pediatric migraine, menstrual migraine, refractory migraine, intractable migraine or acute confusional migraine (ACM). [0241] 10. The dosage unit according to any one or more of embodiment 1 to 9 characterized in that the dosage unit has an area selected from the ranges of at least 1 cm.sup.2, at least 2 cm.sup.2, at least 3 cm.sup.2, at least 4 cm.sup.2, at least 5 cm.sup.2, at least 6 cm.sup.2, at least 7 cm.sup.2, at least 8 cm.sup.2, at least 9 cm.sup.2, at least 10 cm.sup.2, at least 11 cm.sup.2 or at least 12 cm.sup.2, preferably at least 6 cm.sup.2. [0242] 11. The dosage unit according to any one or more of embodiment 1 to 10 characterized in that the dose of the API is selected as a subtherapeutic dose, preferably selected as not more than 1/10, more preferably not more than 1/35, of a therapeutic dose. [0243] 12. The dosage unit according to any one or more of embodiment 1 to 11 characterized in that the dosage unit has a residence time, wherein the residence time is selected to be at least as long as the systemic half-life of the API. [0244] 13. The dosage unit according to any one or more of embodiment 1 to 12 characterized in that the organoleptic features of the composition for producing the dosage unit do not mask the taste of the dosage unit. [0245] 15. The dosage unit according to any one or more of embodiment 1 to 13 characterized in that the composition for producing the dosage unit is essentially free of flavoring agents and/or sweetening agents. [0246] 16. The dosage unit according to any one or more of embodiment 1 to 14 characterized in that the composition for producing the film of the dosage unit comprises [0247] a. solvent up to 95% by weight, up to 90% by weight, up to 80% by weight, up to 70% by, or up to 60% by weight; and [0248] b. polymer up to 35% by weight, up to 30% by weight, up to 25% by weight, or up to 25% by weight; and [0249] c. API up to 30% by weight, up to 20% by weight, up to 10% by weight, or up to 5% by weight; and [0250] d. optionally a plasticizer of up to 15% by weight, up to 10% by weight or up to 5% by weight; [0251] whereby preferably the polymer is a hydrophilic polymer. [0252] 17. The dosage unit according to any one or more of embodiment 1 to 15 for use in the treatment of migraine characterized in that the composition for producing the film of the dosage unit comprises [0253] a. polymer at least 60%, preferably at least 70% and more preferably at least 80% (w/w) of the solid content; and [0254] b. plasticizer up to 30%, preferably up to 25% and more preferably up to 20% (w/w) of the solid content; and [0255] c. propofol as API up to 25%, preferably 22.5% and more preferably up to 20% (w/w) of the solid content [0256] whereby preferably the polymer is a hydrophilic polymer. [0257] 18. The dosage unit according to any one or more of embodiment 1 to 16 for use in the treatment of migraine characterized in that the API is selected as propofol, the dosage is selected as not more than 1/10 of a therapeutic sedative dose, residence time is at least 1 min, the area of the dosage unit is at least 6 cm.sup.2 and the composition for producing the dosage unit is essentially free of flavoring agents and sweetening agents.

Examples

[0258] 1. Dosage Unit Comprising Propofol—Selection of Target Values for Area, Dose and Residence Time

[0259] The aim was to manufacture a dosage unit containing the active pharmaceutical ingredient propofol. The buccal film is supposed to deliver the API through the mucosal tissue into the blood stream without passing the gastro-intestinal tract because of the very low oral bioavailability of propofol. A very low propofol dose, compared to the sedative dose that is applied via i.v. injection, can be included in the dosage unit. According dosage unit can be used in the treatment of acute migraine attacks since the propofol is absorbed directly into the blood stream through the buccal mucosa. The residence time of the film at the buccal mucosa as a combination of the disintegration time of the film and the mucoadhesion of the film on the mucosa is selected in the range between 1 to 5 min to deliver the API through the mucosa. Further targeted features for the mucoadhesive, dissolvable buccal propofol film are listed in Table 5. The dosage strength of the target dosage unit was selected for a full-grown human subject with a total area of non-keratinized parts of the mouth of about 110 cm.sup.2 to be about 5 mg and the target combined propofol dose not to be exceeded was selected as 100 mg. According to Tab. 1 (combination number 96) the minimum area to be covered by a dosage unit is 5.5 cm.sup.2. Consequently an area of 6 cm.sup.2 per single dosage unit was selected. Therefore, if a multitude of said dosage units was to cover all non-keratinized parts of the mouts of said full-grown subject.sup.2, the combined API dose would be about 91.7 mg, since 5 mg (per dosage unit)*110 cm.sup.2 (non-keratinized area of the mouth): 6 cm.sup.2 (area per dosage unit)=91.7 mg.

TABLE-US-00005 TABLE 5 Target attributes for a dosage unit of a propofol film Features Target API Propofol Dosage form Oromucosal, mucoadhesive dissolvable film Route of administration Mucosal (buccal, sublingual . . . ) Indication Acute migraine attack Dosage strength per area 5 mg/6 cm.sup.2 film Residence time 10 s-5 min Organoleptic characteristics No taste masking to prevent possible abuse and misuse Pharmacokinetics Immediate release via the mucosa

[0260] A dosage unit comprising propofol in a dosage wherein the simultaneous application of multiple dosage units in the non-keratinized parts of the mouth does not exceed a sedative therapeutic dose for the treatment of acute migraine and the identification of subjects amendable for treatment with according dosage unit and treatment of subjects suffering from a migraine attack with according dosage unit would provide an innovation. Moreover, the drug approval for drug products with an anesthetic drug such as propofol for the use in non-clinical environments expects a possible prevention strategy to avoid abuse and misuse of the product if less restricted available to the public. The implementation of propofol into a mucoadhesive orally disintegrating film enables an abuse and misuse-deterrent application of propofol for acute migraine attacks due to the limited dose and limited application area at the oral mucosa. Further advantageous with regard to propofol is the fact that every part of the API dose that is taken orally after swallowing is destroyed due to the very low oral bioavailability and no therapeutic effect is experienced.

[0261] In the following section the feasibility formulation trials will be described including their composition, their handling and visual properties and for some formulations furthermore the determined content of propofol per 6 cm.sup.2 film. One formulation was further evaluated in an ex-vivo permeation study on porcine buccal mucosa.

[0262] 2. Initial Formulation Development of Propofol Dosage Unit

[0263] Summary of Formulations for a Buccal Dosage Unit Comprising Propofol

TABLE-US-00006 TABLE 6 Formulation compositions for dosage units Formulations F1 F2 F3 F4 F5 F6 F7 Ingredient [%] [%] [%] [%] [%] [%] [%] Solid content [%] (w/w) 23.66 8.8 13.24 17.2 15.0 17.2 32 +18% API surplus Pullulan 16.4 63.7 2.2 12.8 12.7 12.8 PVP (Kollidon 90F) 52.3 59.3 PVP (Kollidon VA64) 13.2 14.8 HPMC (Pharmacoat603) 60.0 Chitosan 11.1 HPC (Klucel EF) 53.1 52.8 53.1 CMC (Blanose 7LP EP) 25.8 26.3 25.8 Polyacrylic acid 4.3 (Carbopol971PNF) Poloxamer (Kolliphor P407) 16.9 Glycerol 8.3 14.6 PEG 400 17.6 Propofol 9.8 15.1 12.1  8.3  8.2  8.3 8.3 Water 100% 99.04% 100% 80% 100% 18% Ethanol 20% 82% HCl 100% NaOH 0.96% Dosage: API content [mg] n.d. n.d. 2.98  4.25  3.22 5.05 ± 3.65 per 6 cm.sup.2 dosage unit 0.05 Area weight [g/m.sup.2] ~70 ~100

[0264] The formulations shown in Tab. 6 were prepared in this feasibility study for a buccal propofol film. In general, the solvent was filled into the mixing container and the polymers and plasticizer, if used any, were added while stirring the mass. The API propofol was added when the polymer mass was fully dissolved and showed a homogenous appearance. It was noteworthy that almost every polymer mass became white after adding the propofol into the mass, probably due to emulsion formation of the lipophilic API and the hydrophilic polymer mass. The exception was formulation F7 for which the polymer mass stayed clear after adding the propofol which suggests that the propofol is better incorporated in this mass than in the other formulations.

[0265] The films were prepared by solvent casting as soon as the API was evenly stirred into the mass, forming a matrix. The solvent casting process includes the coating of the polymer mass onto a substrate, such as a PET release liner, with a coating knife. A defined gap height is adjusted at the coating knife, which results in the wet film thickness and after drying in the area weight of the prepared film. The film manufacturing including the adjustment of the gap height is repeated until the desired area weight of the film is met. The area weight is a relevant quality attribute since it defines the API content of the prepared films.

[0266] After the coating step, the wet laminate (matrix) is dried in an oven between 65 and 90° C. for 20 to 30 min depending on the solid content and the amount of solvent that needs to be evaporated. The white appearance of the wet film changed to an opaque appearance during the drying step resulting in slight milky films. The dry films were punched into 6 cm.sup.2 pieces that were then evaluated regarding their handling and visual properties. Some of the prepared films were furthermore analyzed for their API content. The mucoadhesion of the buccal films that is needed to provide the buccal absorption of the API was ensured by using at least one mucoadhesive polymer in the formulations.

[0267] A formulation comprising chitosan such as formulation F3 showed reduced mucoadhesive properties. Furthermore, the chitosan is only soluble in an acidic solvent and therefore hydrochloric acid was used for film preparation in formulations containing this polymer. The films did not provide a good taste and mouthfeel since they caused a very dry mouth feel. Thereby reducing the likelihood of misuse, abuse or overdosing of according dosage units.

[0268] Alternatively, other polymers with mucoadhesive properties were challenged as ingredient for the buccal propofol dosage unit. Different Kollidon® types were used in formulation F1 and polyacrylic acid was incorporated in formulation F2 together with the addition of a Poloxamer. Polyacrylic acid showed good mucoadhesive properties.

[0269] Although all the previously named formulations provided films with sufficient handling and visual properties, another mucoadhesive polymer was tested to improve taste, mouthfeel and preparation of the formulations. The sodium carboxymethyl cellulose (CMC) provided good mucoadhesive properties and resulted in films with good handling and visual properties. They are flexible enough to be further processed and they do not stick to the liner or the packaging material.

[0270] For the HPC containing films, such as formulations F4, F5 or F6 no plasticizer was added since the polymer itself already presents some plasticizing properties. The films tend to get sticky when adding additional plasticizer.

[0271] Formulation F4 showed a propofol content below the desired 5 mg/6 cm.sup.2. Therefore, in formulation F5, ethanol was added as solvent in order to prevent problems with the correct adjustment of the API content in the dried films. The film presented nice handling and visual properties but showed a low API content after the drying process. Therefore, to reach the target content of 5 mg propofol per 6 cm.sup.2 dosage unit, a surplus of API was added to the matrix in formulation F6 to balance the API loss during drying. The content of 5 mg was met correctly in this case. Formulation F6 was also used as current formulation to determine the permeation capability of the propofol from a buccal film.

[0272] In formulation F7 propofol was added to formulations free of pullulan to increase the formulation variability. The films presented sufficient visual and handling properties but were not further optimized regarding the API content. Formulation F7 was the only formulation that did not turn white after adding propofol indicating a very well incorporation of the oily API into the polymer mass.

[0273] 3. Biological Example—Penetration and Permeation of a Current Formulation

[0274] The composition of the dosage unit formulation (F6) chosen for penetration and permeation experiments is presented in Table 6. The dosage units of the films were prepared with an area weight of 100.3 g/m.sup.2 and a propofol content of 5.05±0.05 g/6 cm.sup.2 (mean±sd).

[0275] The dosage unit prepared from formulation F6 were tested for ex-vivo permeation on porcine buccal mucosa in vertical Franz-cells. The permeation behavior of the films was compared to a saturated solution of propofol of about 167.8 μg/ml in the acceptor medium of buffer pH 7.0 (FIG. 1). No significant differences could be shown between the saturated solution and the films due to high standard deviations (FIG. 1). The dosage unit of the buccal film however indicates the trend to reach higher cumulative permeation amounts and flux rates than the saturated solution. In this first permeation trial, the steady state of the flux rate was reached after two hours whereby the flux rate of F6 reached a higher niveau (FIG. 2). However, it has to be kept in mind that the drug loading of the permeation cell (API in 1 film piece of 0.82 cm.sup.2 (about 0.68 mg) and API in 1.5 ml of saturated solution (about 0.25 mg)) for the propofol comprising buccal film was higher than for the saturated solution, which might be responsible for the higher permeation.

[0276] The evaluation of the API amount that permeated from the formulation F6 film within 6 hours of the permeation study revealed that around 4% of the API loaded to the donor compartment of the permeation cell reached the acceptor compartment. The extraction of the mucosal tissue after the permeation study with the formulation F6 film showed that around 40% of the API loaded to the donor compartment of the permeation cell penetrated into the mucosal tissue remained in there and had not permeated into the acceptor phase yet. Thereby, successful transmucosal delivery of propofol using a dosage unit of a propofol-comprising film was shown on porcine buccal mucosa in vertical Franz-cells. [0277] FIG. 1: Cumulative permeation data of formulation F6 compared to a saturated solution of propofol in an ex-vivo permeation test on porcine buccal mucosa in vertical Franz-cells (n=8 for F6 and control). [0278] FIG. 2: Flux data of formulation F6 compared to a saturated solution of propofol in an ex-vivo permeation test on porcine buccal mucosa in vertical Franz-cells (n=8 for F6 and control).