Orodispersible solid composition in the form of film for oral administration of thyroid hormones

Abstract

Solid orodispersible compositions in the form of thin films for the oral administration of thyroid hormones are described, characterized by a high stability, and by the bioavailability of the active ingredient for oral absorption. The film compositions described are designed for rapid disintegration in the mouth, for sublingual administration, or to be held in the mouth for longer times before they disintegrate, but in any case without being mucoadhesive films. All the examples described are characterized by being thin and flexible and are suitable for administration even to patients who are not conscious, dysphagic or otherwise unable to swallow.

Description

[0001] “ORODISPERSIBLE SOLID COMPOSITION IN THE FORM OF FILM FOR ORAL ADMINISTRATION OF THYROID HORMONES”

[0002] The present invention concerns an orodispersible solid composition in the form of a thin film for the oral administration of thyroid hormones. More in particular, the invention describes an orodispersible thin, stable and non-mucoadhesive film containing levothyroxine, therefore fast dissolving. Such ready-to-use solid dosage form is administrable without water even to unconscious or dysphagic patients, and can be presented in already approved dosages or in dosages adaptable to the therapeutic need of the patient. Such preparations may be produced by film casting.

[0003] Background of the invention

[0004] Levothyroxine (L-thyroxine, T4 or 3,5,3 ,5'-tetraiodo-L-thyronine) is used for hormone replacement therapy in patients with thyroid or thyroid gland disorders, such as hypothyroidism. Levothyroxine sodium salt hydrate is slightly soluble in water and 96% ethanol.

[0005] Levothyroxine is chemically unstable, sensitive to heat, light, humidity; the stability is also strongly influenced by the excipients with consequent problems of bioequivalence and bioavailability [1] that have appeared since the appearance on the market of solid or liquid formulations, with consequent frequent recalls from the market [2], There are numerous studies reported in the literature concerning the compatibility between active ingredients and excipients. Patel et al. [3] investigated the stability of levothyroxine in combination with different tablet excipients. They showed that excipients normally used as diluents such as anhydrous lactose, starch and microcrystalline cellulose degrade T4 more than mannitol or dibasic calcium phosphate and that tablet stability improves with the addition of a basic pH modifier. A study published in 2020 reports the incompatibility of levothyroxine with lactose, mannitol and sorbitol [3] in 1 : 1 active: excipient mixtures. pH modifiers affect the stability of levothyroxine: a slightly basic pH of 7.6-8.0, obtained by the addition of sodium citrate, seems to improve stability. In contrast, addition of citric acid as an excipient increases T4 degradation [5], The stability of levothyroxine is also affected by the presence of water: in solid formulations the absence of water, which acts as a reaction medium, prevents decomposition. Interaction, therefore, with highly hygroscopic or high moisture-containing excipients causes degradation of T4 [3, 6], Deiodination and deamination are the primary degradation pathways of T4 in the solid state. Levothyroxine is one of the most prescribed drugs in the United States. Since the first introduction to the American market in 1955 there have been numerous recalls from the market due to the instability of the active and the non-uniformity of dosage in the tablets. For this reason, in 2007 the FDA restricted the specifications for T4 tablets from 100±10% to 100±5% of the amount declared on the label both at release and in stability [6], Furthermore, due to the narrow therapeutic index, it is important that the amount of levothyroxine made available by the dosage form is correct, reliable and consistent with what is stated on the label, and that it is so throughout the entire shelflife of the product.

[0006] Several solutions have been proposed to the problem of intrinsic instability of levothyroxine and incompatibility with many excipients used in solid dosage forms: for example US 9,0503,07 discloses levothyroxine solutions and their respective preparation methods that ensure stability, ease of intake and greater dose consistency [7], US 7,723,390 discloses solid pharmaceutical forms, preferably in the form of a soft capsule (softgel) or in a swallowable form of a uniform soft-gel matrix [8],

[0007] Said formulations, in liquid or solid form, do not allow the necessary dosing accuracy; moreover, solid forms, such as soft gels, are not suitable for administration to dysphagic or swallowing impaired patients.

[0008] Among the rapidly dissolving oral forms, the orodispersible films (ODF) to be introduced into the oral cavity are of increasing interest, where they rapidly disperse to release the active ingredient. They consist of single or multilayer sheets of suitable material.

[0009] In accordance with the American Pharmacopoeia, oral films are defined as "thin sheets to be placed in the oral cavity. They contain one or more layers and one layer may or may not contain the active ingredient. Typically these thin sheets are prepared for casting or extrusion" [9].

[0010] Oral films are generally prepared by dissolving the film-forming polymer, for example cellulose, maltodextrins or alginates, in a suitable solvent, such as water or ethanol. To ensure adequate mechanical properties, in addition to the film-forming polymer, it is necessary to introduce plasticisers, which allow flexible and resistant films to be obtained. Plasticizers generally belong to the class of polyols, considered polar solvents.

[0011] Compared to oral solutions, which need to be prepared and dosed at the time, the films are ready to use and ensure accurate dosages

[0010] , Contrary to traditional solid forms, they can be taken without swallowing and without water. Once introduced into the mouth and resting on the tongue, they disintegrate in contact with saliva, allowing administration without additional liquids. However, the particular instability of levothyroxine makes it difficult to formulate a stable and reproducible oral film with an industrial process.

[0012] For example, WO2014 / 049548 discloses the composition of fast-dissolving orodispersible thin films to deliver drugs and food supplements. Described are formulations comprising a film-forming polymer, in particular maltodextrin, in an amount of 40-80% w / w dry; a plasticiser in an amount of 15-55% w / w dry; a surfactant system in an amount of 0.5- 6.0% w / w dry; a homo- or co-polymer of the vinyl acetate in an amount of 2-10% w / w dry and an active in an amount of 0.5-30% w / w dry. No examples are given with levothyroxine.

[0013] US 2023 / 0338320 discloses oral films containing levothyroxine in order to overcome the difficulty in swallowing solid dosage forms or significant volumes of solutions by dysphagic patients.

[0014] US 2023 / 0338320 lists various film-forming polymers (cellulose, polysaccharides), plasticisers, buffers, sweeteners, solvents. The method of preparation, in general, consists of solubilising the active ingredient in the solvent, to which the film-forming polymer is added, directly or by pre-solubilisation thereof in another portion of solvent. Then the plasticisers and the other excipients are added. The mixture is poured onto a glass surface and dried in an oven at 30-40°C until a non-adhesive film is formed. In particular, the obtained films have a thickness between 0.5 mm and 5.0 mm and an area between 0.5 cm2and 50 cm2. However, the dimensional characteristics of the films are not suitable for obtaining orodispersible, fast- dissolving and non-mucoadhesive films. Furthermore, the described production process is not compatible with large-scale industrial production.

[0015] Therefore, there remains a need for stable dosage forms based on thyroid hormones, with correct and constant dosage and characterized by ease of administration.

[0016] Description of the Invention

[0017] It has now been found that, contrary to expectations arising from the known destabilizing effects of water and organic solvents, thyroid hormones can be formulated in orodispersible films, despite the use of a water-based production intermediate. It has been found in particular that orosoluble films containing thyroid hormones such as levothyroxine can be obtained by using as film-forming polymers a starch, or a mixture of starch and its derivatives in which the percentage on a molar basis of linear chains with 1,4-a glycosidic bonds does not exceed 42.0% of the total polymers used. The films of the invention may also contain water, one or more plasticisers, pH modifiers, such as citric acid and glycine, and excipients commonly compatible with the active ingredient, with the exception of preservatives and surfactants.

[0018] The films of the invention are characterized by high stability, understood as the property of complying with the specifications in a reasonable time at room temperature, or for at least three months at the accelerated stability conditions provided for by the ICH guidelines.

[0019] The invention overcomes both the swallowing problems, thanks to the formulation in a thin film, and the stability problems of the known formulations.

[0020] The invention, in a further aspect thereof, relates to a process for preparing said films comprising: a) preparing a starch paste from a dispersion in water of starches, or mixtures of starches and derivatives thereof, in a proportion of from 15% to 32% by weight, preferably from 17% to 30% by weight, at a temperature of from 65 to 75 °C, preferably from 68 to 72°C; b) adding thyroid hormone and plasticisers to the starch paste obtained in a); c) film casting of the mixture obtained in b) in the absence of surfactants.

[0021] The thyroid hormone is preferably levothyroxine, as such or in sodium salt form, typically in a percentage of 0.01% to 0.3% by weight of the film so as to provide dosages in the range 13 - 200 pg / dose.

[0022] Starches are polysaccharides consisting of two homopolymers of glucose: amylose and amylopectin. Amylose is a linear polymer consisting only of a-1,4 glycosidic bonds, while amylopectin is a branched polymer consisting of a-1,4 glycosidic and a-1,6 glycosidic bonds. The molecular weight may range from 50. 106to 500.106Da. Starches are extracted from different plant species and the ratios of amylose to amylopectin vary significantly based on the source of the starch. Some plants may have a much lower amylose content (such as glutinous rice), while others (such as some types of waxy maize) may have an amylopectin content of almost 100%, thus affecting the overall percentage of a-l,4-glycosidic bonds

[0011] , Table 1 shows the percentages of amylose and the gelation temperatures of some starches. Gelation takes place by heating in an aqueous environment.

[0023] Table 1: Characteristics of starches By starch derivatives is meant in particular maltodextrins, consisting of D-glucose units (typically from 3 to 17 units) bonded by a-1,4 glycosidic bonds with occasional a-1,6 glycosidic bonds, obtained by partial acid or enzymatic hydrolysis. Maltodextrins are characterized by the equivalent dextrose value, which must be less than 20.

[0024] The film-forming polymer, both starches and mixtures of starches and derivatives thereof, preferably maltodextrins, is present in proportions of from 55 to 75% by weight, preferably from 60 to 70%.

[0025] The films may also contain a plasticiser, preferably selected from polyalcohols such as glycerol, sorbitol and mannitol, in proportions of from 12 to 30% by weight, preferably from 15 to 25% and buffering agents in percentage by weight from 0.25% to 5.5%.

[0026] The compositions of the invention may contain other excipients commonly used in dosage forms, such as pH modifiers such as glycine and citric acid, and other components compatible with the active ingredient useful for improving the organoleptic properties of the film, such as flavours, sweeteners, colourants.

[0027] The compositions of the invention may be prepared by a process involving the preparation of an in-water mixture of starches and possibly maltodextrins as film formers. The aqueous mixture is heated to the temperature necessary for gelation. In a preferred embodiment of the process, the glycerol in which the levothyroxine sodium has previously been dissolved is added to the starch mixture. Finally, the other excipients provided for in the formulation are added. The mixture that is obtained is homogeneous and does not need surfactants, it remains physically stable up to 5 days from the end of the preparation: the viscosity does not undergo significant variations and phase separation problems are not noticed. The mixture is coated onto a polyester liner and subsequently dried to evaporate the water. The residual water after drying of the starting mixture is present in the films in proportions between 8 and 20% by weight.

[0028] During the coating phase there is no shrinkage of the mass on the liner, as often occurs during the coating of water-based polymer blends. The dry coating is cut so as to obtain the finished film and the latter is individually packaged in a sachet of suitable material.

[0029] The films of the invention are characterized by a thickness ranging from 80 pm to 150 pm (0.08 - 0.15 mm) and rapid disintegration.

[0030] By rapid disintegration it is meant that according to Ph. Eur. current edition

[0012] , the pharmaceutical form disintegrates within 3 minutes. This allows the film to disintegrate quickly in contact with the saliva in the oral cavity, so as to quickly release the active ingredient.

[0031] The invention provides a stable product in accordance with the pharmacopoeial requirements and quality specifications defined by the ICH guidelines, for a suitable period of time, ensuring practical storage conditions, for example at room temperature, or for at least three months at the accelerated stability conditions provided for by the ICH guidelines

[0013] ,

[0032] Examples 1 and 2 describe the formulations obtained as described in the prior art documents.

[0033] Comparative Example 1

[0034] An orodispersible film containing levothyroxine sodium was prepared as described in WO2014 / 049548

[0014] ,

[0035] Table 2: Formulation 1

[0036] The batch was analysed at TO and after 45 days of accelerated stability (40°C-75% RH). The results show that the percentage content of levothyroxine is reduced from the initial 93.7% to 41.8% at the end of the study, losing 51.9% of its initial value. The film cannot be considered stable.

[0037] Comparative Example 2

[0038] A batch was prepared using hydroxypropyl methyl cellulose (Methocel El 5) as the film- forming polymer as described in US 2023 / 0338320

[0015] ,

[0039] Table 3: Formulation 2

[0040] The batch was analysed at TO and after 30 days of accelerated stability (40°C-75% RH).

[0041] The results show a decrease in levothyroxine titre of 32.0%, from 95.1% obtained at TO to 63.1% obtained after 30 days at 40°C-75% RH. This test confirms that levothyroxine degrades rapidly and that the films are not stable.

[0042] Due to the well-known instability of levothyroxine and its homologues and the failure of the tests carried out according to the prior art, binary (levothyroxine sodium: excipient) and ternary (levothyroxine sodium: water: excipient) compatibility tests were performed to verify the stability of the active ingredient with the excipients most commonly used for the preparation of non-mucoadhesive orodispersible films.

[0043] Example 3

[0044] The mixtures prepared and analysed at TO were placed in accelerated stability conditions at 40°C-75%RH. The assessment of the levothyroxine titre was carried out immediately after the preparation of the mixtures and at pre-established times. Upon reaching a decrease in levothyroxine titre of 15% or more, the excipient was considered incompatible and the study was terminated.

[0045] The results, normalized with respect to TO and reported in Table 4, show an incompatibility between the active ingredient and high HLB surfactants such as polysorbate 80 (TWEEN 80), polyoxyl glyceride (Labrafil®) and sucrose ester, opacifiers such as talc and zinc oxide, dyes such as yellow iron oxide (El 72) and film-forming polymers such as maltodextrin and polyvinylpyrrolidone-vinyl acetate (PVP-VA).

[0046] Table 4: Compatibility studies

[0047] The unstable nature of Levothyroxine is confirmed by the data reported in the table above which are consistent with the results of Examples 1 and 2.

[0048] The ingredients commonly used for the formulation of orodispersible films do not guarantee the chemical stability of levothyroxine necessary to obtain a product that is marketable or reproducible with an industrial process. Example 4

[0049] In this formulation we used rice starch as the only film-forming polymer, which contains at most 20% of linear chains containing a-1,4 glycosidic bonds, glycerol as a plasticiser, sucralose as a sweetener and brilliant blue E133 as a colourant.

[0050] Table 5: Formulation 3

[0051] A batch containing 200 pg / film of levothyroxine sodium was prepared. The batch was analysed at TO, and thereafter, an adequate number of films were placed in the climate chamber for the accelerated stability study at 40°C-75%RH. The samples were analysed every month for 3 months. The results are shown in Table 6.

[0052] Table 6: Accelerated stability of Formulation 3

[0053] The batch complies with the specifications throughout the accelerated stability study.

[0054] Example 5

[0055] A proportion of maltodextrins DE=6 corresponding to a total amount of linear chains containing a-1,4 glycosidic bonds equal to 40.1% of the total dry weight of the film-forming polymers was added to the rice starch. Table 7: Formulation 4

[0056] A batch containing 200 pg / film levothyroxine was analysed at TO and after 1, 2 and 3 months of storage in the climatic chamber at 40°C-75%RH. The results are shown in Table 8.

[0057] Table 8: Accelerated stability of Formulation 4

[0058] The batch complies with the specifications throughout the accelerated stability study.

[0059] The above two examples confirm the possibility of obtaining stable orodispersible films based on thyroid hormones, using as film-forming excipients one or more glucose-based polymers in which the total proportion of linear chains with 1,4-a glycosidic bonds does not exceed 42.0% of the total of the polymers themselves, a plasticiser and the excipients necessary for obtaining a film with the right mechanical properties and with pleasant organoleptic properties.

[0060] Example 6

[0061] To prepare the films according to the invention, the film-forming polymers (starch or starch and its derivatives) are added to water at room temperature. The obtained dispersion is heated to a temperature comprised between 65°C and 75°C, at which a change in the physical characteristics of the mixture is observed as the starch starts the gelatinization process. When the mixture reaches the desired viscosity, it is cooled to room temperature. Subsequently, under continuous stirring, the plasticiser in which the levothyroxine sodium was previously dissolved and finally the other excipients provided for in the formulation are added, mixing until completely homogeneous. The final mixture has a viscosity between 10000 cP and 30000 cP. The mixture is coated on a support, generally polyester, and dried continuously until a uniform and bubble-free film roll is obtained, despite the absence of surfactants. The roll is then cut to obtain the final films, having an area between 3 cm2and 18 cm2and a weight between 45 and 270 mg. The films are plastic, resistant and disintegrate quickly (< 3 minutes), according to the disintegration test provided by the European Pharmacopoeia (Ph. Eur., 2.9.1) for solid oral forms. The films can be made without the use of surfactants and the production process, which takes place by film casting, can be easily industrialised.

[0062] Example 7 The titre analyses were performed in HPLC. The column is a Zorbax Eclipse XDB-C18

[0063] (150 mm X 4.6 mm) with a particle size of 5 pm, thermostated at 35°C. The mobile phase consists of a 70:30 mixture of water and acetonitrile acidified with the addition of 0.1% phosphoric acid (85% solution). The DAD-UV detector is set at 225 nm, the flow is 1.2 ml / min, and the injection volume is 20 pl. Analyses of related substances were performed using HPLC. The column is an Uptisphere Interchim 120A CN (250 mm X 4.6 mm) with a particle size of 5 pm, thermostated at 25°C. The mobile phase consists of a 70:30 mixture of water and acetonitrile acidified with the addition of 0.1% phosphoric acid (85% solution). The DAD-UV detector is set to 225 nm, the flow is 1.0 ml / min, and the sample injection is 50 pl.

[0064] REFERENCES

[0065] 1. Collier JW, Shah RB, Gupta A, Sayeed V, Habib MJ, Khan MA. Influence of formulation and processing factors on stability of levothyroxine sodium pentahydrate. AAPS PharmSciTech. 2010 Jun; 11(2):818-25. doi: 10.1208 / sl 2249-010-9434-8. Epub 2010 May 8. PMID: 20454876; PMCID: PMC2902299.

[0066] 2. Won, C. M. Kinetics of Degradation of Levothyroxine in Aqueous Solution and in Solid State. Pharmaceutical Research. 1992 9: 131-137.

[0067] 3. Patel H, Stalcup A, Dansereau R, Sakr A. The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets. Int J Pharm. 2003 Oct 2;264(l-2):35-43. doi: 10.1016 / s0378-5173(03)00387-9. PMID: 12972334.

[0068] 4. Ledeti I, Romanescu M, Circioban D, Ledeti A, Vlase G, Vlase T, Suciu O, Murariu M, Olariu S, Matusz P, Buda V, Piciu D. Stability and Compatibility Studies of Levothyroxine Sodium in Solid Binary System s-Instrumental Screening, Pharmaceutics. 2020 Jan 10;12(l):58. doi: I0.3390 / pharmaceuticsl2010058. PMID: 31936742; PMCID: PMC7022666.

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[0071] 7. Psarrakis Y, Lioumis K. I. Method for the preparation of a levothyroxine solution. US 9,050,307. 2015, United state patent.

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Claims

CLAIMS1. An orodispersible solid composition in the form of a thin film comprising a thyroid hormone, a film-forming polymer consisting of starch or a mixture of starch and maltodextrins in which the percentage of the linear chains consisting of a-1,4 glycosidic bonds does not exceed 42% of the total amount of film-forming polymer.

2. A composition according to claim 1, wherein the thyroid hormone is levothyroxine or its sodium salt.

3. A composition according to claim 2, wherein the weight percentage of levothyroxine is between 0.01% and 0.3%.

4. A composition according to one or more of claims 1 to 3, wherein the weight percentage of the film-forming polymer is between 55% and 75%.

5. A composition according to one or more of claims 1 to 4, comprising a plasticiser.

6. A composition according to claim 5, wherein the plasticiser is selected from glycerol, sorbitol and mannitol in weight percentages from 12% to 30%, preferably from 15% to 25%.

7. A composition according to one or more of claims 1 to 6, comprising buffering agents in weight percentage from 0.25% to 5.5%.

8. A composition according to one or more of claims 1 to 7 free of surfactants.

9. A process for preparing the compositions of claims 1-8 comprising: a) preparing a starch paste from a dispersion in water of starches, or mixtures of starches and maltodextrins, in a proportion from 15% to 32% by weight, preferably from 17% to 30% by weight, at a temperature from 65 to 75 °C, preferably from 68 to 72°C; b) adding thyroid hormone and plasticisers to the starch solder obtained in a); c) film casting the mixture obtained in b) in the absence of surfactants.

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