Orodispersible film

Abstract

Object of the present invention is an orodispersible film and a method for preparing it, wherein said orodispersible film is characterized by comprising (% w / w on the final weight of the dried film): - A film-forming substance which is at least one polyvinylpyrrolidone, PVP, in concentrations between 45 and 87.5% by weight; - At least one plasticizer in concentrations between 7.5 and 25% by weight; - Starch, in concentrations between 2.5 and 45% by weight.

Description

[0001] ORODISPERSIBLE FILM

[0002] STATE OF THE ART

[0003] Orodispersible films are a dosage form of consolidated use, used to administer active ingredients orally without the need to take water. These films disintegrate quickly in the mouth, releasing the active ingredient.

[0004] Hydrocolloids plasticized with polyalcohols such as by way of example only, glycerine, propylene glycol and sorbitol are usually used for their production.

[0005] The problems to be addressed when designing orodispersible films are mainly linked to: i) film tenacity; ii) aesthetic appearance; iii) tackiness.

[0006] Tenacity is known to be improved with the addition of nanofillers, such as kaolin, foldedonite or others of synthetic origin.

[0007] A film is preferably opacified, so as to make imperfections less visible that would be too obvious if the film were transparent. In this regard, the prior art teaches adding titanium dioxide.

[0008] Finally, the production and storage of the dosage forms in controlled humidity environments entails the phenomenon of tackiness.

[0009] One of the first polymeric materials used to make orodispersible films was Polyvinylpyrrolidone K 90 (PVP K 90, MW 90,000 Da): plasticized with glycerine, it allows obtaining transparent films with satisfactory tenacity. The use of lower molecular weight PVP instead results in the formation of films with lower mechanical properties and greater tackiness.

[0010] The need to identify titanium dioxide substitutes as opacifying additives in medicinal products is strongly felt. Regulation (EU) 7SS22. / 63 prohibits the use of titanium dioxide as a food additive, keeping it on the list of additives authorised for use as a colourant in medicines, pending the finding of valid substitutes.

[0011] It is therefore an object of the present invention to identify a formulation suitable for obtaining orodispersible films that meet the tenacity and tackiness parameters, and are sufficiently opaque, without the addition of titanium dioxide.

[0012] DESCRIPTION

[0013] The object of the present invention is an orodispersible film comprising or consisting of: A film-forming substance which is at least one polyvinylpyrrolidone, PVP 45-87.5%;

[0014] Starch: 2.5-45%;

[0015] Plasticizer: 7.5-25%; where the percentages are weight percentages calculated on the final weight of the dried film.

[0016] Said PVP is preferably selected from low or medium molecular weight PVPs. By way of example, said PVP is selected from the group comprising PVP K12, PVP K17, PVP K30, PVP K90. Preferably, it is PVP K30 or PVP K90. In a preferred embodiment, it is PVP K30, wherein the formulations comprising it show the optimal characteristics.

[0017] In one embodiment, said starch is selected from the group comprising: corn starch, pregelatinized corn starch, pregelatinized and modified corn (i.e. AMPRAC 01) and modified starch (i.e. AMPRAC 03). In a preferred form, said starch is non-pregelatinized, optionally modified starch.

[0018] Plasticizers are substances that, by intercalating between the polymer chains of the film-forming polymers, make them more flexible and therefore less prone to breakage, preventing them from compacting, i.e. reducing polymer -polymer interactions. Said plasticizers are selected from the group comprising: polyols, glycerol, propylene glycol, low molecular weight PEG (200-600), organic esters, phthalic acid esters (dibutyl / diethyl phthalate), citric acid esters (triethyl / acetyl triethyl), dibutyl sebacate, triacetin, oils and glycerides, castor oil, acetylated monoglycerides, fractionated coconut oil, preferably it is selected from the group comprising polyols, such as propylene glycol and glycerol, citric acid esters, sebacic acid esters, triacetin, or mixtures thereof. Even more preferably, said plasticizers are propylene glycol, glycerine, sorbitol, maltitol, citric acid esters and mixtures thereof.

[0019] Said composition is conveniently loaded with active ingredients, of natural or synthetic origin, or biotechnological.

[0020] By way of example, the active ingredient for therapeutic use is an ingredient with essentially topical action of the oral cavity selected from antibacterial, antifungal, antiviral or disinfectant agents of the oral cavity, or it is an ingredient with essentially systemic action selected from the group comprising anti-inflammatories, drugs for the treatment of diseases of the central nervous system, muscle relaxants, antiemetics, antihistamines, beta-blockers, antiasthmatics, antihypertensives, antitussives, antidiarrheals, laxatives, type V phosphodiesterase inhibitors, anti-kinetosis agents.

[0021] In one embodiment, said active ingredients are selected from the group comprising: Piroxicam, Ketoprofen, Diclofenac, Tramadol, Morphine, Nifedipine, Diazepam, Lorazepam, Alprazoiam, Bromazepam, Triazolam, Lormetazolam, Zolpidem, Paracetamol, Selegiline, Atenolol, Salbutamol, Sumatriptan, Clozapine, Ceterizine, Levothyroxine, Triiodothyronine and their pharmaceutically acceptable salts.

[0022] In one embodiment, said active ingredients are selected from the group comprising: DNA drugs, RNA drugs, peptides, monoclonal antibodies, hormones.

[0023] In one embodiment, said active ingredients are for veterinary use.

[0024] In one embodiment, said film is suitably loaded with nanoparticles, polymeric, lipidic, inorganic or hybrid particles of nanometre size, and / or microparticles, particles of micrometre size and / or emulsions. Conveniently, said particles incorporate active ingredients of interest.

[0025] In one embodiment, said film is loaded with food supplements, e.g. natural extracts and medicinal plants selected from the group comprising: Ginkgo biloba, Rhodiola rosea, Panax ginseng, Bacopa monnieri, Echinacea, Ashwagandha, Valerian, Passion flower, Maca, Chasteberry, Fennel, Peppermint, Ginger, Turmeric, Saw palmetto, Boswellia serrata, Tribulus terrestris, Griffonia simplicifolia (5-HTP), Astragalus, Chamomile, Lemon balm; Vitamins and minerals selected from the group comprising: Vitamin C, Vitamin D3, Vitamin B6, Vitamin B12, Folic acid (vitamin B9), Vitamin K2, Vitamin E, Calcium, Magnesium (citrate, bisglycinate, etc.), Zinc, Iron, Potassium, Selenium, Iodine, Manganese; Amino acids and derivatives, selected from the group comprising leucine, isoleucine, valine, L-glutamine, L-carnitine, L-arginine, L-theanine, Taurine, Beta-alanine, Creatine monohydrate, Tyrosine; Proteins and protein derivatives selected from the group comprising Whey proteins, Casein, Plant proteins (pea, rice, soybean); Probiotics, prebiotics and enzymes selected from the group comprising Lactobacillus spp., Bifidobacterium spp., Saccharomyces boulardii, Inulin, fructo-oligosaccharides, Digestive enzymes (e.g. bromelain, papain, amylase, lipase); Natural hormones and circadian rhythm regulators selected from the group comprising: Melatonin, Estrogenic phytocompounds (soy isoflavones), 5-http; Fatty acids and lipid compounds selected from the group comprising Omega-3, Linseed oil, Borage oil, Evening primrose oil, Soy lecithin, Phosphatidylserine, Alpha-lipoic acid; other bioactive compounds and cofactors such as Coenzyme Q10, Resveratrol, Quercetin, methylsulfonylmethane, Glucosamine, Chondroitin, NAG (N-acetylcysteine), PQQ (pyroloquinoline quinone), Caffeine, Guarana, Theobromine, Nicotinamide riboside / NAD+ precursors.

[0026] In one embodiment, said film also comprises flavour masking agents and / or dyes.

[0027] Further object of the present invention is a method for preparing an orodispersible film according to the present invention comprising:

[0028] Suspending, in a polar solvent, starch, PVP and at least one plasticizer and, optionally, at least one active ingredient;

[0029] Keeping said mixture under gentle stirring;

[0030] Spreading said mixture;

[0031] Drying said spread mixture obtaining a film that, suitably cut, is ready to be packaged.

[0032] In one embodiment, said film has a thickness between 25 and 300 microns, preferably between 50 and 150 microns.

[0033] In one embodiment, said drying takes place at a T between 65 and 90°C.

[0034] In one embodiment, said solvent is water. In this embodiment, said at least one plasticizer is pre-emulsified in said water with the addition of surfactants. Starch and PVP are then added to said emulsion.

[0035] In one embodiment, said solvent is alcohols, in particular isopropanol. In this embodiment, said starch, PVP and at least one plasticizer are directly suspended in said solvent.

[0036] Said surfactants are selected from the group comprising alkyl sulphates, sulphated alkyl ethers, sarcosinates, sulphosuccinates, ethoxylated fatty acids, ethoxylated fatty alcohols, alkylamides, sorbitol esters, polyethylene glycols, ethoxylated triglycerides, preferably said surfactant consists of one or more surfactants selected from the group comprising sorbitan derivatives, sorbitol derivatives, sucrose esters, fatty acid esters and mixtures thereof.

[0037] Surprisingly, the authors of the present invention have demonstrated that the addition of starch to a PVP allows to obtain orodispersible films that show advantageous tenacity and tackiness parameters, and have a pleasant aesthetic appearance even without the addition of titanium dioxide. In addition, the films thus obtained maintain the required dissolution rate. Surprisingly, the authors of the present invention have observed that the increase in the lipophilicity of the film due to the fact that these comprise insoluble plasticizers and starch does not compromise its dissolution rate, contrary to what can be observed with films comprising cellulose ethers and maltodextrins.

[0038] Furthermore, the films according to the present invention show improved mechanical characteristics and increased opacity.

[0039] The following examples are merely for the purpose of better describing the invention, they are not to be intended in any way as limiting the scope thereof which is defined by the claims below.

[0040] EXAMPLES

[0041] Example 1: Formulations based on PVP, starch and a plasticizer

[0042] The following series of orodispersible films have been set up:

[0043] Series A: plasticizer = glycerine (series A);

[0044] Series B: plasticizer = citric acid esters, with water solvent, or with isopropanol solvent.

[0045] PVP K30, PVP K25, PVP K17 and PVP K12 were used.

[0046] For comparative purposes, the following films have been set up:

[0047] MO, Ml: PVP K30 has been replaced by maltodextrin DE 6

[0048] Cl: starch has been replaced with calcium carbonate.

[0049] Technological performance was determined in terms of disaggregation assay, tensile property determination assay and opacity determination assay.

[0050] Preparation of orodispersible films, plasticizer glycerine (Series A)

[0051] The components are dispersed in water and left under gentle stirring to remove any incorporated air. Subsequently, the polymer mixture is spread at a constant thickness and then dried at a temperature between 65°C and 90°C.

[0052] The samples obtained are described in table 1.

[0053] Table 1

[0054] Preparation of orodispersible films, plasticizer citric acid esters (Series B)

[0055] The components are dispersed in isopropanol (Bli-B3i) or in water (B4a-Blla) and left under gentle stirring until the moment of use. In the case of aqueous-based formulations, the citric acid esters (TBC) are emulsified in water by adding surfactants so as to stabilise the mixture and the system obtained is kept under gentle stirring to remove any incorporated air. Subsequently, the polymer mixture is spread at a constant thickness and then dried at a temperature between 50°C and 90°C. As a control, sample Pl was prepared, which does not comprise starch.

[0056] The samples obtained are described in table 2.

[0057] Table 2

[0058] Preparation of orodispersible films, comparison of different types of starch (Series C)

[0059] The following formulations were set up with corn starch (i.e., A7, Al 0), pregelatinized corn starch (i.e., A8), pregelatinized and modified corn (AMTRAC 01; i.e., A9). The components are dispersed in water and left under gentle stirring to remove any incorporated air. Subsequently, the polymer mixture is spread at a constant thickness and then dried at a temperature between 65°C and 90°C.

[0060] The samples obtained are described in table 3.

[0061] Table 3

[0062] Example 2: Disaggregation assay

[0063] The assay was carried out following the prescriptions of the European Pharmacopoeia and was considered as met when the disaggregation time was less than 3 min (Tablet Monograph 01 / 2018:0478).

[0064] The disaggregation times measured for each of the samples are reported in table 4.

[0065] Table 4

[0066] All formulations according to the invention met the assay. As expected, the assay is also met by the composition MO, according to the known art, with maltodextrins and glycerol. Conversely, comparative sample Ml comprising starch, prepared using maltodextrin instead of PVP K30, did not give satisfactory results. This result is indicative of the fact that starch, added to orodispersible film formulations known in the state of the art, prevents the necessary disaggregation thereof.

[0067] Example 3: Tensile property determination assay

[0068] The assay was carried out in accordance with the method described by Cilurzo et al., Eur.J Pharm. Biopharm. 2008. The assay was considered as met if the elastic modulus (Y) is significantly greater than the reference formulation (P0). Prior to testing, the thickness of each sample was measured with an electronic micrometre.

[0069] Young's modulus, or elastic modulus (Y) was calculated as the slope of the linear portion of the stress-strain curve. The results are expressed as force per unit area (MPa).

[0070] Tensile strength (TS): was calculated by dividing the maximum load by the original cross-sectional area of the sample, and is expressed as force per unit area (MPa).

[0071] Elongation at break percentage (E): was calculated by dividing the extension at the time of sample break by the initial length of the sample gauge and multiplying by 100.

[0072] The results are reported in table 5.

[0073] Table 5

[0074] All formulations according to the invention showed reinforced tensile properties with respect to the control formulation PO, as demonstrated by the significantly higher value of the elastic modulus (Y). Formulation BlOa, characterized by comprising lower molecular weight PVP, shows an elastic modulus comparable to that observed with the control formulation PO.

[0075] The formulations plasticized with citric acid esters (samples B4a, B6a, B9a) appear less ductile than the series with glycerine (A1-A6). The differences in terms of tenacity (TS) are not such as to affect the manipulation of the films thus obtained, except for the composition A6, which comprises 50% of starch, a quantity that proved excessive.

[0076] Interestingly, formulation B4a, which contains 2.5% starch, leads to films tough enough to be able to be manipulated while the same composition, in the absence of starch, (Pl) is too brittle to be manipulated. This evidence is confirmed by increasing the starch content (Samples from B4a to B9a).

[0077] Example 4: Opacity determination assay

[0078] The assay was carried out using film samples and determining the increase in the absorbance value of a light ray at a wavelength of 700 nm. The results are reported in table 6.

[0079] Table 6

[0080] An amount of starch equal to 2.5% was sufficient to reduce the intensity of a light ray passing through the orodispersible film. The formulations prepared with corn starch (A7) gave results superimposable with the formulations prepared with AMTRAC 03 demonstrating that the use of corn starch and acetylated corn starch is equivalent. In contrast, pregelatinized starch (A8) and AMTRAC 01 (pregelatinized acetylated corn starch; A9) are not suitable for the production of opaque RVT films.

[0081] To obtain an effect comparable to that obtained with 10% starch (A3), it was necessary to add 25% calcium carbonate (Cl) indicating that the starch has a greater opacifying effect. Example 5: Formulations loaded with active ingredients

[0082] To evaluate the loading capacity of the orodispersible film according to the present invention, four small molecules [diclofenac sodium, levothyroxine (T4), triiodothyronine (T3), paracetamol, ketoprofen, thymine, ondansetron, naltrexone], an enzyme (betagalactosidase) and a plant extract (turmeric dry extract) were added to the formulations A3 and B7a. The formulations are detailed in table 7.

[0083] Table 7 The obtained films were subjected to disaggregation assay, results in table 8, and tensile property determination assay, results in table 9.

[0084] Table 8

[0085] Table 9

[0086] All formulations met the disaggregation, mechanical properties determination and opacity assays (data not shown), confirming that the formulations according to the present invention retain the desired properties even when loaded with active ingredients, be they small molecules, peptides, or natural extracts.

[0087] Example 6 (comparative): formulations based on PVP, starch and a plasticizer

[0088] The following orodispersible film formulations were set up according to the procedure described in Example 1, Series A.

[0089] PVP K30 and PVP K12 were used. Different types of plasticizer were used, such as propylene glycol, glycerine and

[0090] PEG4000.

[0091] In the case of C7, a film comprising Sorbitol and Sucralose was set up.

[0092] The percentage of water used varies between 45% (C3-C10) and 70% (C2).

[0093] The technological performance was determined on the basis of the feasibility of forming a film with satisfactory characteristics to be used as an orodispersible film.

[0094] In particular, the following were evaluated:

[0095] 1. The spreadability of the polymer mixture

[0096] 2. The tackiness of the film 3. The flexibility of the film

[0097] The samples obtained are described in table 10.

[0098] The percentages indicated refer to the percentages by weight after drying the mixture. The last row of the table indicates the percentage of water added to the initial mixture. Table 10

[0099] Example 7 (comparative'): test of determination of the ability to form an orodispersible film of the compositions referred to in Example 6

[0100] The ability to form a film with satisfactory characteristics to be used as an orodispersible film was evaluated on the basis of the following requirements: 1. The possibility of spreading the polymer mixture on a silicone support, which represents the material of choice for the preparation of films by the casting technique (coating and subsequent drying);

[0101] 2. In the event that requirement 1 is not met, the percentage of water in the mixture is decreased and the possibility of spreading said mixture on a support is re-evaluated; In the case of the formation of homogeneous films, it was continued with:

[0102] 3. The evaluation of the tackiness of the film which must be absent to allow correct manipulation according to the probe tack test method. Said test was performed according to a standard internal procedure using an Instron 5965 dynamometer equipped with a 50 N load cell and a stainless steel flat surface probe (diameter:

[0103] 5mm). In each experiment, the probe was brought closer to the surface of the film and a constant force of 0.05 N was applied to the sample for 5 seconds. At this point, the probe was removed with a detachment speed of 0.1 mm / s, by measuring the force needed to separate the film from the surface of the probe (Detachment Force). The Detachment Force values were calculated as the maximum detachment force normalized with respect to the area of the probe.

[0104] 4. Determining the flexibility of the film, which is essential to allow cutting and packaging operations. This characteristic was evaluated using the Folding Endurance test; said test counts the number of times the sample is folded until it breaks. In this case, the film is then cut into 5 cm long strips, wound and then cyclically unwound on a steel tube with a diameter of 12 mm, until it breaks.

[0105] The results obtained are reported in table 11.

[0106] Table 11

[0107] Key:

[0108] A. the mixture does not wet the support, shrinking does not ensure uniformity of the dosage.

[0109] B. met only on materials with high critical surface tension (> 35 dynes / cm) not suitable for the industrial production of orodispersihle films.

[0110] C. Met.

[0111] * test not feasible due to the adhesiveness of the formulation. All comparative formulations contain percentages of PVP or plasticizer outside the limits claimed by the present invention.

[0112] As shown in table 10, none of the comparative formulations tested has characteristics such as to allow the formation of a film suitable for orodispersibility.

[0113] Polymer mixtures with a percentage of PVP < 45% and a percentage of plasticizer <25% are too liquid to be spread on a support (e.g. C2, C6, CIO) or the resulting film is too tacky to withstand the flexibility test (e.g. C3, C8). The observed data is closely correlated to the percentages of PVP and plasticizer used in the mixture; in fact, varying the molecular weight of the pyrrolidone used (PVP K30 and PVP K12) and the type of support do not improve the film-forming characteristics.

[0114] Polymer mixtures with a percentage of PVP > 45% and a percentage of plasticizer >25% are too liquid to be spreadable on a support (e.g. C9) or the resulting film is too tacky to withstand the flexibility test (e.g. C4, C5).

[0115] The mixture comprising in addition to PVP and plasticizer 10% of sorbitol and 10% of sucralose (e.g. C7) has a viscosity suitable for being spread on a silicone support, but this condition occurs only in the presence of sorbitol and sucralose. However, the film obtained is excessively plastic and tacky.

[0116] Advantageously, with the present invention specific ratios between PVP and plasticizers have been defined which surprisingly give the composition the characteristics necessary to produce an orodispersible film.

Claims

CLAIMS1. Orodispersible film comprising:A film-forming substance consisting of at least one polyvinylpyrrolidone (PVP) in concentrations between 45 and 87.5% by weight;At least one plasticizer in concentrations between 7.5 and 25% by weight;Starch, in concentrations between 2.5 and 45% by weight where said percentages are percentages by weight calculated on the total weight of the dried film.

2. The orodispersible film according to claim 1, wherein said at least one PVP is a low or medium molecular weight PVP.

3. The orodispersible film according to claim 1, wherein said at least one PVP is PVP K30.

4. The orodispersible film according to one of claims 1 to 3, wherein said plasticizer is selected from the group comprising propylene glycol, glycerine, sorbitol, maltitol, citric acid esters and mixtures thereof.

5. The orodispersible film according to one of claims 1 to 4, wherein said starch is corn starch, optionally modified corn starch.

6. The orodispersible film according to one of claims 1 to 5, loaded with active ingredients or with nanoparticles and / or microparticles and / or emulsions incorporating them.

7. The orodispersible film according to claim 6, wherein said active ingredients have topical action in the oral cavity, selected from the group comprising antibacterial, antifungal, antiviral or oral disinfectant agents.

8. The orodispersible film according to claim 6, wherein said active ingredients are systemically active and selected in anti-inflammatories, drugs for the treatment of diseases of the central nervous system, muscle relaxants, antiemetics, antihistamines, beta-blockers, antiasthmatics, antihypertensives, antitussives, antidiarrheals, laxatives, type V phosphodiesterase inhibitors, anti-kinetosis agents.

9. The orodispersible film according to claim 6, wherein said active ingredients are selected from the group comprising DNA drugs, RNA drugs, peptides, monoclonal antibodies, hormones.

10. The orodispersible film according to claim 6, wherein said active ingredients are food supplements.

11. The orodispersible film according to claim 6, wherein said active ingredients are for veterinary use.

12. A method for preparing an orodispersible film according to one of claims 1 to 11 comprising: - Suspending, in a polar solvent, starch, PVP, at least one plasticizer and, optionally, at least one active ingredient;Spreading said mixture on a support;Drying said spread mixture; obtaining a film that, suitably cut, is ready to be packaged.

13. The method according to claim 13, wherein said solvent is water and said at least one plasticizer is emulsified in said water with the addition of surfactants and starch and PVP are added to said emulsion.

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