WO2017042681A1

WO2017042681A1 - Orodispersible films having fast disaggregation time for therapeutic or food use.

Info

Publication number: WO2017042681A1
Application number: PCT/IB2016/055298
Authority: WO
Inventors: Francesco Cilurzo; Francesco Roversi
Original assignee: Pharmafilm S.R.L.
Priority date: 2015-09-07
Filing date: 2016-09-05
Publication date: 2017-03-16
Also published as: ITUB20153446A1

Abstract

Orodispersible films comprising: a) An active ingredient for food or therapeutic use, b) A polymer mixture comprising a copolymer of (meth)acrylic acid- (meth)acrylic acid C1-C5 ester in salt form with an alkaline metal cation and a plasticizer, wherein the weight ratio between said polymer and the plasticizer is comprised between 9.5: 0.5 and 5.5: 4.5. and characterized by: a disaggregation time lower than 140 s a percent elongation at break (ε%) lower than 140%, a tensile stress (TS) higher than 1 MPa, an elastic modulus (or Young's modulus) higher than 0.3 MPa. These films have much superior mechanical properties compared to oral soluble films prepared with natural polymers, as well as a better stability over time due to a reduced sensitivity to humidity.

Description

Title: "Orodispersible films having fast disaggregation time for therapeutic or food use."

DESCRIPTION

FIELD OF THE INVENTION The present invention relates to quick disintegration orodispersible films for therapeutic or food use.

PRIOR ART

Oral soluble (orodispersible) films are part of the broader category of oral pharmaceutical films, complex polymeric matrices that can be used efficiently as pharmaceutical deliver}- forms. (1)

Specifically, orodispersible films are solid enteral pharmaceutical forms designed to quickly disintegrate in the oral cavity and reach the systemic circulation through gastro-intestinal absorption.

The above features make the oral soluble films particularly interesting in pediatrics and geriatrics, where inability to swallow, dysphagia or chrono-induced digestive malfunction may be responsible for poor patient's adherence to therapy and a difficulty in identifying the dosage form suitable for the administration of the drug.

In this sense, orodispersible films offer an excellent alternative to solid and liquid oral formulations of the conventional type: the ease of administration greatly increases the patient's compliance, even in those cases in which there is difficulty in swallowing; when compared with quick disintegration tablets, which are fragile and easily susceptible to breakage, oral soluble films are more stable and resistant than the others, offering mechanical properties, i.e. flexibility and handling, which facilitate the production thereof.

Compared to liquid dosage forms, widely used both in pediatrics and in geriatrics, oral soluble films allow for a more accurate dosage of the active ingredient and an improved stability over time compared to formulations in solution or suspension. (1 , 2)

Despite the many advantages, orodispersible films are enteral pharmaceutical forms still relatively new and which have, especially at the production and storage level, several drawbacks. (2)

The most common limitation of oral pharmaceutical films is instability over time, linked to a greater or lesser sensitivity of the formulation to the environmental humidity; an excess or a deficiency of water within the composition can change the mechanical properties of the polymer, causing the formation of films difficult to be handled by the patient because sticky or too fragile. (1 ) Moreover, the interposition of water molecules between the polymeric chains of the formulation can also alter the chemical properties of the film, leading to a premature disintegration of the pharmaceutical form or to an instability of the active ingredient contained therein.

The choice of the polymer forming the film is certainly the critical step of the production of an orodispersible film, not only because it is the component at a higher concentration, but also because the physical-chemical profile of the polymer is decisive in the realization of an effective pharmaceutical formulation, which respects critical quality parameters such as mechanical strength; stability; drug release profile; residual water content; appearance; organoleptic features.

The most commonly used materials for the production of orodispersible films, alone or in combination with synthetic materials, are polysaccharides; however, in contact with the saliva, said polymers tend to swell, causing an unpleasant sensation in the mouth, very little appreciated by the patient.

Moreover, even in the high structural variability, polysaccharides structurally consist of the repetition of saccharide units, responsible for the physical-chemical incompatibility of the above polymers and of the oral pharmaceutical forms they constitute with some active ingredients.

The need is therefore felt to have new orodispersible films available consisting of film-forming materials other than polysaccharides.

The copolymers of acrylic acid are among the biocompatible materials most frequently used in the pharmaceutical field for the production of formulations for oral administration; however, their applications are to date limited to the manufacture of gastroresistant pharmaceutical forms.

SUMMARY OF THE INVENTION

The applicant has now surprisingly found that orodispersible films comprising:

a) An active ingredient for food or therapeutic use

b) A polymer mixture comprising a copolymer of (meth)acrylic acid- (meth)acrylic acid C1-C5 ester in salt form with an alkaline metal cation and a plasticizer, wherein the weight ratio between said polymer and the plasticizer is comprised between 9.5: 0.5 and 5.5: 4.5.

and characterized by:

A disaggregation time lower than 140 s

A percent elongation at break (ε%) lower than 140%

A tensile stress (TS) higher than 1 MPa

An elastic modulus (or Young's modulus) higher than 0.3 MPa. possess satisfactory tensile properties to ensure the packaging and handling procedures by the patient, as well as a better stability over time due to a reduced sensitivity to environmental humidity.

DETAILED DESCRIPTION OF THE INVENTION

The term orodispersible film refers to a solid dosage form that dissolves in the oral cavity in less than 3 minutes, without it being necessary to chew or drink and which can be in variable shape or thickness depending on the formulation requirements. (3). The term copolymer of (meth)acrylic acid- (meth)acrylic acid C1-C5 ester refers to the polymer consisting of alternating units of acrylic acid or methacrylic acid and acrylic or methacrylic acid ester, wherein the chain of the alkoxy group may have a variable length between 1 and 5 carbon atoms.

In the formulation of the present invention, the above copolymer is in the form of a salt with an alkaline metal cation, wherein salt refers to the ionic complex formed between the alkaline metal cation and the acid groups of the macromolecule.

The alkaline metal cation used in the oral soluble films of the present application is preferably selected from those of sodium and potassium.

Preferably, the copolymer of mixture b) is the alkaline metal salt of the copolymer of (meth)acrylic acid- (meth)acrylic acid C1-C5 ester wherein the co-monomers constituting the macromolecule are combined in a weight ratio comprised between 1 : 1 and 1 :2.

Preferably, the copolymer of mixture b) is the alkaline metal salt of the methacrylic acid-methyl methacrylate copolymer wherein the co-monomers constituting the macromolecule are combined in a weight ratio comprised between 1 : 1 and 1 :2. These types of polymers are commercially available under the trademark Eudragit ® L 100 and Eudragit ® S 100.

More preferably, the copolymer of mixture b) is the alkaline metal salt of the methacrylic acid-ethyl acrylate copolymer wherein the co-monomers constituting the macromolecule are combined in a weight ratio of 1 : 1 and is commercially available under the trademark Eudragit® L 100-55.

Preferably, the plasticizer of mixture b) is selected from glycerin and PEG 400.

The active ingredient for food use can be selected from breath freshener compounds, plant extracts or other active ingredients with nutritional or healthy activity such as vitamins, minerals or probiotics. The active ingredient for therapeutic use contained in the pharmaceutical forms of the present invention can have local activity and therefore have anti-inflammatory, analgesic, antibacterial, antifungal, antiviral, anti-plaque or disinfectant activity. The active ingredient may also carry out a systemic activity and be selected from anti- inflammatory drugs, analgesics, antipsychotics, hypnotics, anxiolytics, antiemetics, anti-migraine drugs, muscle relaxing drugs, antiparkinson drugs, anti-kinetosis drugs, antihistamines, anti-asthmatics, cough drugs, antihypertensives, phosphodiesterase-5 inhibitors.

Active ingredients contained in such formulations are preferably selected from the group consisting of: Ketoprofen, diclofenac, olanzapine, tadalafil, alprazolam, selegiline, ebastine, nifedipine, metoclopramide, ondansetron, rizatriptan, salbutamol.

Moreover, depending on the organoleptic features of the ingredient, the film may be prepared using flavor masking agents, such as sweeteners and/or flavoring agents. The films object of the invention can be produced by known processes, such as that described in EP1689374 and which is briefly described by the following steps:

c) Solubilizing NaOH or KOH in water, in a thermostated bath at a temperature comprised between 50°-60°.

d) Adding the copolymer of (meth)acrylic acid-(meth)acrylic acid C1-C5 ester to the solution obtained in step a),

e) Adding the plasticizer to the solution obtained in step b) at a temperature of 40°,

f) Adding the active ingredient to the mixture obtained from c)

g) Spreading and drying the mixture obtained from d) on a silicone paper liner h) Cutting the films obtained from e) to the desired size.

The oral soluble films obtained according to the recipe of the present invention have specific chemical-physical features which make them superior to the more common orodispersible films based on polysaccharides. Specifically, the polymeric films of the present invention have in vitro disintegration times of less than 140 s, well below the 3 minutes mentioned in the relevant monographs of the Pharmacopoeia; they have an elongation at break of less than 140%, which allows a controlled ductility of the material without deformations in the production steps; they have a tensile stress (σ) higher than 1 MPa and an elastic modulus higher than 0.3 MPa, indices of a good toughness and resistance to breakage, without adversely affecting the flexibility of the material.

For the purposes of the present invention, percent elongation at break (ε%) is the degree of deformation (ductility) of the polymer film upon the application of a tension force, before said film breaks. Elongation is an important feature for purposes of production, since the higher the ε%, the easier it is that there is a stretching of the polymeric material in the cutting steps of the final dosage forms.

The percent elongation is defined as the percentage ratio between the extension of the film at the time of breaking (L - L₀) and the initial length of the sample (L₀), according to the equation: ε /₀ = -__ -— ILL _{* l}oo

The tensile stress (σ) instead represents the tenacity of the polymeric film, or the stress necessary to move from a reversible deformation to an irreversible deformation of the orodispersible film itself.

The toughness of the material is of great importance for the stability of the final product, since it must be sufficient to prevent accidental breakage of the solid dosage form during the various production, packaging, storage and distribution steps.

This index is calculated by dividing the maximum load applied along the main axis of the sample (F) by the initial cross-sectional area of the polymeric film produced (Ao) and is therefore measured in Pascal (Pa), as a force on unit area: σ = F/A₀

The flexibility of the polymeric films of the present invention is determined by the elastic modulus (or Young's modulus), characteristic quantity of a polymeric material that measures the resistance of the structure to tensile stress.

Very low elastic modulus values are indicative of a too flexible material for proper handling by the patient.

The elastic modulus (E) is described as the ratio of tension (σ) and deformation of the material in the case of uniaxial load conditions (ε) and is therefore measured in Pascal (Pa).

The formula for the calculation of E is as follows:

σ

E = - ε

EXAMPLE 1: Preparation of placebo orodispersible films

A thermostated bath is prepared at about 50-60 °C in which the dissolution of the alkaline metal hydroxide is carried out in fresh deionized water. When completely dissolved, the copolymer Eudragit L 100 or the copolymer Eudragit S 100 is added under magnetic stirring until complete salification of the polymer and until the mixture formed is homogeneous, without aggregates.

Once the temperature of the bath has been lowered to 40 °C, the plasticizer is added and the mixture is left to stand overnight at room temperature and without stirring, in order to aid the disappearance of the bubbles.

The polymeric mixture thus prepared is spread and subsequently dried on a silicone paper liner, through the use of a Laboratory-coating unit Mathis LTE-S (M) (CH); the instrument's process parameters have been adapted to the individual formulations in order to obtain films with a thickness of about 100 microns and qualitatively acceptable from a visual and handling point of view.

Films which may prove difficult to handle (difficulty of spreading the mixture on a support, strong shrinkage before or after drying, inability to drying, obtaining a product not definable as film) were excluded a priori for impossibility of production.

The formulations from which it was possible to produce films are those given in Table 1.

EuLNa EuLK EuSNa EuSK PEG Gly

Formulation

(%) (%) (%) (%) (%) (%)

1 90 - - - 10 -

2 80 - - - 20 - ar 3 70 _ _ _ 30 _

4 60 40

5 50 - - - 50 - 6 40 60

7 30 70

8 - 90 - - 10 -

9

ar - 80 - - 20 - o

10 - 70 - - 30 -

11 - 60 - - 40 -

12 - - 90 - 10 -

13 - - 80 - 20 - ar

o 14 - - 70 - 30 -

15 - - 60 - 40 - 16 50 50

Table 1: Percent weight/total weight compositions of mixture b). EuL = Eudragit L 100; EuS = Eudragit S 100; Na = salification obtained by NaOH; K = salification obtained by KOH. PEG = Polyethylene glycol (PEG 400); Gly = Glycerin.

1.1. Methodology - Determination of tensile properties.

The analysis of tensile properties was performed using an electronic dynamometer Instron 5965, equipped with a load cell of 50 N. The test is performed in accordance with the ASTM standards (International Test Method for Thin Plastic Sheeting) (D882-02) .

To perform the characterization tests, the films were cut into strips sized 6 cm² (3 cm x 2 cm), packed in aluminum envelopes hermetically sealed and stored in an oven at 25 °C.

After a period of 13 days in these conditions, the films were subjected to tensile tests for the determination of mechanical properties such as Tensile Stress (σ), Percent Elongation at Break (ε%) and Elastic Modulus (E).

The test results are expressed as mean ± standard deviation of 5 measurements for each formulation.

Once the absence of imperfections in the matrix had been verified, the film samples were longitudinally positioned between two pneumatic grips spaced apart by 40 mm and programmed in such a way to move away at a speed of 12.5 mm/min. The test is concluded upon the break of the film.

1.2.Methodology - Determination of the disintegration time.

The disintegration assay was performed according to the specifications given in the European Pharmacopoeia, in the monograph "DISINTEGRATION OF TABLETS AND CAPSULES", using 6 cm² samples. Three tests were performed for each formulation and the results of the disintegration time (T_D) were expressed as the average of the three.

The disintegration medium used is artificial saliva at 37 °C, the composition of which in water comprises:

- Na₂HP0₄ 2.38 g/L

- KH₂PO₄ 0.19 g/L,

- NaCl 8 g/L

The test was considered finished upon the complete disintegration of the film samples, which must not exceed 3 minutes based on the specifications of the Pharmacopoeia.

1.3.Results

The formulations 1-26 in Table 1 were subjected to tensile tests and to the disintegration test, using the methodologies described at points 1.1 and 1.2.

The results of these tests are reported hereinafter in Table 2.

T_D

Formulati Tensile Properties of Films Thicknes

(second s on σ (MPa) ε (%) E (MPa)

s) (μιη)

14.687±1.05 18.676±3.896 4.037±0.12 71.0±3.2

1 30

3 5

1.132±0.33 80.6±5.3

2 20 3.397±0.645 37.833±13.590

4

3.492±0.29 92.2±21.

3 30 9.286±0.318 5.776±0.938

7 2

273.768±37.26 0.399±0.13 109.4±7.

4 30 1.538±0.127

1 0 1

144.870±34.19 1.235±0.41 100.8±1

5 30 3.706±0.274

6 6 OJ.

378.818±111.6 0.048±0.01 134.4±5.

6 30 0.289±0.061

62 7 0

254.042±40.24 0.094±0.01 107.8±1

7 30 0.782±0.073

6 5 08

3.125±0.20 88.8±8.9

8 15 9.804±0.852 18.348±1.282

6

2.931±0.39 102.2±7.

9 15 8.191±1.667 21.369±7.977

4 4

1.848±0.25 93.6±8.3

10 40 5.327±0.481 47.242±18.054

5

11 20 5.875±1.628 55.676±24.793 2.669±0.80 108.0±3. 0 5

0.335±0.17 121.4±1

12 120 1.498±0.446 44.220±13.645

6 32

2.607±0.38 80.0±5.8

13 30 9.038±1.127 31.239±5.244

8

120.223±65.47 0.083±0.02 133.8±2

14 90 0.568±0.1 12

0 2 4J,

510.084±80.1 1 0.455±0.16 107.2±2

15 40 0.462±0.046

2 0 05

958.407±45.41 0.121±0.03 113.6±3.

16 120 0.541±0.046

5 3 6

208.024±69.71 0.145±0.04 121.0±8.

17 60 0.205±0.026

2 2 7

0.311±0.14 110.4±1

18 90 1.208±0.154 69.074±26.442

8 H9

130.039±21.44 0.643±0.21 95.2±16.

12 20 1.997±0.231

4 6 5

379.074±100.7 0.076±0.01 118.4±1

20 40 0.578±0.121

06 3 3

0.132±0.03 73.2±6.5

21 60 0.627±0.022 900.000±0.000

7

12.942±3.15 3.882±0.63 75±5

22 24 9.206±4.069

6 6

2.203±0.17 70±6

23 35 9.371±0.404 43.327±7.554

6

2.378±1.32 25±4

24 14 9.005±2.341 8.001±2.150

7

10.123±1.40 2.016±0.45 26±5

25 11 24.565±4.245

0 3

1.168±0.31 33±9

26 8 6.691±2.000 25.682±7.573

3

Table 2.

Table 2 shows that formulations 1-3, 8-1 1, 12-13, 18-19, 22-23 and 24-26 allow obtaining orodispersible films with excellent mechanical properties and competitive disintegration times.

The above compositions allow obtaining oral soluble forms which disintegrate very quickly in contact with saliva, making the disintegration time (T_D) significantly lower than the three minutes given by the Pharmacopoeia. The Tensile Stress (σ) much higher than 1 MPa suggests that films 1-3, 8-11, 12-13, 18-19, 22-23 and 24-26 have considerable toughness, especially if we take into account the thickness obtained for some of these films.

High values of σ ensure that the resulting oral soluble film is less subject to accidental breakage during the various handling steps of the pharmaceutical form (from the production to the patient).

The high toughness does not affect the flexibility of the polymeric films of the above compositions, where the elastic modulus values remain above 0.3 MPa. Lower values lead to too "soft" films hardly applicable to the oral cavity by the patient. Finally, formulations 1-3, 8-11, 12-13, 18-19, 22-23 and 24-26 have also shown to have low values of percent elongation and in particular lower than 140%; values exceeding this limit leads to production difficulties, with particular reference to uniformity of dosage, related to the stretching of the polymeric material in the cutting step.

The oral soluble formulations that meet these requirements are those whose weight ratios are between 9.5: 0.5 and 5.5: 4.5.

Example 2 - Preparation of the orodispersible films containing active ingredients.

Formulation 2, comprising Eudragit L 100 salified with NaOH and PEG-400 in a weight ratio of 1 :4, was selected to make orodispersible films delivering the active ingredient.

The choice of the above formulation was made at a preliminary level on the basis of the best disintegration time, limited to the group of formulations a.

While formulation 2 is not the best among the optimal formulations mentioned in Example 1, the above was chosen to assess to what extent the addition of the active ingredient could affect the mechanical properties of the film.

The four active ingredients intended to be delivered by means of the film are reported in Table 3; the amounts to be loaded were selected on the basis of preparations available on the market.

Active ingredient Amount delivered (mg)

12.5 mg

Diclofenac sodium

25 mg Ketoprofen 25 mg

Olanzapine 2.5 mg

Tadalafil 2.5 mg

Table 3.

The preparation of the above orodispersible films delivering the drug was conducted as described in Example 1 for the placebo formulations, with the only exception that the active ingredient was added just after the plasticizer, before the mixture was left to rest.

With each of the selected active ingredients it was possible to make non-adhesive films that could be handled and with the active ingredient uniformly distributed.

The characterization of the tensile properties and of the disintegration time allowed verifying that the addition of an active component to the starting polymeric mixture does not alter the chemical- hysical profile of the oral form (Table 4).

As can be seen in Table 4, the disintegration times of the film with active ingredient are consistent with those originally obtained from the placebo film and still lower than the 3 minutes indicated in the monograph of the Pharmacopoeia.

The films obtained all have good tensile properties, with percent elongation in the ranges object of the invention.

BIBLIOGRAPHIC REFERENCES MENTIONED IN THE DESCRIPTION:

1. Oral Films: current status and future perspective I - Galenical development and quality attributes; Ana Filipa Borges, Claudia Silva, Jorge F.J. Coelho, Sergio Simoes; Journal of Controlled Release 206 (2015) 1-19

2. Advances in orodispersibile films for drug delivery; Eva Maria Hoffmann, Armin Breitenbach, Jorg Breitkreutz; Expert Opinion on Drug Delivery 2011 8(3).

3. Orodispersible Film: A Novel Approach for Patient Compliance; Rajesh Asija*, Manmohan Sharma, Avinash Gupta, Shailendra Bhatt; International Journal of Medicine and Pharmaceutical Research, 2013: Vol.1(4): 386-392

Claims

1. Orodispersible films comprising:

a) An active ingredient for food or therapeutic use

b) A polymer mixture comprising a copolymer of (meth)acrylic acid-

(meth)acrylic acid C1-C5 ester in salt form with an alkaline metal cation and a plasticizer, wherein the weight ratio between said polymer and the plasticizer is comprised between 9.5: 0.5 and 5.5: 4.5.

and characterized by:

- a disaggregation time lower than 140 s

a percent elongation at break (ε%) lower than 140%

a tensile stress (TS) higher than 1 MPa

an elastic modulus (or Young's modulus) higher than 0.3 MPa.

2. Orodispersible films according to claim 1, wherein said alkaline metal cation is selected from that of sodium or potassium.

3. Orodispersible films according to claim 1 or 2, wherein the copolymer of mixture b) is the alkaline metal salt of the (meth)acrylic acid-(meth)acrylic acid C1-C5 ester copolymer wherein the above co-monomers are in a weight ratio comprised between 1 : 1 and 1 :2 with respect to each other.

4. Orodispersible films according to claim 3, wherein the copolymer of mixture b) is the alkaline metal salt of the methacrylic acid-methyl methacrylate copolymer wherein the co-monomers constituting the macromolecule are combined in a weight ratio comprised between 1 : 1 and 1 :2.

5. Orodispersible films according to claim 3, wherein the copolymer of mixture b) is the alkaline metal salt of the methacrylic acid-ethyl acrylate copolymer wherein the co-monomers constituting the macromolecule are combined in a weight ratio of 1 : 1.

6. Orodispersible films according to any one of claims 1-5, wherein the plasticizer of mixture b) is selected from glycerin and PEG 400.

7. Orodispersible films according to claims 1, 2, 3, 4 and 6, wherein the polymer mixture b) comprises the sodium salt of the methacrylic acid-methyl

methacrylate copolymer in a weight ratio of 1 : 1 and PEG 400, wherein copolymer and plasticizer are in a weight ratio comprised between 9.5: 0.5 and 6.5: 3.5.

8. Orodispersible films according to claim 1, 2, 3, 4 and 6, wherein the polymer mixture b) comprises the potassium salt of the methacrylic acid-methyl methacrylate copolymer in a weight ratio of 1 : 1 and PEG 400, wherein the copolymer and the plasticizer are in a weight ratio comprised between 9.5: 0.5 and 5.5: 4.5.

9. Orodispersible films according to claim 1, 2, 3, 4 and 6, wherein the polymer mixture b) comprises the sodium salt of the methacrylic acid-methyl

methacrylate copolymer in a weight ratio of 1 :2 and PEG 400, wherein copolymer and plasticizer are in a weight ratio comprised between 9.5: 0.5 and 7.5: 2.5

10. Orodispersible films according to claims 1, 2, 3, 4 and 6, wherein the polymer mixture b) comprises the potassium salt of the methacrylic acid-methyl methacrylate copolymer in a weight ratio of 1 :2 and PEG 400, wherein copolymer and plasticizer are in a weight ratio comprised between 9.5: 0.5 and 7.5: 2.5

11. Orodispersible films according to claim 1, 2, 3, 4 and 6, wherein the polymer mixture b) comprises the sodium salt of the methacrylic acid-methyl

methacrylate copolymer in a weight ratio of 1 :2 and glycerin, wherein copolymer and plasticizer are in a weight ratio comprised between 8.5: 1.5 and 5.5: 4.5

12. Orodispersible films according to claim 1, 2, 3, 4 and 6, wherein the polymer mixture b) comprises the sodium salt of the methacrylic acid-methyl

methacrylate copolymer in a weight ratio of 1 : 1 and glycerin, wherein copolymer and plasticizer are in a weight ratio comprised between 7.5: 2.5 and 5.5: 4.5

13. Orodispersible films according to each of claims from 1 to 12 for therapeutic or food use.

14. Process for the production of orodispersible films according to claims 1-13, comprising the following stages:

c) Solubilizing NaOH or KOH in water, in a thermostated bath at a temperature comprised between 50°-60°. d) Adding the copolymer of methacrylic acid C1-C5 ester/methacrylic acid to the solution obtained in stage c),

e) Adding the plasticizer to the solution obtained in stage d) at a temperature of

40°,

f) Adding the active ingredient to the mixture obtained from e)

g) Spreading and drying the mixture obtained from f) on a silicone paper liner h) Cutting the films obtained from g) to the desired size.