WO2020171780A1

WO2020171780A1 - Three dimensionally printed films

Info

Publication number: WO2020171780A1
Application number: PCT/SI2020/050006
Authority: WO
Inventors: Egidij Capuder; Brina Ornik; Matjaž POLAK
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-02-22
Filing date: 2020-02-12
Publication date: 2020-08-27
Anticipated expiration: 2021-08-22
Also published as: SI25783A

Abstract

The present invention relates to three dimensionally printed films comprising at least one layer and at least one lipophilic and /or lipophobic active substance. In particular, three dimensionally printed films comprising cannabinoids, preferably CBD, are described. The invention further relates to a printable composition, method of preparation of the films and use thereof.

Description

Three dimensionally printed films

Field of the Invention

The present invention relates to three dimensionally printed films for delivering lipophilic and lipophobic active substances, printable compositions, methods of making three dimensionally printed films and using the same. More specifically, the invention discloses three dimensionally printed films having at least one layer and one active substance.

Background of the Invention

Oral films are a group of flat films which are administered into the oral cavity. They are placed on or under the tongue, where they then dissolve. Trans mucosal films are absorbed by the body directly via the oral mucosa. Advantage of oral thin film

formulations resides in their ability to bypass the gastrointestinal tract and barriers in the gastrointestinal tract to avoid drug absorption such as first pass metabolism and decomposition of the active ingredient in the stomach. Quicker onsets of actions at lower dose are available.

An additional advantage for these dosage forms, when compared to tablets, capsules and other dosage forms that must be swallowed, is that some patient populations have difficulty swallowing, such as children and the elderly. Other advantages are convenient dosing, no water needed, no risk of chocking, possibility of taste masking, enhanced stability, availability of large surface area that leads to rapid disintegration within oral cavity, dose accuracy in comparison to syrup or oil drops.

Generally, the commercially available thin films intended for the oral and/or buccal route are produced by solvent casting method, hot-melt extrusion, semisolid casting, solid dispersion extrusion and rolling. Most commonly, both, the percentage of active substance and total load is limited.

Both, lipophilic and lipophobic active substances can be of interest to be delivered by oral or any other films. Lipophilic substances must be properly formulated to be delivered by water soluble matrix of the film.

Cannabinoids are typical representatives of lipophilic substances. A cannabinoid is one of a class of diverse chemical compounds that acts on cannabinoid receptors in cells that alter neurotransmitter release in the brain. Ligands for these receptor proteins include the endocannabinoids (produced naturally in the body by animals), the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured artificially). The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is another major constituent of the plant. There are at least 1 13 different cannabinoids isolated from cannabis, exhibiting varied effects. Raw botanical extracts of cannabinoids, in their concentrated form, are typically viscous oils at room temperature and pressure. These oils contain cannabinoids, plant waxes, plant lipids, and sometimes plant pigments such as chlorophylls. These raw botanical extracts present some problems for incorporation into oral dissolvable film when treated like dry, solid, crystalline active substances.

The cannabis compounds are generally administered by inhalation of smoke or vapors, ingestion of edible capsules or liquid extracts such as tinctures or oils, use of topical solutions and ingestible films or wafers. But each mode of delivery has its own disadvantages. For example, the current delivery systems of smoking, and vaporizing are unhealthy, inconvenient and lack proper dosage control. Oral administration of cannabis compounds, like any medication is not always“fast-acting”, a property clearly desirable in the treatment of acute breakthrough pain, for example. Besides, some pediatric and/or geriatric patients have difficulty taking an oral medication due to inability to swallow, nausea or other gastrointestinal problems. Alternative to solid dosage forms, e.g. liquids, syrups or suspensions often deteriorate rapidly upon exposure to heat or other atmospheric conditions and consequently have a relatively short shelf life. The films or wafers containing cannabis extracts are often very sticky, have a bitter after- taste and hence can contribute to patient non-compliance. In addition, conventional thin films or wafers often do not include a high load of the active ingredient.

THC and CBD are highly hydrophobic, which presents challenges for formulating compositions suitable for convenient administration to human and animal subjects. A need therefore exists for stable and convenient THC and CBD dosage forms.

US 10,092,61 1 discloses a method of obtaining an extract of Cannabis plant and pharmaceutical dosage forms (oral thin films, transdermal patches) comprising the extract. The manufacture of the described oral thin films includes the casting and drying of a viscous liquid or slurry. US 2017/0290870 discloses oral thin film comprising a matrix and active agent, e.g. extracted substance obtained from cannabis or hemp, uniformly dispersed in the matrix. The film includes 1 % to 70% by weight of active agent in the film.

US 2016/0051510 disclose oral dissolvable thin films that include botanical extract. Method of preparing the thin films includes hot extruding, casting and condensing the slurry to provide the thin film.

WO 2018/094037 discloses oral thin films comprising plant extracts comprising cannabidiol and methods of making them. The method of preparing the described films includes preparation of viscous solution comprising cannabidiol which is fed through a casting machine. The extruded film is then dried or heated to evaporate excess solvent. The sheet may then be divided into dosage units or other sized portions for further processing.

Generally, the commercially available and other prior art thin films intended for oral and/or buccal route are produced by conventional film forming methods, e.g. solvent casting method, hot-melt extrusion, semisolid casting, solid dispersion extrusion and rolling.

Dose uniformity is a common problem of thin films prepared by conventional methods. In addition, special physical and mechanical features for film processing e.g. tensile strength are required.

Therefore, there is a need to prepare a film formulation by a simple process.

Advantages of the present invention:

Customized film formulation regarding dose and taste can be produced by a three dimensional (3D) printing process. Unlimited combination of active substances and layers possible, useful also for high doses and high loads. Highly simplified industrial process, requiring no special physical and mechanical features for the film processing and therefore enables simplified composition. Summary of the invention

The present disclosure provides three dimensionally printed films for delivering lipophilic and lipophobic active substances, methods of making and using the same. Preferably it provides three dimensionally printed films comprising cannabis compounds, most preferably THC and CBD. The present disclosure further provides printable

compositions which enable a defined printing process.

Detailed description of the invention

A first aspect of the present invention is directed to a three dimensionally printed film comprising at least one layer comprising a lipophilic and /or lipophobic active

substance. Additional layers, comprising the same or different active substance, may be present depending on the needs.

The lipophilic and the lipophobic active substance may be selected from medicaments, e.g. analgesics, muscle relaxants, antihistamines, decongestants, anti-inflammatories, antibiotics, antivirals, psychotherapeutics, hormones, cardiovascular agents, vitamins, minerals, steroids, nutraceuticals, vaccines, diagnostics.

As used herein“active substance” means any substance that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of the disease, or effects the structure or any function of the body of man or animals.

Therefore“active substance” as used herein is intended but not limited for use in the fields of human and veterinarian medicine, diagnostic, food, food supplements, medical devices, cosmetics. Preferably active substance is selected from cannabidoids.As used herein the term“cannabinoid” refers to a chemical substance that shows direct or indirect activity at a cannabinoid receptor and includes but is not limited to purified food and pharmaceutical grade substances, which may be obtained by purification from a natural source or via synthetic means. The cannabinoid substance may be a raw botanical extract of cannabinoids in the form of an emulsion without waxes and oils, oil, paste, liquid, resin or crystal, purified isolated individual cannabinoids of different purity, synthetic cannabinoids and derivatives thereof, cannabidiol (CBD),

tetrahydrocannabinol (THC), derivatives thereof or any combinations of cannabinoids. The most important cannabinoid substances include THC and CBD. Preferably the film may contain THC and/or CBD in any ratio. The cannabinoid substance may be extracts of the cannabis plants and also individual cannabinoids, whether or not derived from cannabis plants, and also combinations thereof. Cannabinoids can be combined by any other lipophilic or lipophobic substance.

As used herein, "Cannabis" includes wild type Cannabis saliva and variants thereof, including cannabis chemotypes which naturally contain widely different amounts of individual cannabinoids.

When the active substance is CBD, then it may be present in a purity of at least 90% wt and up to about 100% wt, with little or no trace of THC. When the active substance is THC, it may be present in a purity of at least 90% wt and up to about 100% wt, with little or no trace of CBD. The active substance may be present in the film in an amount from about 1 % to about 70% wt.

The amount of active substance that can be used in the films of the present invention depends on the dose needed to provide desired amount of the active substance. In case the active substance is CBD, CBD represents from about 1 % wt of the film to about 70% wt of the film. In case the active substance is THC, THC represents from about 1 % wt to about 70% wt of the film.

The film according to the present invention includes at least one film forming polymer. The film forming polymers can be selected from the group consisting of pullulan, hydroxy propyl methyl cellulose (HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone (PVP), carboxymethyl cellulose, polyvinyl alcohol (PVA), sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxy vinyl polymer, amylose, high amylose starch, hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein. The polymers can be used alone or in combination.

A preferred film forming polymer is PVP, in amounts ranging from about 3% wt to about 40% wt of the film, preferably from about 8% wt to 35% wt of the film. PVP can be used in combination with HPMC and PVA.

The film according to the present invention further comprises a plasticizer. Said plasticizer comprises one or more of: polyols, glycols, acetins, carboxylic acid, and esters of carboxylic acid. More particularly, optionally said plasticizer comprises one or more of: polyethylene glycol, glycerol, triacetin, citric acid, and triethyl citrate. Optionally said plasticizer or plasticizers are present in an amount from about 0.5% wt to about 20% wt of the solid film. More particularly, optionally said plasticizer or plasticizers are present in an amount from about 2% wt to about 15% wt of the solid film.

The film of the invention may further comprise a disintegrating agent selected from croscarmellose sodium, sodium starch glycolate, polyvinyl pyrrolidone,

carboxymethylcellulose, hydroxy propyl methyl cellulose, alginate, mannitol, glucose, derivatives thereof, and combinations thereof, or the like. The disintegrating agent is present in the amount from about 3% wt to about 45% wt, preferably from about 8% wt to about 30% wt.

The film according to the present invention may further comprise a surfactant. The surfactant may be selected from sodium lauryl sulfate, poloxamers, sorbitan esters, polysorbates (PEG-ylated sorbitan (a derivative of sorbitol) esterified with fatty acid), sorbitans, stearic acid, derivatives thereof, and combinations thereof. Preferably the surfactant is selected from Poloxamer 407 and Polisorbat.

Suitable amount of surfactant is ranging from about 1 % wt to 35% wt, preferably from about 5 to about 25% wt.

The film of the present invention may further comprise a mucoadhesive agent. Suitable mucoadhesive agents include, e.g., carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone (povidone), sodium alginate, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycols, carbopols, polycarbophils, carboxyvinyl copolymers, propylene glycol alginate, alginic acid, methyl methacrylate copolymers, tragacanth gum, guar gum, karaya gum, ethylene vinyl acetate,

dimenthylpolysiloxanes, polyoxyalkylene block copolymers, pectin, chitosan,

carrageenan, xanthan gum, gellan gum, locust bean gum, and

hydroxyethylmethacrylate copolymers.

The film of the present invention further comprises taste masking agents, flavouring agents, sweeteners and colouring agents.

The films described herein may be any of desired thickness. Size and shape depend on the intended use. The thickness of the one layered sheet can range from 50 m to 1000 m, preferably from 80 m to 300 m. The thickness of the multi layered films can range from 80 m to 5000 m. The film of the invention can be formulated as immediate or controlled release and can be administered, but not limited to, as sublingual, buccal, topical dosage form.

Composition of the present invention can be formulated as one or more unit dosage form, potentially applying a score line.

The film described herein enables high dosing accuracy.

Another object of the present invention is directed to a three dimensionally printed film comprising at least one layer comprising a cannabinoid substance.

Cannabinoid substance may be combined by any other lipophilic or lipophobic substance. Additional layers, comprising the same or different active substance, may be present depending on the needs.

Another object of the invention is directed to a three dimensionally printed film

comprising at least one layer comprising CBD as active substance. CBD may be natural or synthetic, present in the form of oil, wax, crystals, resin, powder or paste.

According to a preferred embodiment, the three dimensionally printed film according to the invention comprises, based on the total weight of the film,

(A) CBD oil: 10 - 47 % wt,

(B) PVP: 10 - 35 % wt,

(C) HPMC: 2 - 20 % wt,

(D) Surfactant: 5 - 20% wt,

(E) Mannitol: 2 - 20 % wt,

(F) Optionally further excipients.

According to a particularly preferred embodiment, the three dimensionally printed film according to the invention comprises, based on the total weight of the film,

(A) CBD oil: 10 - 47 % wt,

(B) PVP: 10 - 35 % wt,

(C) HPMC: 2 - 20 % wt,

(D) Glycerol: 3 - 15 % wt,

(E) Poloxamer 407: 5 - 20% wt,

(F) Mannitol: 2 - 20 % wt,

(G) Edible colour 5 - 25 % wt, (H) Mint aroma: 0,5 - 5% wt,

(I) Optionally further excipients.

Solvents used for preparation of printable composition in the form of printing liquid paste.:

Water - solvent: 20 - 80 % wt to non-volatile components

Ethanol - solvent: 200 - 400 % wt to non-volatile components

Solvents might be predominantly selected from protic and aprotic polar groups.

Possible edible colour has the following composition: glucose syrup, saharose, lemon, safran, gel formation agent - caragenan, acidification agents - lactic acid, colour E133.acetic acid, Na-lactat, preservative - potassium sorbat,

Suitable dose depends on the disease to be treated. Dose may vary from about 2 mg to about 150 mg.

Furthermore, another object of the invention is a printable composition which typically forms a paste consistency and enables a defined printing process.

The printable composition comprises:

A. Active substance, 10 - 47 % wt.,

B. At least one film forming polymer, 10 - 35 % wt,

C. At least one disintegrating agent, 5 - 25 % wt,

D. Surfactant, 5 - 20 %wt,

E. Plasticizer, 3 - 15 % wt,

F. Ethanol, 200 - 400 % wt to non-volatile ingredients,

G. Water, 20 - 80 % wt to non-volatile ingredients,

H. Optionally further excipients and solvents.

Composition ranges for non-volatile ingredients are defined for composition without solvents.

The printable composition is suitable for three dimensionally printing of the films of the invention. The active substance of the printable composition may be lipophilic or lipophobic and may be selected from medicaments, e.g. analgesics, muscle relaxants, antihistamines, decongestants, anti-inflammatories, antibiotics, antivirals, psychotherapeutics, hormones, cardiovascular agents, vitamins, minerals, steroids, nutraceuticals, vaccines, diagnostics.

Other ingredients of the printable composition are the same as described above in relation to the three dimensionally printed film of the invention.

A further object of the invention is a CBD printable composition which comprises:

A. CBD oil, 10 - 47 % wt,

B. PVP, 10 - 35 % wt,

C. HPMC, 2 - 20 % wt,

D. Surfactant, 5 - 20 % wt,

E. Glycerol, 3-15 % wt,

F. Mannitol, 2- 20 % wt,

G. Ethanol 200 - 400 % wt to non-volatile ingredients,

H. Water 20 - 80 % wt to non-volatile ingredients,

I. Optionally further excipients and solvents.

Another object of the invention is a method for preparing the three dimensionally printed film of the present invention. The method includes the following steps: a) preparing the printable composition, b) three dimensional printing, c) drying the film. The thin film of the invention is made by a three dimensional (3D) printing process. Suitable 3D printing techniques include fused deposition modelling (FDM), dispensing valve, jetting and air/pulse technology and combinations thereof.

1 . FDM (hot melt extrusion)

Filament from appropriate polymer is extruded through a pre-heated nozzle. Mixture for printing is heated twice, first during filament preparation and second during the 3D printing process. Process temperature is equal or higher than melting point of the polymer.

2. 3D printing with dispensing valves

The deposition of the film material is achieved via fluid or paste dispensing valves, where different types of valves can be used. Pressure or mechanically activated valves (pinch, spool, needle or diaphragm valves) deposit the material, which is stored in a pressurized chamber, or gravity feed to the depositing needle. When the valve is open the material flows onto the printing surface.

The valve is mounted on a mechanical actuator (linear stage, robotic arm or similar) which moves according to the computer program. The program defines the shape.

3. Jetting

Printing head (INK JET) with high resolution is dispensing printing liquid to the printing surface at room temperature, or higher or lower depending on the fluid properties. The printing head is driven with a drop-on-demand of printing driver. After printing liquid is deposited on printing area, final shape is achieved with increased temperature or UV light (polymerization).

4. Air pulse dosing

No dosing valves are used to deposit printed material onto printed area. Dosing of the printing paste through printing nozzle is controlled with air (gas) pressure in the dispensing chamber.

Layers of the material can be deposited via any of the described methods, forming a 3D printed structure.

Preferable printing device for three dimensional printing of the instant dosage form is needle dosing type with pneumatic dispensing valve.

Typical process parameters of 3D printing:

Air pressure 0,5 - 10 bars

XY needle speed 0-1 10 mm / s

ID (inside diameter) of printer nozzle 0,2 - 1 ,2 mm

Any other type of dispensing valve can be used, e.g. extrusion type or piston driven type.

Useful solvents include alcohols, preferably ethanol, water, aprotic solvents e.g.

acetonitrile, acetone, isopropanol. Preferable solvent is a combination of ethanol and water in ratio from 0 to 100 v/v, preferably from 5 to 20 % v/v

The printing liquid paste should have a proper viscosity.

In particular, the following items are provided by the present inventors:

1 . A three dimensionally printed film comprising at least one layer comprising lipophilic and / or lipophobic active substance.

2. The film according to item 1 wherein the active substance is selected from a group of cannabinoids.

3. The film according to items 1 and 2 wherein the active substance is a raw botanical extract of cannabinoids.

4. The film according to items 1 and 2 wherein the lipophilic substance is THC.

5. The film according to items 1 and 2 wherein the lipophilic substance is CBD.

6. The film according to item 1 and 2 wherein the lipophilic active substance is mixture of THC and CBD in any ratio.

7. The film according to items 1 and 6, where in the amount of THC is less than 0.2% wt.

8. The film according to items 1 and 4 wherein THC is in form of oil, wax, oil, crystals, resin, powder or paste. 9. The film according to items 1 and 5 wherein CBD is in form of oil, wax, crystals, resin, powder or paste.

10. The film according to items 1 and 5 which comprises:

(A) CBD oil: 10 - 47 % wt,

(B) PVP: 10 - 35 % wt,

(C) HPMC: 2 - 20 % wt,

(D) Surfactant: 5 - 20% wt,

(E) Mannitol: 2 - 20 % wt,

(F) Optionally further excipients.

1 1 .The film according to items 1 and 5 which comprises:

(A) CBD oil: 10 - 47 % wt,

(B) PVP: 10 - 35 % wt,

(C) HPMC: 2 - 20 % wt,

(D) Glycerol: 3 - 15 % wt,

(E) Poloxamer 407: 5 - 20% wt,

(F) Mannitol: 2 - 20 % wt,

(G) Edible color 5 - 25 % wt,

(H) Mint aroma: 0,5 - 5% wt,

(I) Optionally further excipients.

12. The film according to item 1 wherein the layer comprises additional lipophilic or lipophobic active substance.

13. The film of item 1 comprising one or more additional layers.

14. The film of items 1 and 13 wherein the additional layer comprises an additional active substance.

15. The film of items 1 and 14 wherein the additional active substance is selected from medicaments, nutraceuticals, vaccines, diagnostics, food, food supplements, medical devices and cosmetics.

16. The film according to any proceeding items wherein the at least one layer further comprises a film forming agent selected from the group consisting of pullulan, hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone (PVP), carboxymethyl cellulose, polyvinyl alcohol (PVA), sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxy vinyl polymer, amylose, high amylose starch, hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein.

17. The film according to item 16 wherein the film-forming polymer is polyvinyl

pyrrolidone

18. The film according to iteml 6 wherein the film-forming polymer is polyvinyl

pyrrolidone in combination with hydroxypropylmethyl cellulose.

19. The film according to iteml 6 wherein the film-forming polymer is polyvinyl

pyrrolidone in combination with, polyvinyl alcohol.

20. The film according to any of the proceeding items wherein the amount of film

forming agent is from 3% wt to 40% wt, preferably from 8% wt to 35% wt of the film.

21 .The film according to any of the proceedings items wherein the at least one layer further comprises a disintegrating agent selected from a group of croscarmellose sodium, sodium starch glycolate, insoluble polyvinyl pyrrolidone, hydrxypropylmethyl cellulose, carboxymethylcellulose, alginate, mannitol, glucose, derivatives thereof, and combinations thereof.

22. The film according to item 21 wherein the disintegrating agent is present in the

amount from 3% wt to 45% wt, preferably from 8% wt to 30% wt.

23. The film according to any of the proceeding items wherein at least one layer further comprises a surfactant selected from a group of sodium lauryl sulfate, poloxamers, sorbitan esters, polysorbates, sorbitans, stearic acid, derivatives thereof, and combinations thereof.

24. The film according to item 23 wherein the amount of surfactant is from 1 % wt to 35% wt, preferably from 8% wt to 25% wt.

25. The film according to items 23 and 24 wherein the surfactant is selected from

Poloxamer 407 and Polisorbat. 26. The film according to any of the proceeding items wherein at least one layer further comprises a plasticizer selected from a group consisting of polyols, glycols, acetins, carboxylic acid, and esters of carboxylic acid.

27. The film according to item 26 wherein the plasticizer is selected from polyethylene glycol, glycerol, triacetin, citric acid, and triethyl citrate.

28. The film according to items 26 and 27 wherein the amount of plasticizer is from 0.5% wt to 20% wt, preferably from 2% wt to 15% wt.

29. The film according to any of previous items, wherein the film is prepared by a

process which comprises the following steps: a) preparing a printable composition; b) three-dimensional printing of the film; and c) drying the film.

30. A printable composition comprising the following ingredients:

A. Active substance, 10 - 47 % wt,

B. At least one film forming polymer, 10 - 35 % wt,

C. At least one disintegrating agent, 5 - 25 % wt,

D. Surfactant, 5 - 20 %wt,

E. Plasticizer, 3 - 15 % wt,

F. Ethanol, 200 - 400 %wt to non-volatile ingredients,

G. Water, 20 - 80 % wt to non-volatile ingredients,

H. Optionally further excipients and solvents wherein the composition ranges for non-volatiles ingredients are defined for composition without solvents.

31 . A printable composition comprising the following ingredients:

A. CBD oil, 10 - 47 % wt,

B. PVP, 10 - 35 % wt,

C. HPMC, 2 - 20 % wt, D. Surfactant, 5 - 20 % wt,

E. Glycerol, 3-15 % wt,

F. Mannitol, 2- 20 % wt,

G. Ethanol 200 - 400 % wt to nonvolatile ingredients,

H. Water 20 - 80 % wt to nonvolatile ingredients,

I. Optionally further excipients and solvents wherein the composition ranges for non-volatiles ingredients are defined for composition without solvents.

32. A method of preparing a three dimensionally printed film comprising the steps of a) preparing a printable composition; b) three-dimensional printing of a film; and c) drying the film.

33. A process according to item 32 wherein a technique of dispensing valve is used in the three-dimensional printing step.

34. A process according to items 32 and 33 wherein the film is printed using needle dosing type with pneumatic dispensing valve.

35. A process according to item 32 wherein fused deposition modelling is used in the three dimensional printing step.

36. A process according to item 32 wherein ink jetting three dimensional printing is used.

37. A process according to item 32 wherein three dimensional printing air/pulse

technology is used.

38. A process according to item 32 wherein the film is dried for 1 - 2 hours at 30° - 50°C

39. The film according to item 1 for use as a medicament.

40. The film according to items 1 and 5 for use as a food supplement. 41 . The film according to items 1 , 5 and 40 for use in adults with a daily intake of CBD up to 130 mg.

42. The film according to item 1 , for use in adults and children comprising at least CBD and THC as active substances.

43. The film according to item 1 for use as a diagnostic.

44. The film according to item 1 for use as a vaccine.

45. The film according to item 1 for use as a medical device.

46. The film according to item 1 for use as a cosmetic.

47. Use of cannabinoid for the preparation of a three dimensionally printed film

according to item 1 .

48. The film according to item 1 wherein the active substance is selected from

medicaments, nutraceuticals, vaccines, diagnostics, food, food supplements, medical devices, cosmetics.

49. A three dimensionally printed film which comprises the following ingredients:

(J) Active substance: 10 - 47 % wt,

(K) Film forming polymer: 10 - 35 % wt,

(L) Disintegrating agent: 5 - 25 % wt,

(M) Plasticizer: 3 - 15 % wt,

(N) Surfactant: 5 -20% wt,

(O) Optionally further excipients.

The present invention is illustrated using the following non-limiting examples:

Examples:

Example 1 :

Preparation of a three dimensionally printed film

PVA and sugars were dissolved in water. PVP, CBD oil and Polysorbate were dissolved in ethanol. The obtained mixtures were mixed to get a homogeneous paste (printable composition) suitable for 3D printing.

These films were 3D printed using needle dosing type with pneumatic dispensing valve.

Parameters:

Air pressure: 5 bars

XY needle speed: 40 mm / s

ID (inside diameter) of printer nozzle: 0,8 mm After printing the films were dried at 50°C for 1 hour.

Example 2:

Preparation of a three dimensionally printed film

HPMC and sugars were dissolved in water. PVP, CBD oil, Melatonin and Polysorbate were dissolved in ethanol. The obtained mixtures were mixed to get a homogeneous paste (printable composition) suitable for 3D printing.

These films were 3D printed using needle dosing type with pneumatic dispensing valve. Parameters:

Air pressure: 5 bars

XY needle speed: 40 mm / s

- ID (inside diameter) of printer nozzle: 0,7 mm After printing the films were dried at 50°C for 1 hour.

Claims

1 . A three dimensionally printed film comprising at least one layer comprising

lipophilic and / or lipophobic active substance.

2. The film according to claim 1 wherein the active substance is selected from a group of cannabinoids.

3. The film according to claims 1 and 2 wherein the active substance is a raw

botanical extract of cannabinoids.

4. The film according to claims 1 and 2 wherein the lipophilic substance is THC.

5. The film according to claims 1 and 2 wherein the lipophilic substance is CBD.

6. The film according to claims 1 and 2 wherein the lipophilic active substance is mixture of THC and CBD in any ratio.

7. The film according to claims 1 and 5 wherein CBD is in form of oil, wax, crystals, resin, powder or paste.

8. The film according to claims 1 and 5 which comprises:

(A) CBD oil: 10 - 47 % wt,

(B) PVP: 10 - 35 % wt,

(C) HPMC: 2 - 20 % wt,

(D) Surfactant: 5 - 20% wt,

(E) Mannitol: 2 - 20 % wt,

(F) Optionally further excipients.

9. The film according to claims 1 and 5 which comprises:

(A) CBD oil: 10 - 47 % wt,

(B) PVP: 10 - 35 % wt,

(C) HPMC: 2 - 20 % wt,

(D) Glycerol: 3 - 15 % wt,

(E) Poloxamer 407: 5 - 20% wt,

(F) Mannitol: 2 - 20 % wt,

(G) Edible colour 5 - 25 % wt, (H) Mint aroma: 0,5 - 5% wt,

(I) Optionally further excipients.

10. The film according to claim 1 wherein the layer comprises additional lipophilic or lyophobic active substance.

1 1 .The film of claim 1 comprising one or more additional layers.

12. The film of claims 1 and 10 wherein the additional active substance is selected from medicaments, nutraceuticals, vaccine, diagnostics, food, food supplements, medical devices, cosmetics.

13. The film according to any proceeding claims wherein the at least one layer

further comprises a film forming agent selected from the group consisting of pullulan, hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone (PVP), carboxymethyl cellulose, polyvinyl alcohol (PVA), sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid,

methylmethacrylate copolymer, carboxy vinyl polymer, amylose, high amylose starch, hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein.

14. The film according to claim 13 wherein the film-forming polymer is polyvinyl

pyrrolidone

15. The film according to claim 13 wherein the film-forming polymer is polyvinyl

pyrrolidone in combination with hydroxypropylmethyl cellulose.

16. The film according to claims to any of proceeding claims wherein the amount of film forming agent is from 3% wt to 40% wt, preferably from 8% wt to 35% wt of the film.

17. The film according to any of the proceedings claims wherein the at least one layer further comprises a disintegrating agent selected from a group of croscarmellose sodium, sodium starch glycolate, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, carboxymethylcellulose, alginate, mannitol, glucose, derivatives thereof, and combinations thereof.

18. The film according to claim 17 wherein the disintegrating agent is present in the amount from 3% wt to 45% wt, preferably from 8% wt to 30% wt.

19. The film according to any of the proceeding claims wherein at least one layer further comprises a surfactant selected from a group of sodium lauryl sulfate, poloxamers, sorbitan esters, polysorbates, sorbitans, stearic acid, derivatives thereof, and combinations thereof.

20. The film according to claim 19 wherein the amount of surfactant is from 1 % wt to 35% wt, preferably from 8% wt to 25% wt.

21 . The film according to claims 19 and 20 wherein the surfactant is selected from Poloxamer 407 and Polisorbat.

22. The film according to any of the proceeding claims wherein at least one layer further comprises a plasticizer selected from polyethylene glycol, glycerol, triacetin, citric acid, and triethyl citrate.

23. The film according to claim 22 wherein the amount of plasticizer is from 0.5% wt to 20% wt, preferably from 2% wt to 15% wt.

24. The film according to any of the proceeding claims, wherein the film is prepared by a process which comprises the following steps: a) preparing a printable composition; b) three-dimensional printing of the film; and c) drying the film.

25. A printable composition which comprises the following ingredients:

A. Active substance, 10 - 47 % wt,

B. At least one film forming polymer, 10 - 35 % wt,

C. At least one disintegrating agent, 5 - 25 % wt,

D. Surfactant, 5 - 20 %wt,

E. Plasticizer, 3 - 15 % wt,

F. Ethanol, 200 - 400 %wt to non-volatile ingredients,

G. Water, 20 - 80 % wt to non-volatile ingredients,

26. The printable composition according to claim 25 wherein the active substance is CBD and which further comprises 2 - 20 % wt of mannitol.

27. A method of preparing a three-dimensionally printed film comprising the steps of a) preparing a printable composition; b) three-dimensional printing of a film; and c) drying the film.

28. A method according to claim 27 wherein the film is printed using needle dosing type with pneumatic dispensing valve.

29. A method according to claim 27 wherein the film is dried for 1 - 2 hours at 30° - 50°C .

30. The film according to claim 1 for use as a medicament.

31 . The film according to claim 1 for use as a food supplement.

32. The film according to claims 1 , 5 and 31 for use in adults with a daily intake of CBD up to 130 mg.

33. The film according to claim 1 , for use in adults and children comprising at least CBD and THC as active substances.

34. Use of cannabinoid for the preparation of a three dimensionally printed film

according to claim 1 .