WO2019069123A1 - Process for the preparation of bi/multi-layer film, multi-layered film produced thereof and apparatus for producing such multi-layer films - Google Patents

Process for the preparation of bi/multi-layer film, multi-layered film produced thereof and apparatus for producing such multi-layer films Download PDF

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WO2019069123A1
WO2019069123A1 PCT/IB2017/057873 IB2017057873W WO2019069123A1 WO 2019069123 A1 WO2019069123 A1 WO 2019069123A1 IB 2017057873 W IB2017057873 W IB 2017057873W WO 2019069123 A1 WO2019069123 A1 WO 2019069123A1
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layer
multi
layers
method
film
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PCT/IB2017/057873
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French (fr)
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Anwar S Daud
Nidhi P. SAPKAL
Minal BONDE
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Zim Laboratories Ltd.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • A61K31/375Ascorbic acid, i.e. vitamin C; Salts thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415Pyridoxine, i.e. Vitamin B6
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007Drug-containing films, membranes or sheets

Abstract

The present invention is directed to a method of manufacturing a multi-layer film, the method comprising the step of:- manufacturing each layer of the multi-layer film separately; placing each layer obtained in step (a) over one another; and applying heat and pressure for suitable period of time, wherein at least one layer of two adjacent layers of the multi-layer film comprises one or more of a binding excipient having a melting point in the range of 30°C to 100°C, preferably, 35 C to 70 C as an integral component of said layer and said binding excipient binds the layers together on application of heat and pressure. The invention is also directed to the apparatus for producing such multi-layer films and the films produced therefrom.

Description

PROCESS FOR THE PREPARATION OF BI/MULTI-LAYER FILM, MULTI-LAYERED FILM PRODUCED THEREOF AND APPARATUS FOR PRODUCING SUCH MULTI-LAYER FILMS

TECHNICAL FIELD

The subject matter described herein generally relates to a process for the preparation of Bi/Multi- layer film, Multi-layered film produced thereof and also apparatus for producing such Multi-layer film. The subject matter described herein particularly relates to process for the preparation of Multi-layer film for oral, transmucosal, transdermal or topical applications in humans or animals, Multi-layered films produced thereof and also apparatus for producing such films.

BACKGROUND Thin film is a dosage form that is used for delivering various active pharmaceutical agents, nutraceuticals and dietary additives. When administered by oral route, these films have many advantages over existing oral solid dosage forms like, tablets, orally disintegrating tablets, capsules, etc. When compared to tablets or capsules thin films do not require swallowing and hence are an ideal dosage form for pediatric, geriatric, mentally challenged and dysphagic patients. Specifically, when compared to orally disintegrating tablets, thin films are quite flexible and are not friable so can withstand stress during transportation and handling.

Liquid formulations are generally preferred for patient populations having difficulty in swallowing but, the same have issues of storage, transport and handling. Instances of dose non- uniformity are also quite high with liquid formulations. Thin films being, unit solid dosage form that require much less volume for storage and is free from spillage but is fast dissolving. These attributes of thin films obviate such limitations of liquid formulations.

Thin films also offer a very convenient way of drug administration through buccal, sublingual and transdermal routes as these have higher surface area for faster drug permeation and can be made mucoadhesive. Some of the products based on this technology are already in the market.

With the rise in popularity of thin film delivery system, need for adding additional attributes to this technology has been felt very strongly. Many therapeutic conditions require multi drug therapy. Sometimes for this purpose two or more than two API are administered together in one dosage form. At times these API's might be incompatible requiring special treatment. Bi/multi- layer tablets are prepared in cases when there is need to formulate incompatible actives together. Similar concept has also been adopted in thin film dosage form. Bi/multi-layer films are required to formulate when more than two incompatible ingredients are present together. Such multilayer films can also be used for delivering single / multi API with varying release profiles. Additionally, in case of buccal, sublingual and transdermal films, one of the layers of the Multilayer film, may be a backing layer, which is required for adherence to mucosal or skin surfaces or to maintain unidirectional permeation of active ingredients through the mucosal surfaces.

Different process for preparing multilayer films have been used. These films are prepared by casting second layer on the first layer before or after the drying of first layer. In such cases when the first layer is still wet, casting of another layer over it leads to mixing of contents at the interface. This mixing leads to chemical interactions and thus this method is not suitable for incompatible actives. US 2008/0057087 describes a method wherein the second layer is casted on the first layer when the first layer has dried. The solvents used in both the layers are not miscible with each other thus lowering chances of interaction or migration of components from one layer to another. But this method may not be suitable for preparing multilayer films when an active component exhibits solubility in the solvents used in both the layers. Therefore interactions will be observed while formulating incompatible actives in a multi-layer film formulation. Moreover, it is also difficult to control dose uniformity in top layer as it is difficult to control wet film thickness and a lot of product is wasted during this adjustment.

US 9655843 B2, Example 1 also describes the method of preparation of two layered film, wherein the backing layer was casted, cured and dried. After two coating and drying iterations, the mucoadhesive polymeric layer was casted onto the backing layer, cured and dried. This method may also faces issues relating to a wet layer being added over a dried first layer. If the solvent system used in both the layers is different then the casting of second layer over the first layer does not result in the film with smooth surfaces because of the interfacial tension between two layers. In case of same solvent systems in both the layers, there are chances of migration of API from mucoadhesive layer to backing layer resulting in inconsistent rate of permeation through transmucosal membranes. Additionally, because of the difficulty in adjustment of wet film thickness, there will be issues of content uniformity. EP 1079813B 1 reports casting of one layer over the other while the first layer is completely wet or partially dried. This disclosure mentions the use of hydrophilic solvents in both layers. In such cases when a wet film is casted on already dried film layer because of thin nature of base layer, it gets dissolved to some extent. Due to this process mixing between two layers take place and chemical interaction between incompatible actives or active-excipients may be observed. Additionally, this process is not suitable for incorporating thermolabile actives into base layer as the base layer is exposed to heat two times, firstly during drying of base layer and secondly during drying of subsequent layers. This disclosure also mentions preparation of bilayer films using lamination of individual layers on to each other. During the process of lamination one layer is dried while the other layer is partially wet. In this method there will be need of additional drying steps after lamination that again may not be suitable for thermolabile actives and presence of extra moisture may also cause chemical degradation.

Thus, there is a need of process for preparation of bi/multi-Iayer films that is free from issues like interaction between components of the adjacent layers, exposure to high temperature, content non-uniformity etc.

SUMMARY OF INVENTION:

To achieve the said objectives, this invention provides a method of manufacturing a multi-layer film, the method comprising the step of:- a) manufacturing each layer of the multi-layer film separately;

b) placing each layer obtained in step (a) over one another; and

c) applying heat and pressure for suitable period of time,

wherein at least one layer of two adjacent layers of the multi-layer film comprises one or more of a binding excipient having a melting point in the range of 30°C to 100°C, preferably, 35°C to 70°C as an integral component of said layer and said binding excipient binds the layers together on application of heat and pressure.

The present invention is also directed to an apparatus for carrying out the method, wherein the apparatus comprises:

a) means for precisely placing the layers of the bi/multi-layer film over one another while the layers are moving or are stationary; b) means for heating the multi-layer film while the layers are moving or are stationary; and

c) means for applying pressure to press the layers together as said layers move in intermittent or continuous motion.

The present invention is also directed to a multi-layer film, produced by the method and apparatus of the invention.

DETAILLED DESCRIPTION

The present invention in an aspect of the invention provides a method of manufacturing a multilayer film, like bi-layer, tri-layer etc. In this aspect of the invention, the individual layers of the bi-layer or multi-layer film are prepared separately and then placed on to each other to obtain bi/multi-layer film. In an embodiment of this aspect the individual layers are prepared using conventional methods, however, at least one layer of such bi-layer or at least one layer of the two neighboring layers of a Multi-layer comprises one or more of a specialized excipient/binding excipient (as the case may be) apart from the other excipients required for making said films. These specialized excipients have property of melting between temperatures of 30°C to 100°C, more preferably between 35°C to 70°C. The individual layers, at least one of which comprises, one or more of these specialized binding excipients are placed over each other and then exposed to heat and pressure, simultaneously, or one after the other. Heat converts the solid specialized binding excipients into molten form. When in molten form such specialized binding excipients of one layer get intermixed with the similar excipients of second layer, or migrate towards the second layer not comprising the same. The application of pressure further facilitates this intermixing/migration process. When the pressure and temperature conditions are relieved, cooling occurs and firm binding between the two layers occurs. The two layers are joined to each other by the long chain molecules that interlink both the layers and bind them together.

The rise in temperature is not very high and only for a suitable period. The suitable period of time is taken such that it controls migration of other excipients and actives (retaining purity of each layer), so that it doesn't affect stability of the actives. The suitable duration of application of heat and pressure has to be taken depending on the type of specialized binding excipient used. It should be sufficient to convert the specialized binding excipient to a molten state thus should not be longer so as to affect the other excipients and API, result in deformation of films and/or degradation of sensitive APIs.

In specific embodiments these specialized binding excipients can be selected from the list (But not limited to), provided below or their combinations:-

Figure imgf000006_0001

Different grades of the above excipients may also be used provided the melting point criteria is met. For instance, Polyethylene glycol is commonly referred to by its abbreviated synonym PEG. Polyethylene glycol is available in different grades based on its molecular weight. The number, which follows PEG, indicates the average molecular weight of the polymer. Any pharmaceutically acceptable grade of polyethylene glycol may be used in the method and films of the invention provided the melting point criteria is met. Similarly, even Polyethylene oxide is available in different grades and any pharmaceutically acceptable grade of polyethylene glycol may be used in the method and films of the invention provided the melting point criteria is met.

In specific embodiment of the invention the individual layers containing these specialized excipients are placed over each other and then exposed to a temperature suitable for melting the binding specialized excipient and in the range of about 40 °C to about 1 10 °C, preferably 40 °C to about 80 °C for around 0.5 m/min to around 1 m/min and a pressure in the rage of about 5 kgF to about 10 KgF depending on the type of specialized binding excipient used. Higher values may result in deformation of films and/or degradation of sensitive APIs while lower values do not give appropriate binding between the layers. Again, the suitable duration of application of heat and pressure has to be taken depending on the type and amount of specialized binding excipient used. Longer application can again result in deformation of films and/or degradation of sensitive APIs while lower values do not give appropriate binding between the layers.

In specific embodiment of the invention the quantity of these specialized excipients should be in the range of 10% to 90% in a layer, preferably 30% to 70%. Lesser amounts will result in poor binding between the layers and higher amounts will interfere with the optimized film properties like, tackiness, disintegration, film removal from surface etc.

In specific embodiments of the invention two layers, more than two layers can also be bonded together by adding these specialized excipients into the composition of all the layers.

In specific preferred embodiments of the invention, preferably the layers containing more heat sensitive actives will constitute the layer that does not contain specialized binding excipient and is not directly exposed to heat.

In an embodiment the active in each layer has a homogenous release profile. In another embodiment, the actives in each layer have different release profile.

In an embodiment, the outer or one of the layers is adapted to be suited for immediate release of the drug whereas the inner or another layer is for maintaining the sustainability of the dose.

Further in an embodiment of the invention the active in one layer does not affect the release profile of the active in any of the adjacent layers of the multi-layer film. In an embodiment of the invention the active in the layer can be an active pharmaceutical ingredient or nutraceuticals or cosmetically active ingredient. In further embodiment the active may be a chemical ingredient or a herbal extract.

In an embodiment of the invention the bi/multilayer film can be administered by oral, sublingual, buccal, topical, transdermal, vaginal, nasal or any other transmucosal route.

In specific embodiments the step of heating the layers comprises passing the layers through a heating chamber at the desired temperature and then pressing both the layers by passing between rollers. In specific embodiment the step of heating the layers and applying pressure, may occur simultaneously, for instance by passing the layers through heated rollers. In another embodiment, the pressing rollers may be grooved or ridged or may have some embossed designs, that leave permanent impression on the film layers during sealing. Such a step can be of help in product identification or for giving patient instructions and will help in prevention of counterfeiting the product. The so produced impressions will also prevent problem of sticking when films are stacked together or for providing useful instructions to the user of the product. The purpose can also be to enable packing of such films together with minimum surface being in contact, thus, contributing to additional attributes such as improved stability, ease of dispensing etc.

In another embodiment of the invention, the specialized excipients can be sprayed on the top of a layer when another layer is being placed over it, before heat and pressure treatment.

For multiple layer films, each layer is placed on the top of the earlier layers, heated and pressed.

The unwinding speed of all the rollers is kept identical for maintaining content uniformity throughout the film.

In specific embodiments, at least one layer comprises an active ingredient. In specific embodiments, at least one layer is inert and may act as a backing layer. The final bi/multi-layer films can be cut to desired shapes and sizes to get the desired dose.

Another aspect of the invention is directed to an apparatus for performing the method of the invention, comprising;

a) means for placing the layers of the multi-layer film above one another;

b) means for heating the multi-layer film; and

c) means for applying pressure to press the layers together.

In an embodiment two or more layers are unwounded from the two different rollers and one layer is placed just above the other layer, and passed over a belt. In an embodiment, the means for heating the one or more layer comprises an infrared heater, heating chamber with hot air or electrically heated elements. During heating the layers maybe stationary or in motion. Along the belt, the layer(s) are heated using infrared heater from at least one end, preferably top end. Along the belt, the layer(s) may be heated by passing the layers through a heated chamber.

In another embodiment the means for pressing the layers comprises pressure rollers. After a portion of the film is exposed to heat, the layers are pressed with the help of pressure rollers. In another embodiment of this aspect, the means for pressing the layers comprises pressure rollers with heating coils placed internally, so that heat and pressure are applied simultaneously.

For multiple layer films, each layer is placed on the top of the earlier layers, heated and pressed. The unwinding speed of all the rollers is kept identical for maintaining content uniformity throughout the film.

Another aspect of the invention is directed to an apparatus as shown in Figure 1 , for performing the method of the invention and forming a bi-layer (4)/ Multi-layer film, comprising :

a) means for precisely placing the layers of the bi/multi-layer film (1 ,2) over one another while the layers are moving or are stationary;

b) means for heating (3) the multi-layer film while the layers are moving or are stationary; and

c) means for applying pressure (3) to press the layers together as said layers move in intermittent or continuous motion

In another embodiment of the invention, the apparatus also comprises a means for spraying the specialized excipients can be on the top of a layer when another layer is being placed over it, before heat and pressure treatment.

The final bi/multi-layer films can be cut to desired shapes and sizes to get the desired dose.

In specific embodiments of the invention, the layers comprise same or different active. When different actives are used, they may be compatible or incompatible with each other. In specific embodiments of the invention, the layers comprise pharmaceutically active substances that are incompatible may be selected from, however nor limited to the therapeutic class consisting of: analgesic, antiallergic agent, anti- Alzheimer agent, antiasthmatic, antibiotics, antidepressant agent, antihypertensive, anti-inflammatory agent, Antimicrobial, antimigraine, antiparkinsonic, antipyretic, antipsychotic, antispasmodics, antithrombotics, antitussive agent, antiviral agents, hypnotic/sedative agent, gastrointestinal function conditioning agent, cardiovascular system conditioning agent, hypolipidemic agents, Chemotherapy agents, hypoglycemics, hormones, proteins, anticancer, opioids, diuretics, vasodilators,

In specific embodiments of the invention, the layers comprise nutreaceuticals selected from, however nor limited to the group consisting of all vitamins and dietary supplements.

In specific embodiments of the invention, the layers comprise, herbal ingredients selected from, however nor limited to the group consisting of all herbal or plant extracts or specific chemical constituents thereof.

EXAMPLES

The different embodiments of the invention are explained with the examples below, which do not in any way limit the scope of the invention. The method can be applied to any two or more pharmaceutically active substances, nautreacuials, herbal ingredients, cosmetic etc Example 1- Formulation of incompatible active pharmaceutical ingredients (Montelukast 5 mg and Levocetirizine 2.5 mg ) together

Individual &Bi-layer film preparation methodology as per conventional technology (1.1 , 1.2, 1.3, and 1.5) and the method of the invention (1.4, 1.6) have been disclosed in the present example and the properties of bilayer obtained by the invention's method have been compared to the results of the bi-layer obtained by conventional method.

Experiment 1.1- Preparation of Individual film of Levocetirizine 2.5 mg To prepare Levocetirizine 2.5 mg film, Levocetirizinedihydrochloride(8.33%), Sucralose (3.33%), Mentha oil (1.67%), Vitamin E acetate (5%), Glycerin (6.67%), Propylene glycol ( 1 1.67%), Polacrilline pot. (6.75%), Sodium hydroxide (2.5%), Sunset yellow Color (0.03%), Polysorbate 80 (6.67%), Hypromellose- medium viscosity (47.38%) were weighed & added to purified water and mixed for 15 min to form a dispersion. The so prepared dispersion was casted on a support, to form a layer of uniform thickness and dried at a temperature of 80° C to form a film.

Experiment 1.2- Preparation of Individual film of Montelukast 5 mg

To prepare Montelukast 5 mg film, Montelukast sodium ( 13. 125%), Sucralose (1.875%), Mentha oil ( 1.875%), Titanium dioxide ( 1.875%), Vitamin E acetate (7.5%), Glycerin (7.5%), Propylene glycol (10%), Neotame (0.375%), Butylated Hydroxy Anisole (2.5%), Butylated Hydroxy Toluene (0.9%) , Yellow Oxides of Iron (0.5%), Hypromellose- low viscosity (51.975%), were weighed & added to purified water and mixed for 15 min to form a dispersion.

The so prepared dispersion was casted on a support, to form a layer of uniform thickness and dried at a temperature of 80° C. Experiment 1.3- preparation of combination film of Montelukast 5 mg and Levocetirizine 2.5 mg

To prepare Combination film of Montelukast 5 mg and Levocetirizine 2.5 mg, Levocetirizine dihydrochloride(6.25%), Montelukast sodium ( 13.125%), Sucralose (1.875%), Mentha oil ( 1.875%), Titanium dioxide ( 1.875%), Vitamin E acetate ( 1 1.25%), Glycerin (7.5%), Propylene glycol ( 10%), Polacrilline pot. (4.6875%), Sodium hydroxide ( 1 .875%), Neotame (0.375%), Butylated Hydroxy Anisole (2.5%), Butylated Hydroxy Toluene (0.9%), Yellow Oxides of Iron (0.5%), Hypromellose- medium viscosity (35.4125%), were weighed & added to purified water and mixed for 15 min to form a dispersion.

The prepared dispersion was casted on a support, to form a layer of uniform thickness and dried at a temperature of 80° C to form a film. Experiment 1.4:- preparation of individual films of Montelukast ODS 5 mg (Heat sealable individual layer as per the invention comprising heat sealing excipients)

To prepare Heat sealable individual layer films of Montelukast ODS 5 mg, Montelukast sodium (10.5%), Sucralose (1.5%), Mentha oil (2.12%), Titanium dioxide (1 .5%), Vitamin E acetate (5.26%), Glycerin (6%), Polysorbate 80 (4%), Butylated Hydroxy Anisole (2%), Butylated Hydroxy Toluene (0.72%), Yellow Oxides of Iron (0.4%) Hypromellose - high viscosity (8%), PVP K90 (10%), Polyox N80 (48%), were weighed & added to purified water and mixed for 15 min to form a dispersion.

The prepared dispersion was casted on a support, to form a layer of uniform thickness and dried at a temperature of 80° C to form a film.

Experiment 1.5:- Preparation of Bilayer film using conventional method

To prepare a double layered film by conventional method of layering one film on the other while the top layer is in dispersion phase, the dispersion of experiment 1.2 was layered on film obtained from experiment 1.1. The resulting bilayer film was dried at temperature of 80°C.

Experiment 1.6:- preparation of Double layered film of the invention

Double layered film of individual layers prepared in experiment no 1.1 &heat sealing layer film 1 .4 were prepared using the heat sealing method of the invention by placing the said layers over one another and applying a temperature of 50 °C, and Pressure of 7 kgF, for 0.5 m/min.

The individual & Bi-layer films obtained above in experiments 1 .1 to 1.6 were then analyzed to determine the assay, dissolution rate and amount of impurities etc. in each layer by the methods provided below.

For Experiment 1.1 :- The assay was performed using liquid chromatographic method. The liquid Packing Column was C I 8 (250cm X 4.6 mm, 5μηι), Princeton SPHER 100 is suitable. The column temperature was maintained at 30°C. The mobile phase consisted of 0.05 M potassium dihydrogen phosphate and acetonitrile in the ratio of 60:40. The injection volume was 20 \xL and the flow rate was 1.0 mL / min. A Wavelength: 230 nm was detection. The dissolution rate was determined using USP type 2 (Peddle). The medium used was 900mL, of Phosphate Buffer with a pH of 6.8. The speed of the peddle was 50 RPM. The experiment was conducted at 37.0 OC± 0.5 for 30 minutes For determining impurities liquid chromatography setup similar to the above was used.

For Experiment 1.2: and 1.4- The assay was performed using liquid chromatographic method. The liquid Packing Column was C I 8 (150cm X 4.6 mm, 5μπϊ), Princeton SPHER. The column temperature was maintained at 40°C. The mobile phase consisted of a mixture of A) A mixture of acetate buffer solution and Acetonitrile. The injection volume was 10 μΐ and the flow rate was 1.0 mL / min. A Wavelength: 240 nm was detection. The sample temperature was around 5°C.

The dissolution rate was determined using USP type 2 (Peddle). The medium used was 900mL, of, 0.5% w/v solution dodecyl sulphate in water. The speed of the peddle was 50 RPM. The experiment was conducted at 37.0 OC± 0.5 for 30 minutes

For determining impurities liquid chromatography setup with Packing Phenyl ( 100 mm X 4.6 mm, 5 μιτι) (Phenomenex Luna is suitable) was used. A Wavelength of 255nm is used for detection. The Flow Rate of the liquid phase is 1 .5 mL/min and the Injection Volume is 15 μL. the Column Temperature was maintained at 50 oC.

For Experiment 1.3, 1.5 and 1.6:- The assay was performed using liquid chromatographic method. The liquid Packing Column was a stainless steel column 25 cm x 4.6 mm, packed with octadecylsilane bonded to porous silica (5 μηι). The column temperature was maintained at 40°C. The mobile phase consisted of a mixture of acetate buffer solution and Acetonitrile. The injection volume was 20 iL and the flow rate was 1 .0 mL / min. A Wavelength: 240 nm was detection. The dissolution rate was determined using USP type 2 (Peddle). The medium used was 900mL, of, 0.5% w/v solution dodecyl sulphate in water. The speed of the peddle was 50 RPM. The experiment was conducted at 37.0 OC± 0.5 for 30 minutes

The results of the above analysis are outlined in Table 1 below: Table 1 :- Results of Experiment no. 1.1 to 1. 6

Figure imgf000014_0001
Levocetrizine dihydrochloride and montelukast sodium are salts of ions of opposite nature. So when films of these drug molecules are prepared separately the films are stable and no chemical degradation is shown. However, when these films are prepared in combination these actives interact with each other and give rise to impurities. It can be seen in the initial result of Example. 1.3 that individual impurity has become 1 .8% and total impurity has become 3.7%, which is more than the specified limits of 1.0% and 2.0% respectively. In the Example 1.5 when bi-layered film was prepared using conventional method, individual impurity was 1.4 %> and total impurity was 2.8%o which was again more than specified limits. While by the method of the invention, these impurities were controlled as shown by the results given in table 1 above. (Individual impurities 0.23% and total impurities 0.50)

Example 2 - Formulation of incompatible active nautreacuials (Folic acid 0.5mg & Pyridoxine HCI lmg (layer 1), Ascorbic acid 25 mg ODS (layer 2)) together

Individual & Bi-layer film preparation methodology as per conventional technology (2.1 , 2.2, 2.3, 2.6) and the method of the invention (2.4, 2.5) have been disclosed in the present example and the results of bilayer obtained by the invention method have been compared to the results of the bi- layer obtained by conventional method.

Experiment 2.1- Preparation of Individual film of Folic acid 0.5mg & Pyridoxine HCI lmg

To prepare Folic acid 0.5mg & Pyridoxine HCI l mg film, Folic acid (2.14%), Pyridoxine HC1(6.000%), Hypromellose- low viscosity (65.71 %), Propylene Glycol (8.57%), Glycerin (5.71 %), Sucralose (4.57%), Titanium Dioxide (2.86%), Mentha oil (2.86%), Butylatedhydroxyanisole (1 .43%) and Butylatedhydroxytolune (0.14%)were weighed & added to purified water and mixed for 15 min to form a dispersion. The prepared dispersion was casted on a support, to form a layer of uniform thickness and dried at a temperature of 50° C to form a film.

Experiment 2.2- Preparation of Individual film of Ascorbic acid 25 mg

To prepare Ascorbic acid 25 mg ODS film,Hypromellose- low viscosity (30.03%), Hypromellose -high viscosity ( 14. 12%), Propylene Glycol (3.75%), Sucralose(2.00%), Titanium Dioxide ( 1 .25%), Vitamin C /Ascorbic acid (32.81 %), Sodium ascorbate (12.91 %), were weighed & added to purified water and mixed for 15 min to form a dispersion.

The prepared dispersion was casted on a support, to form a layer of uniform thickness and dried at a temperature of 50° C. to form a film Experiment 2.3:- Preparation of a combination film of Folic acid, Pyridoxine HCI, Ascorbic acid using conventional method

To prepare combined film, Folic acid (0.94%), Pyridoxine HCI ( 1.88%), Hypromellose- low viscosity (30.03%), Hypromellose -high viscosity ( 12.50%), Propylene Glycol (3.75%), Sucralose (2.00%), Titanium Dioxide (1.25%), Butylated hydroxyanisole (0.63%), Butylated hydroxytolune (0.06)%, Vitamin C (Ascorbic acid) (32.81 %), Sodium ascorbate ( 12.91 %) were weighed & added to purified water and mixed for 15 min to form a dispersion.

The prepared dispersion was casted on a support, to form a layer of uniform thickness and dried at a temperature of 50° C. to form a film

Experiment 2.4:- preparation of individual films of Folic acid 0.5mg & Pyridoxine HCI lmg, (Heat sealable individual layer as per the invention comprising heat sealing excipients) To prepare Heat sealable individual layer films of Folic acid (2.14%), Pyridoxine HC1(6.000%), Hypromellose- low viscosity (30.00%), Polyox N 80 (35.71 %), Propylene Glycol (8.57%), Glycerin (5.71 %), Sucralose (4.57%), Titanium Dioxide (2.86%), Mentha oil (2.86%),Butylated hydroxyanisole ( 1 .43%), Butylated hydroxytolune (0.14%), were weighed & added to purified water and mixed for 15 min to form a dispersion.

The prepared dispersion was casted on a support, to form a layer of uniform thickness and dried at a temperature of 50° C to form a film.

Experiment 2.5:- Preparation of Double layered film of the invention

Double layered film of individual layers prepared in experiment no 2.2 & heat sealing layer film 2.4 were prepared using the heat sealing method of the invention by placing the said layers over one another and applying a temperature of 50 °C, and Pressure of 7 kgF, for 1 m/min.

Experiment 2.6:- Preparation of Bilayer film using conventional method

To prepare a double layered film by conventional method of layering one film on the other while the top layer is in dispersion phase, the dispersion of experiment 2.2 was layered on film obtained from experiment 2.1. The resulting bilayer film was dried at temperature of 50°C. The individual & Bi-layer films obtained above in experiments 2.1 to 2.6 were then analyzed to determine the assay by the liquid chromatographic method provided as below: For Experiment 2.1 and 2.4:- The assay was performed using liquid chromatographic method. The liquid Packing Column was Packing C I 8 (250 mm X 4.6 mm, 5 μιη) (Princeton SPHER-100 is suitable). The 5 column temperature was maintained at 30°C. The mobile phase consisted of 3 g of hexane- 1 - sulphonic acid sodium salt in a mixture of water, methanol and glacial acetic acid in the ratio of 150:50:2. The injection volume was 10 [ih and the flow rate was 1.0 mL / min. A Wavelength: 283 nra was detection.

10 For Experiment 2.2:- The assay was performed using liquid chromatographic method. The liquid Packing Column was Sillica gel F 254 percoated plate (Merck Sillica gel 60 F 254 Plates are suitable. The column temperature was maintained at 30°C. The mobile phase consisted of 20 volumes of water and 120 volumes of ethanol (96%). The injection volume was 20 and the flow rate was 1.0 mL / min. A Wavelength: 254 nm was detection.

15

For Experiment 2.3, 2.5 and 2.6:- The assay was performed using liquid chromatographic method. The liquid Packing Column was a Packing C I 8 (250 mm X 4.6 mm, 5μιτι) (Hypersil BDS is suitable). The column temperature was maintained at 40°C. The mobile phase consisted of 3 g of hexane- l -sulphonic acid sodium salt in a mixture of water, methanol and glacial acetic 20 acid in the ratio of 150:50:2. The injection volume was 20 \L and the flow rate was 1.0 mL / min.

A Wavelength: 280 nm was detection.

The results are provided in Table 2 below:-

Table 2: -Assay results for Experiment 2

Figure imgf000017_0001
NMT

150%)

Folic 131.50 100.00 129.43 129.16 105.3 acid 7 (NLT

90% and

NMT

1 50%)

Ascorbic 136.98 137.98 139.19 138.0 acid 3

(NLT

90% and

NMT

150%)

pH 5.00-5.50 2.5-3.5 2.5-3.5 5.00-5.50

In the combination formulation of folic acid, pyridoxine and ascorbic acid, folic acid undergoes degradation because of acidic pH of ascorbic acid. In the conventional method, folic acid degradation was shown by reduction in assay from 131.5%) to 105.37%) when combined with ascorbic acid. While in the method of the invention (2.6) there was no degradation as revealed by 129.16%) Assay value.

As would be evident from the above Tables 1 and 2, the bi-layer produced by method and apparatus of the invention helps achieve high concentration of each active with least impurities (Refer 1.5/1 .6 and 2.5/2.6 results in tables above).

Example 3- Preparation of bilayer film comprising a Drug loaded film with inert backing layer

Drug loaded film was prepared by dissolving weight quantities of Fentanyl citrate (0.001 %), Hypromellose (74.7%), Sodium CMC (5.1 %), Hydroxy propyl cellulose (10.3%), Propylene glycol (9.9%)in water. The resulting dispersion was then casted into thin film. The inert backing layer was prepared by mixing Hypromellose (40.8%), Ethyl cellulose (24.8%), PEG 6000, (34.3%o), Diethyl phthalate (0.1 %) in isopropyl alcohol & casting the film. Both the films were then passed through a chamber heated between 60°C to 80°C & were pressed together at a pressure of 7 kg F for l m/min. Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.

Claims

We claim:
1 . A method of manufacturing a multi-layer film, the method comprising the step of:- d) manufacturing each layer of the multi-layer film separately;
e) placing each layer obtained in step (a) over one another; and
f) applying heat and pressure for suitable period of time,
wherein at least one layer of two adjacent layers of the multi-layer film comprises one or more of a binding excipient having a melting point in the range of 30°C to 100°C, preferably, 35°C to 70°C as an integral component of said layer and said binding excipient binds the layers together on application of heat and pressure.
2. The method as claimed in claim 1 , wherein the heat and pressure are applied simultaneously, or pressure is applied after heat.
3. The method as claimed in claim 1 , wherein the binding excipient is selected from the group consisting of Polyethylene oxides, Copovidone, Polyvinyl caprolactum, Poloxamer 188, Poloxamer 407, PEGs, their different grades and their combinations thereof.
4. The method as claimed in claim 1 , wherein each layer is placed over one another and then exposed to a temperature in the range of about 40 °C to about 1 10 °C, preferably about 40 °C to about 80 °C.
5. The method as claimed in claim 1 , wherein the pressure applied is in the range of about 5 kgF to about l O KgF.
6. The method as claimed in claim 1 , wherein the one or more binding excipient is present in the range of about 10% to about 90% in a layer, preferably between about 30% to about 70%.
7. The method as claimed in claim 1 , wherein one or more layers of the multi-layer film comprise one or more of the binding excipients.
8. The method as claimed in claim 7, wherein the binding excipient is added during the manufacture of each layer prior to heating.
9. The method as claimed in claim 1 , wherein at least one of the layers of the multi-layer film comprises one or more actives.
10. The method as claimed in claim 1 , wherein the actives are cosmetically active substances, pharmaceutically active substances, an herbal active compound or a nutraceutical.
1 1 . The method as claimed in claim 1 , wherein the active in one layer does not affect the release profile of the active in any of the adjacent layers of the multi-layer film.
12. The method as claimed in claim 1 , wherein the actives in each layer of the multi-layer film have same or different release profiles.
13. The method as claimed in claim 1 , wherein the step of heating the layers comprises passing the layers through a heating chamber at the desired temperature and then pressing the layers together by passing between suitable pressing devices.
14. The method as claimed in claim 1 , wherein the step of heating the layers and applying pressure, occur simultaneously.
15. An apparatus for carrying out the method as claimed in claim 1 , wherein the apparatus comprises:
a) means for precisely placing the layers of the bi/multi-layer film over one another while the layers are moving or are stationary;
b) means for heating the multi-layer film while the layers are moving or are stationary; and
c) means for applying pressure to press the layers together as said layers move in intermittent or continuous motion.
The apparatus as claimed in claim 15, wherein means for heating the multi-layer film comprise an infrared heater, or hot air or electrically heated elements.
The apparatus as claimed in claim 15, wherein means for pressing the layers comprises pressure rollers.
18. The apparatus as claimed in claim 15, further comprising a means for spraying the binding excipient on the top of a layer when another layer is being placed over it, before heat and pressure treatment.
19. The apparatus as claimed in claim 17, wherein the pressure rollers are grooved or ridged or have some embossed designs that leaves permanent impression on the film layers during sealing for product identification, preventing counter fileting or giving patient instructions.
20. The multilayer film produced by the method as claimed in claim 1.
21 . The multilayer film as claimed in claim 20, wherein the Multi-layer film can be administered by oral, sublingual, buccal, topical, transdermal, vaginal, nasal or any other transmucosal route.
PCT/IB2017/057873 2017-10-07 2017-12-13 Process for the preparation of bi/multi-layer film, multi-layered film produced thereof and apparatus for producing such multi-layer films WO2019069123A1 (en)

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