CN114917205A - Oral dissolving film composition - Google Patents

Abstract

The invention relates to an oral dissolving film composition. In particular, the present invention relates to oral film compositions comprising an active ingredient, a film forming polymer, polydextrose and a surfactant. The oral film composition has the advantages of good taste and uniform distribution of active ingredients, and the active ingredients are not aggregated after long-time storage.

Description

Oral dissolving film composition

The application is a divisional application of Chinese patent application with the application number of 201811402659.4, the application date of 2018, 11 and 23 and the name of 'an oral dissolving film composition'.

Technical Field

The invention relates to the field of pharmacy, and in particular relates to an oral dissolving film composition and a preparation method thereof.

Background

Oral administration is the most common mode of administration of a drug, but different dosage forms are suitable for different users. Some dosage forms such as tablets, capsules, etc. have a problem of difficulty in taking them for the elderly, children and some patients with dysphagia. Other preparations such as granules, oral liquid, dry suspension and the like have larger volume for taking medicines with the same dosage, thereby further increasing the difficulty degree of taking by patients; the mouth dissolving film agent has the advantages that the specific surface area of the preparation is large, the preparation can be quickly dissolved in the oral cavity, and the preparation is dispersed into a suspension of the medicine and the auxiliary materials, so that the medicine and the auxiliary materials are convenient to swallow without drinking water; the orally dissolving film agent has the advantages of small dosage of auxiliary materials, accurate content, better stability compared with a solution or suspension type pharmaceutical preparation, less compatibility change and easy carrying. In addition, the film may have a high mucoadhesiveness such that the film adheres to the inside of the mouth or palate of the user, thereby limiting or completely preventing removal thereof by the user, avoiding abuse of the drug.

There are many documents in the prior art which report oromelt film formulations and methods for their preparation, such as US7425292, US8765167, US9095577 and the like.

Polydextrose (CAS: 68424-04-4) is water-soluble dietary fiber with good performance, and has application value and development potential in a plurality of fields such as medicine, health products, antifreeze, baked food and the like. Polydextrose is widely used in various pharmaceutical preparations, but is mainly in solid dosage forms, the solution of polydextrose can be used as a binding agent for wet granulation, and can also be used as an auxiliary material for direct tabletting, and the polydextrose solution can be used together with other materials and can be used as a coating material for tablets.

The medicines of film dosage form are generally synthesized high molecular film forming materials, and the problems of large brittleness, poor flexibility, difficult control of stability, poor taste and the like of the film due to difficult control of humidity after film forming exist. In order to make the oral film agent soft and not easy to break and improve the mouth feel, auxiliary materials with moisture retention performance and the mouth feel of the preparation need to be added.

The film agent product also has some problems in the storage process, for example, after the film agent is stored for a long time, active substances in the film agent can be aggregated, the taste and dissolution of the film agent are influenced, and the treatment effect is poor.

Disclosure of Invention

The invention aims to provide a novel oral dissolving film composition and a preparation method thereof, which improve the taste and uniformity of an oral dissolving film.

In one aspect, the invention provides an orally-dissolvable film composition comprising an active ingredient, a film-forming polymer, polydextrose, and a surfactant.

The active ingredient according to the invention may be a pharmaceutical or cosmetic active ingredient, such as a drug, an antigen or allergen, an oral cleansing component, a flavouring agent, a fragrance, an enzyme, a preservative, a sweetener, a colouring agent, a fragrance, a vitamin or a combination thereof.

Examples of useful drugs include, among others, ace-inhibitors, antianginals, antiarrhythmics, antiasthmatics, cholesterol-lowering drugs, analgesics, anesthetics, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antidotes, antihistamines, antihypertensive agents, antiinflammatory agents, antilipidemic agents, antimanics, antiemetics, antimigraines, antithyroid agents, antineoplastics, antivirals, acne agents, alkaloids, amino acid agents, antitussives, anti-urics, antivirals, anabolic agents, systemic and non-systemic antiinfectives, antineoplastics, flaccid agents, antirheumatics, appetite stimulants, biological response modifiers, blood regulators, bone metabolism regulators, cardiovascular agents, central nervous system stimulants, cholinesterase inhibitors, contraceptives, decongestants, food additives, Dopamine receptor agonists, endometriosis therapeutics, enzymes, erectile dysfunction therapeutics, gastrointestinal tract preparations, analogous therapeutics, hormones, hypercalcemia and hypocalcemia therapeutics, immunomodulators, immunosuppressants, migraine preparations, motion sickness therapeutics, muscle relaxants, obesity therapeutics, osteoporosis preparations, oxytocics, parasympathetic blockers, parasympathomimetics, prostaglandins, psychotherapeutics, respiratory preparations, sedatives, smoking cessation aids, sympathetic blockers, tremors, urinary tract preparations, vasodilators, purgatives, antacids, ion exchange resins, antipyretics, appetite suppressants, expectorants, anxiolytics, antiulcer agents, anti-inflammatory substances, coronary artery dilators, cerebral vessel dilators, peripheral vessel dilators, psychoactive drugs, stimulants, antihypertensive drugs, Vasoconstrictors, migraine remedies, antibiotics, tranquilizers, antipsychotics, antineoplastics, anticoagulants, antithrombotic agents, hypnotics, antiemetics, antinociceptives, anticonvulsants, neuromuscular agents, hyperglycemic and hypoglycemic agents, thyroid and antithyroid agents, diuretics, antispasmodics, uterine relaxants, antiobesity agents, erythropoietic agents, antiasthmatic agents, cough suppressants, mucolytic agents, DNA and gene modifiers, and combinations thereof.

In some embodiments, useful active ingredients may be anti-migraine agents, such as sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, and the like; analgesics such as oxycodone, ibuprofen, aspirin, acetaminophen, and the like; antiemetics such as granisetron, azasetron, tropisetron, ramosetron, ondansetron, lerisetron, cilansetron and the like; antipsychotics such as olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and the like; drugs for treating erectile dysfunction, such as sildenafil, tadalafil, vardenafil, apomorphine, alprostadil, and the like; the medicine for treating hepatopathy is selected from glycyrrhizic acid, glutathione, adefovir dipivoxil, entecavir, lamivudine, tenofovir, sofosbuvir, etc.

In some preferred embodiments, the active ingredient may be ondansetron, zolmitriptan, olanzapine, entecavir, or tadalafil.

The film-forming polymer of the present invention may be one or more water-soluble polymers, water-insoluble polymers, or a combination of water-soluble and water-insoluble polymers.

The water-soluble polymer includes, but is not limited to, water-soluble polysaccharides, cellulose polymers or cellulose derivative polymers, and water-soluble synthetic polymers.

The water-soluble polysaccharides include, but are not limited to, alginates, carrageenans, guar gum, gum arabic, agar, xanthan gum, gellan gum, gum arabic and related gums, karaya gum, tragacanth gum, and pectin.

The cellulose polymers and cellulose derivative polymers include, but are not limited to, alkyl celluloses, hydroxyalkyl celluloses, and hydroxyalkyl alkyl celluloses (e.g., methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose), cellulose esters and hydroxyalkyl cellulose esters (e.g., cellulose acetate phthalate), carboxyalkyl celluloses, carboxyalkyl alkyl celluloses, carboxyalkyl cellulose esters (e.g., carboxymethyl cellulose and alkali metal salts thereof). In some preferred embodiments, the cellulose polymers and cellulose derivative polymers include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and combinations thereof. The most preferred cellulose polymer is hydroxypropyl methylcellulose.

The synthetic polymers include, but are not limited to, polyacrylic acids and polyacrylates, polymethacrylic acids and polymethacrylates, polyalkylene oxides (e.g., polyethylene oxide), polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate, polyvinyl pyrrolidone, polyvinyl acetate copolymers, and poly crotonic acid, and may also be phthalated gelatin, succinylated gelatin, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates and methacrylates having, for example, a tertiary or quaternary amino group (e.g., diethylaminoethyl). The most preferred synthetic polymer is polyoxyethylene.

The water insoluble polymers include, but are not limited to, ethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, acrylic polymers, vinyl acetate, sulfonated polyester sodium salt, carboxylated acrylics, trimethylpentanediol/adipic acid/glycerol crosspolymer, polyglycerol-2-diisostearate/IPDI copolymer, carboxylated vinyl acetate copolymer, vinylpyrrolidone/vinyl acetate/alkyl aminoacrylate terpolymer, vinylpyrrolidone/vinyl acetate copolymer.

The film-forming polymer does not comprise polydextrose.

In certain preferred embodiments, the film-forming polymer is a combination of polyoxyethylene and hydroxypropylmethylcellulose. Wherein the weight ratio of the polyoxyethylene to the hydroxypropyl methylcellulose is 1: 1-8: 1.

The surfactants of the present invention may be nonionic, anionic, cationic and zwitterionic surfactants. For example, one or more of poloxamer, tween-80, glyceryl monostearate, sucrose fatty acid ester, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated castor oil 40, polyethylene glycol 1000 Vitamin E succinate (Vitamin E TPGS), polyglycerol-10 laurate, carbomer, sodium dodecyl sulfate (SLS), Sodium Dodecyl Sulfate (SDS), docusate sodium, sodium cholate, sodium deoxycholate, potassium oleate, lecithin, chitosan, polylysine, a protein, a phospholipid, phosphatidylcholine, gelatin, acacia, and more preferably poloxamer.

Useful nonionic surfactants include, but are not limited to, poloxamer, tween 20, tween 21, tween 40, tween 60, tween 61, tween 80, tween 81, tween 85, sucrose fatty acid esters, polyhydroxystearate 15, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated castor oil 40, polyethylene glycol 1000 Vitamin E succinate (Vitamin E TPGS), polyglycerol-10 laurate, carbomer, copovidone, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glyceryl monostearate, polyoxyethylene 400 monolaurate, polyoxyethylene 400 monostearate, polyoxyethylene 400 monooleate.

Useful anionic surfactants include, but are not limited to, dioctyl sodium succinate (DOSS), sodium dodecyl sulfate (SLS), Sodium Dodecyl Sulfate (SDS), docusate sodium, sodium cholate, sodium deoxycholate, sodium taurocholate, potassium oleate, sodium oleate.

Useful cationic surfactants include, but are not limited to, polymers, biopolymers, poly-N-methylpyridinium, pyridinium sulfate chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polystyrene, polymethyl methacrylate trimethylammonium bromide (PMMTMABr), hexyl methyl trimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl dimethyl methacrylate sulfate.

Useful zwitterionic surfactants include, but are not limited to, proteins, phospholipids, zwitterionic polymers, and the like, and can be, for example, phosphatidylcholine, lecithin, gelatin, and the like.

Based on the total weight of the oral soluble film composition, the content of the active ingredient is 1-30%, preferably 1-20%, the content of the film forming polymer is 30-90%, preferably 40-70%, the content of the polydextrose is 10-60%, preferably 20-40%, and the content of the surfactant is 1-5%, preferably 2-4%.

In certain embodiments, the compositions of the present invention further comprise one or more sweeteners or flavoring agents, such as sucrose, mannitol, sucralose, ammonium mono-glycyrrhetate, aspartame, eucalyptus oil, sweet orange oil, peppermint oil, menthol, and the like. The sweetening or flavoring agent is present in an amount of 0.1% to 40% based on the total weight of the oral film composition.

The oral film compositions of the present invention may also include other adjuvants such as pigments, antioxidants, preservatives, and the like.

In certain embodiments, the oral film compositions of the present invention are monolayer films.

In another aspect, the present invention provides an oral film composition comprising, based on the total weight of the oral film composition:

1) 1-20% of ondansetron, zolmitriptan, olanzapine, entecavir or tadalafil;

2) 10% -50% of polyoxyethylene;

3)10 to 30 percent of hydroxypropyl methylcellulose;

4) 1-5% of surfactant selected from one or more of polyethylene glycol 1000 vitamin E succinate, polyvinylpyrrolidone, sodium dodecyl sulfate, Tween 80, poloxamer and docusate sodium, preferably poloxamer;

5) 10% to 60% polydextrose, and optionally,

6) 0.1-40% of sweetening agent or aromatic, selected from one or more of sucrose, mannitol, sucralose, ammonium mono-glycyrrhetate, aspartame, eucalyptus oil, sweet orange oil, peppermint oil and menthol.

In certain embodiments, the polydextrose content may be 20% to 40%.

According to another aspect of the present invention, a method for preparing the oral membrane composition of the present invention comprises mixing the active ingredient, the membrane forming polymer, polydextrose, and the surfactant to obtain a gum solution, knife coating the gum solution, and drying.

Among them, the solvent used in the preparation process may be water, an organic solvent or a combination thereof, preferably a combination of water and alcohol, more preferably a combination of water and ethanol.

The oral film composition has the advantages of good taste and uniform distribution of active ingredients. Because polydextrose is added, the prepared oral soluble film is not irritated, has no gritty feel and good flexibility, and improves the compliance of patients. In addition, the oral dissolving film has certain flexibility and toughness, and is not easy to break, break and the like in the processes of transportation, storage and use.

The addition of a surfactant such as poloxamer also achieves unexpected technical effects. Compared with a commercially available preparation without a surfactant and other existing film agent products, the film agent composition disclosed by the invention has the advantages that the film agent components are fewer, the film forming appearance and the mouth feel are good, the storage stability is excellent, the active ingredients are not aggregated after being stored for a long time, and the effective period of the product is prolonged.

Drawings

FIG. 1 shows the dissolution of ondansetron oral film dosage in four media prepared by the present invention;

FIG. 2 shows a commercially available ondansetron oral solution

Appearance micrographs;

FIG. 3 is a photomicrograph of the appearance of the ondansetron oral solution film preparation A obtained in example 1;

FIG. 4 is a drawing showing

Comparing appearances of the materials after being placed for different times;

fig. 5 is a comparison of the appearance of formulation a when left for various periods of time.

Detailed Description

Example 1: ondansetron oral soluble film

The dosage of each prescription is shown in Table 1, and the prescription evaluation is shown in Table 2.

Table 1:

the ondansetron raw material is crushed by a mechanical crusher (the aperture of a screen is 0.5 mm). The ondansetron with the prescription dose is placed in a main tank of a homogenizer, and the poloxamer (not added in the preparation D), the absolute ethyl alcohol and the water are added and stirred uniformly. Adding polydextrose, polyoxyethylene water solution and hydroxypropyl methylcellulose water solution into the main tank, vacuum stirring, and high-speed shearing for 15min to obtain glue solution. And (4) blade-coating the glue solution on a continuous coating machine, drying, forming, cutting into a film with a specified area, packaging and sealing.

Table 2:

by analyzing the dissolution time, the taste, the breaking force and the 180-degree bending experimental result of the film agent in the oral cavity, the polydextrose can obviously improve the taste of the film agent in the oral cavity and increase the flexibility of the film agent. The addition of the surfactant helps the raw materials to be uniformly dispersed and prevents the raw materials from aggregating.

Example 2: entecavir oral dissolving film

The dosage and evaluation of each prescription are shown in Table 3.

TABLE 3

Dispersing entecavir with absolute ethyl alcohol. Adding poloxamer water solution, and stirring until the entecavir is completely dissolved. Adding maltitol, lemon essence, lemon yellow, polydextrose, polyoxyethylene and hypromellose water solution, and stirring. Shearing at high speed, and standing to obtain glue solution. And (4) blade-coating the glue solution on a continuous coating machine, drying, forming, cutting into a film with a specified area, packaging and sealing.

Through experimental analysis, polydextrose can improve the mouthfeel and texture of the orodispersible film.

Example 3 dissolution test:

according to the dissolution determination method (the fourth method of 0931 of the four-part general rule of the 2015 edition of Chinese pharmacopoeia), 2 x 3cm of ondansetron oral dissolution film preparation A obtained by coating through a continuous coating machine is fixed at the central position of two layers of discs, a mesh disc is placed at the lower part of a dissolution cup to be parallel to a rotating surface of a paddle bottom and to be spaced by 25 +/-2 mm, and the dissolution temperature is 37 +/-0.5 ℃, the volume of a dissolution medium is 900ml, and the rotating speed is 50 revolutions per minute. The dissolution media are 0.1M hydrochloric acid solution, pH4.5 acetate buffer solution, pH6.8 phosphate buffer solution and purified water.

Results (see fig. 1): the dissolution conditions of the ondansetron oral dissolution film agent prepared by the invention in four mediums have no obvious difference, and the dissolution rate reaches more than 80% in 10 min. Has the characteristics of an instant film agent.

Example 4: ondansetron oral film appearance contrast

The self-made preparation and the commercial preparation are placed for a long time at 10-30 ℃, and appearance changes are compared.

FIG. 2 is a commercial ondansetron oral solution film stored for 2.5 years

Photograph (50 x magnification), fig. 3 is a photograph of home-made ondansetron oral membrane preparation a (50 x magnification) left for 4 years. It is evident from the photographs that the oral film preparation A prepared by adding the surfactant was more uniform in appearance and no distinct particles were visible.

FIG. 4 shows a commercially available ondansetron oral solution

Controls for different periods of time left (left 4 years, right 2 years) and figure 5 shows control for different periods of time left for formulation a (left 4 years, right 3 months). It can be seen that also after 4 years of standing, the uniformity of the commercial film products was poor, while the uniformity of the home-made product remained good.

Example 5:

the sample of formulation a from example 1 was subjected to stability tests under different standing conditions, and the results are shown in the table below. As can be seen from the table, after being placed for 36 months, the film agent of the invention has no obvious change in quality and good stability.

Conditions of standing	30℃，RH 65％	25℃，RH 60％
			Time (moon)	Total impurities (%)	Total impurities (%)
0	0.30	0.30
			3	0.31	0.31
6	0.25	0.24
			9	0.30	0.28
12	0.31	0.32
			18	0.32	0.24
24	0.28	0.29
			36	0.26	0.27

The sample of formulation A from example 1 and a commercial reference formulation were subjected to accelerated stability testing at 40 ℃ and 75% RH, with the results shown in the following table. As can be seen from the table, the levels of the relevant substances are significantly better for the home-made formulation A than for the commercial formulation.

Claims (6)

1. An oral film composition comprising, based on the total weight of the oral film composition:

1) 1-20% of ondansetron, zolmitriptan, olanzapine, entecavir or tadalafil;

2)10 to 50 percent of polyoxyethylene;

3)10 to 30 percent of hydroxypropyl methylcellulose;

4) 1-5% of surfactant selected from one or more of polyethylene glycol 1000 vitamin E succinate, polyvinylpyrrolidone, sodium dodecyl sulfate, Tween 80, poloxamer and docusate sodium;

5) 10% to 60% polydextrose, and optionally,

6) 0.1-40% of sweetening or flavoring agent selected from one or more of sucrose, mannitol, sucralose, ammonium mono-glycyrrhetate, aspartame, oleum Eucalypti, sweet orange oil, oleum Menthae Dementholatum, peppermint oil, and menthol,

wherein the weight ratio of the polyoxyethylene to the hydroxypropyl methylcellulose is 1: 1-8: 1.

2. The oral film composition of claim 1, wherein the composition comprises, based on the total weight of the oral film composition:

1) 1-20% of ondansetron, zolmitriptan, olanzapine, entecavir or tadalafil;

2)10 to 50 percent of polyoxyethylene;

3)10 to 30 percent of hydroxypropyl methylcellulose;

4) 1-4% of a surfactant selected from sodium dodecyl sulfate or poloxamer;

5) 10% to 40% polydextrose, and optionally,

6) 0.1-40% of sweetener or aromatic selected from one or more of sucrose, mannitol, sucralose, ammonium glycyrrhetate, aspartame, eucalyptus oil, sweet orange oil, peppermint oil and menthol,

wherein the weight ratio of the polyoxyethylene to the hydroxypropyl methyl cellulose is 1: 1-6: 1.

3. A process for preparing an oral film composition according to claim 1 or 2, comprising mixing the active ingredient, the film-forming polymer, polydextrose and surfactant to obtain a dope, drawing down the dope, and drying.

4. The method of claim 3, wherein the solvent used in the preparation process is water, an organic solvent or a combination thereof.

5. The method of claim 4, wherein the solvent used in the preparation process is a combination of water and alcohol.

6. The method of claim 5, wherein the solvent used in the preparation process is a combination of water and ethanol.

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