CN1791385A - Homogeneous, thermoreversible alginate films transportation system - Google Patents

Abstract

The present invention is directed to a delivery system comprising a homogeneous, thermoreversible gel film, wherein the gel film comprises: (i) a film forming amount of low viscosity polymannan gum, e.g., low viscosity guar gum, and optionally at least one of a plasticizer, a second film former, a bulking agent, and a pH controlling agent; and (ii) an active substance. The present invention is also directed to a process for the manufacture thereof.

Description

Homogeneous thermoreversible alginate membrane transport system

related application

This application claims the benefit of US Provisional Application 60/462793, filed April 14, 2003.

field of invention

The present invention relates to a delivery system comprising a homogeneous thermoreversible gel film, wherein said gel film comprises (i) a film-forming amount of a water-soluble thermoreversible alginate, and a plasticizer, a second film-forming agent, a plasticizer At least one of the dosing agent and the pH control agent is optional, (ii) the active substance. The invention also relates to a method for the preparation of said delivery system.

Background of the invention

In recent years, delivery systems have been increasingly used in refreshing tablets and cleansing tablets to deliver oral care active ingredients, etc. The present invention generally relates to delivery systems comprising gel membranes which can be used to contain and deliver a very wide variety of active substances.

For example, WO 02/43657 discloses the use of a pullulan-free edible film composition comprising at least one film former, at least one bulk filler, at least one plasticizer . These films can contain various substances such as pharmaceuticals and are used in many oral care applications such as breath freshening tablets. A film former is described as any cellulose ether (said to include: methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose; carboxymethylcellulose and its derivatives); modified starches (said to include: acid and enzymatically hydrolyzed corn and potato starches); natural gums (said to include gum arabic, guar gum, locust bean gum, carrageenan, gum arabic ( acacia), karaya, ghatti, tragacanth, agar, tamrind gum, xanthan and their derivatives); edible polymers (said to include microcrystalline cellulose, cellulose ethers, xanthan gums and their derivatives); hydrocolloid powder (referred to include guar gum, locust bean, microcrystalline cellulose, tara and their derivatives); seaweed extract (said to include alginate, carrageenan and their derivatives); and terrestrial plant extracts (said to include konjac, pectin, acacia hemilatex and their derivatives).

WO 00/18365 discloses rapidly mouth erodible films for delivering respiratory deodorants, antimicrobials and salivary stimulators to the oral cavity. The film-forming agent used to make the film of this invention is said to be selected from the group consisting of pullulan, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxymethylcellulose, polyethylene Alcohol, Sodium Alginate, Polyethylene Glycol, Xanthan Gum, Tragacanth Gum, Guar Gum, Gum Arabic, Arabic gum, Polyacrylic Acid, Methyl Methacrylate Copolymer, Carboxyvinyl Polymer, Amylose, higher amylose, hydroxypropylated higher amylose, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate substances, casein and their mixtures. These films are said to overcome the problem of maintaining essential oil interactions and the relatively high oil content of some films used in oral care.

Summary of the invention

In a first embodiment, the present invention relates to a delivery system comprising a homogeneous thermoreversible gel film, wherein the gel film comprises: (i) a film-forming amount of a water-soluble thermoreversible alginate, and a plasticizer, At least one of two film-forming agents, bulking agents and pH control agents; (ii) active substances.

In a second embodiment, the present invention relates to a method of preparing the above-mentioned homogeneous gel membrane delivery system, said method comprising the steps of: (i) treating alginic acid in a device providing sufficient shear force, temperature and retention time The salt, and at least one of the plasticizer, the second film forming agent, the bulking agent and the pH control agent are heated, hydrated, mixed, dissolved and optionally degassed to form a homogeneous molten composition, wherein the temperature equal to or higher than the dissolution temperature of the composition; (ii) adding an effective amount of the active substance before or after forming the molten composition; (iii) cooling the molten composition containing the active substance at or below its gelling temperature, Forms a gel film containing the active substance.

Brief description of the drawings

Figure 1 is a side view, partly broken away, of a fluid mixing apparatus for mixing first and second fluids and vapors useful in the process of the present invention.

Detailed description of the invention

Alginate derived from brown algae (Phaeophyceae sp.) etc. is an unbranched linear chemical polymer containing (1-4) linked β-D-mannuronic acid (M) and α-L- Guluronic acid (G) residues. Alginate is not a random copolymer, but consists of alternating blocks of similar residues, such as MMMM, GGGG, and GMGM, which can generally be used to form alginic acid or alginate.

Alginates that can be used in the present invention include monovalent salts of alginic acid, such as sodium alginate and potassium alginate, and esterified forms of alginic acid, such as propylene glycol alginate. The definition of alginate used in the present invention includes all such ester forms. Other examples of alginates useful in the present invention include magnesium alginate and 3-ethanolamine alginate. These alginates can be used alone or in combination with other alginates of the present invention, which may include small amounts of other cations, as long as they do not interfere with the formation of the gel or the uniformity of the gel film. Adverse effects, as discussed in detail below. Alginate can be fully, partially clarified, or unclarified from the raw material.

It is generally believed that certain alginates, such as sodium alginate, produce thermally irreversible gels in the presence of calcium ions. To the surprise of the present inventors, studies have found that these alginates of the present invention are capable of producing homogeneous thermoreversible gel films with significant film strength. Furthermore, it is generally believed that certain alginates, such as propylene glycol alginate, do not gel. Also to the inventors' surprise, studies have found that propylene glycol alginate produces homogeneous thermoreversible gel films with significant film strength.

Alginate is known to react and cross-link with accessible multivalent cations (ions), such as calcium ions. This crosslinking can adversely affect the film formation and thermoreversibility of alginate gel membranes, depending on the multivalent cations used; for example, magnesium ions do not adversely affect the thermoreversibility of alginate gel membranes Influence. Therefore, it is important that the content of these polyvalent cations in alginate, which can adversely affect the film formation and thermoreversibility of alginate membranes, is below a level that would not affect the film formation or the thermoreversibility of the alginate system. Thermal reversibility causes damage. The amount of such polyvalent cations (such as calcium ions) is usually not higher than 5.0% by weight, more preferably less than 2.0% by weight, more preferably less than 1.0% by weight (based on the dry weight of alginate in the gel film), but The specific amount can vary depending on the influence of other ingredients, the type and source of alginate, and the use of chelating agents. Sufficient chelating agents may be added to minimize the solubility (and residual activity) of the above-mentioned detrimental multivalent cations, such as calcium.

Alginate is used in the present invention in a film-forming amount (eg, an amount that increases the film strength of a gel film), as opposed to trace low alginate, which does not enhance film properties. Thus, for example, in the gel film of the present invention, the film-forming amount of alginate is an amount capable of increasing the film strength of the entire film. According to the application, this film forming amount is usually at least 0.25% by weight (based on dry gel film), preferably 0.5-90% by weight, more preferably 0.5-50% by weight, more preferably 0.25-25% by weight (based on dry gel film) gel film).

The gel films of the present invention are homogeneous thermoreversible films. The "homogeneous film" as used herein refers to a film that is uniform when observed with the naked eye, free of lumps, cracks, undissolved particles that should be dissolved, and non-uniform distribution of insoluble particles. "Fish eyes" (mixed state of liquid and solid) or "gumballs" (non-uniform gel structure) do not meet the definition of "homogeneous" as used herein.

The gel film of the present invention is a homogeneous thermoreversible gel film.

As used herein, "thermoreversible film" means a film that has a melting temperature. Melting temperature as used herein refers to the temperature or range of temperatures at which the gel film softens or flows.

The phrase "gel film" as used herein refers to a thin film formed from structured alginate. Gelled compositions are characterized by the gelation temperature below which the molten mass must be cooled to form a self-supporting structure. Optionally, the molten mass can be cast hot, then cooled, and the solid further concentrated by drying (controlled removal of water) until a gel film is formed from the gel composition. The melting temperature of a thermoreversible gel film is higher than its gelling temperature.

The gel film of the present invention comprises an active substance. The active substances that can be contained in the gel film are selected from the group consisting of oral care agents, breath fresheners, medicaments, nutritional agents, salivation stimulators, vitamins, minerals, colorants, cosmetic ingredients, agricultural actives, sweeteners, At least one of flavoring agent, aroma agent or food.

The homogeneous thermoreversible gel film of the present invention may optionally contain at least one of a plasticizer, a second film forming agent, an extender and a pH control agent. The components incorporated into the gel film and the amounts added may vary according to the desired characteristics of the alginate delivery system.

Examples of such plasticizers include polyhydric alcohols such as glycerin, sorbitol, maltitol, lactitol, fructose, corn starch, polydextrose, solubilizing oils and polyalkylene glycols such as polyethylene glycol and propylene glycol. Depending on the desired elasticity of the delivery system, such plasticizers are generally used in an amount of at least 5% by weight, at least 10% by weight, preferably at least 20% by weight, more preferably at least 30% by weight. The delivery system may be free of any plasticizers.

Examples of second film formers that can be used in the present invention include at least one of starch, starch hydrozylate, starch derivative, cellulose gum, hydrocolloid, alkyl cellulose ether or modified alkyl cellulose ether kind. Examples of hydrocolloids include at least one of the following: kappa carrageenan; kappa-2 carrageenan; iota carrageenan; mannan gums such as locust bean gum or guar gum, including low viscosity guar gum; Dextran; pullulan; gellan (including high acyl and low acyl gellan gum); pectin and their less substantially modified forms and combinations thereof. The κ-2 carrageenan used here has a molar ratio of 3:6-anhydrogalactose-2-sulfate (3:6AG-2S) to 3:6-anhydrogalactose (3:6AG) content of 25 -50%, iota carrageenan has a molar ratio of 3:6AG-2S to 3:6AG content 80-100%, kappa carrageenan has a molar ratio of 3:6AG-2S to 3:6AG content less than kappa-2 carrageenan. For example, kappa carrageenan from Eucheuma cottonii, a common seaweed source for kappa carrageenan, has a molar ratio of 3:6AG-2S to 3:6AG content of less than about 10%; The iota carrageenan of the seaweed source Eucheuma spinosum has a molar ratio of 3:6 AG-2S to 3:6 AG content of greater than about 85%. Kappa-2 carrageenan can be obtained, for example, from Gigartina skottsbergii. Kappa carrageenan, kappa-2 carrageenan, and iota carrageenan are structurally and functionally distinct from each other. If it is desired to use iota, kappa or kappa-2 carrageenan as the second film-forming agent, in a 0.10M sodium chloride solution in which the molecular weight reduced carrageenan accounts for 1.5% of the total solution weight, this carrageenan is at 75 The viscosity at °C is 19 cps or less, more preferably less than 10 cps. This viscosity measurement can be carried out with a Brookfield LVF (Brookfield Engineering Laboratories, Inc.) viscometer, using a #1 spindle with a rotation speed of 60 rpm, and measuring the viscosity after 6 turns. An example of an alkyl cellulose ether useful in the present invention is hydroxyethyl cellulose. Examples of modified alkyl cellulose ethers useful in the present invention include hydroxypropylcellulose and hydroxypropylmethylcellulose. It should be noted that certain secondary film formers, such as carrageenan, may contain cations that have both positive and negative effects on the gel properties and film strength of the carrageenan and/or alginate. Such beneficial cations include potassium, magnesium and ammonium ions. These cations may be present in the carrageenan or may be added from other organic or inorganic sources. The content of these beneficial cations can account for less than 20% of the dry weight of alginate in the gel film (including water). This level can vary depending on the components in the system and the desired melting and sealing temperature.

Other cations, such as calcium (mentioned above), aluminum and chromium ions can detrimentally cross-link alginate and/or adversely affect the stability of carrageenan and should be kept to a minimum, e.g. low 5%, less than 2%, less than 1% of the dry weight of alginate in the xerogel film (including water).

Alginate can be the only film former in the gel film. If the gel film of the present invention comprises a second film former, the content of alginate may be at least 10% by weight, at least 40% by weight, at least 60% by weight, or at least 80% by weight of the total amount of film former in the dry gel film. weight%.

Examples of bulking agents include microcrystalline cellulose, microcrystalline starch, modified and unmodified starches, starch derivatives, inulin, starch hydrozylates, sugars, corn syrup, and polydextrose. The term "modified starch" as used in the specification and claims includes such starches as hydroxypropylated starch, acid thinned starch and the like. Examples of modified starches useful in the present invention include Pure Cote ^™ B760, B790, B793, B795, M250 and M180, Pure-Dent ^™ B890 and Pure-Set ^™ B965 (all available from Grain Processing Corporation, Muscantine, Iowa), and C AraTex ^™ 75701 (available from Cerestar, Inc.). Examples of starch hydrozylates include maltodextrin, also known as dextrin. Unmodified starches, such as potato starch, can also increase film strength when used in combination with hydrocolloids within the scope of the present invention. Generally, modified starch is a product obtained by treating starch, such as acid-treated starch, enzyme-treated starch, oxidized starch, cross-linked starch and other starch derivatives. The modified starch is preferably a derivative in which the side chains are modified with hydrophilic or hydrophobic groups to form a more complex structure with strong interactions between the side chains.

The amount of extender used in the present invention is usually 0-20% by weight of the dry film weight, but if necessary, according to the use of the delivery system, it can also be used in more amounts, such as at least 20% of the dry film, more preferably at least 30%. Note that starch, starch derivatives and starch hydrolysates can have multiple functions. That is, in addition to their use as extenders, they can also be used as secondary film formers. If used as such as extenders and secondary film formers, they are generally present in amounts of at least 10% by weight of the dry gel film, preferably at least 20% by weight.

Examples of the pH controlling agent used in the present invention include bases such as hydroxides, carbonates, citrates and phosphates. pH control agents can be used to increase the stability of the gel film. For certain compositions comprising a secondary film former, a pH control agent may be selected as a source of beneficial cations, such as potassium or ammonium. The pH control agent is used in an amount of 0-4% by weight of the dry gel film, more preferably 0-2% by weight.

Studies have found that the breaking force of the xerogel film of the present invention (for example, containing at least 80% solids) is (for example) at least 250g, at least 1000g, at least 2500g, at least 4000g, at least 5000g, at least 6000g, available Texture Analyzer TA-108S Mini Film Test Rig determination. In addition, measurements have shown that the breaking force of the dry film of the present invention exceeds 7000 and 8000 g.

It has been found that the film of the present invention has a solids content of at least 50%, at least 60%, at least 70%, at least 80%, at least 90% of all components in the gel film. It is understood that as much as 15%, 10%, 5% of the water in the xerogel film is still strongly bound to the solid.

The gel films of the present invention may also contain coloring and flavoring agents, such as sugar, corn syrup, fructose, sucrose, etc., regardless of the presence or absence of other components such as plasticizers, bulking agents, secondary film formers, and the like. One embodiment of the gel film of the present invention comprises the alginate of the present invention, flavoring agent and water to form a high solid content system, for example, the solid content exceeds 50%, 60%, 65%, 75%, 80%, 85% %, 90%.

The films of the present invention may comprise non-thermoreversible gums. However, in order not to adversely affect the homogeneity and thermoreversibility of the gel film of the present invention, the content of this non-thermoreversible film should be less than 50% by weight of the alginate weight, preferably less than 40% by weight, more preferably Preferably less than 30% by weight. Examples of such non-thermoreversible gums include cross-linked and partially cross-linked gums, such as calcium-cured (eg, cross-linked) pectins or alginates. In the absence of divalent cations, calcium-active alginates and pectins, and their less refined forms, are considered thermoreversible gums.

The films of the present invention are generally prepared by a process employing equipment capable of providing sufficiently high shear, temperature (above the gelation temperature) and sufficiently long residence time to obtain a homogeneous molten composition which, after cooling Form a gel. This is usually done in the plant by heating, hydrating, mixing, solubilizing and optionally degassing the composition. Examples of such equipment are Ross mixers, Stephan processors, extruders, common jet boilers and the fluid mixing equipment shown in Figure 1. Ross mixers, Stephan processors and common jet boilers are readily available. Prior to cooling, the melt may be sent to at least one of a pump, mixer, or exhaust, such as an extruder. Note that, as another aspect of the invention, it is not necessary for the melt to be homogeneous in step (i). That is, when using additional equipment such as a mixer, a pump and/or an exhaust chamber, a homogeneous melt can be obtained either before or after feeding the molten composition into at least one of the mixer, pump or exhaust chamber, as long as The melt reaches homogeneity before gelling. The extruded melt can be fed to film-forming or forming equipment (such as a spreader box) to facilitate uniform casting of continuous films, or the extruded melt can be fed to a die to form a film directly from melt delivery equipment or Shaped extrusions. Care must be taken to maintain the melt state until the defined flow/gel structure formation begins. The delivery hose can be insulated and preheated (to maintain the proper temperature) to ensure that the melt can flow until the desired gel film formation process begins. The melt can be forced (by pressure) through the transfer hose mentioned above with other processing methods (such as preheated discharge/plunger-like head (discharge/plunger-likehead), as seen in the Ross processing system) . Other insulation measures can also help maintain the temperature of the melt, such as covering the surface of the melt with Teflon sheets immediately after removing the mixing equipment. Note that, as another aspect of the invention, it is not necessary for the melt to be completely homogeneous in step (i). That is, when using additional equipment such as a mixer, pump and/or exhauster, a homogeneous melt can be obtained before or after feeding the molten composition into at least one of the mixer, pump or exhaust chamber, as long as It is sufficient for the melt to be homogeneous before gelling.

As used herein, "fluid mixing device" refers to the device in FIG. 1 . FIG. 1 shows a fluid mixing device 10 . Fluid mixing apparatus 10 is used to mix vapor 2 with first fluid or slurry 4 and second fluid or slurry 6 to produce a melt or mixed slurry 8 .

The fluid mixing device 10 comprises a first chamber 20 with a first inlet 22 for the vapor 2 to enter the chamber 20, an end 24 of the nozzle for the vapor 2 to exit the chamber 20, a nozzle valve or stem mounted on the nozzle end 24 26. An actuator 30 is connected to the first chamber 20 for controlling the exit velocity or exit pressure of the first fluid (vapor) 2 at the nozzle tip 24 . Actuator 30 may be of the type produced by Fisher Controls U.S.A.

The fluid mixing device 10 also includes a second mixing chamber 40 which is connected to the first chamber 20 at the nozzle end 24 of the first chamber 20 . The second chamber 40 comprises a second inlet 42 for the first fluid 4 to enter the second chamber 40 and a third inlet 44 for the second fluid 6 to enter the second chamber 40 . Inlets 42 and 44 are located downstream of first inlet 22 . As shown in FIG. 1 , the second inlet 42 and the third inlet 44 are located in the same plane, facing each other in the radial direction, preferably completely opposite to the central axis Y of the mixing device 10 (ie, 180° apart). The second chamber 40 forms a generally cylindrical mixing chamber 52 which in turn forms a flow passage extending along the axial length of the mixing chamber 52, starting from the inlet end 54 of the mixing chamber 52 to the outlet end of the chamber 52 56 so far. Actuator 30 may move nozzle valve 26 on inlet port 54 between a sealed position and an open position to control the flow rate of vapor 2 into mixing chamber 52 .

The nozzle end 24 of the first chamber 20 directs the vapor 2 into the inlet end 54 of the mixing chamber 52 . The second inlet 42 and the third inlet 44 respectively introduce the first fluid 4 and the second fluid 6 into the mixing chamber 52 along the radial direction. The vapor 2 , the first fluid 4 and the second fluid 6 mix in the mixing chamber 52 to form a melt or mixture 8 before exiting the mixing chamber 52 . Next, the melt 8 can be formed into a shaped article or formed into a film, for example by casting the mixture 8 onto a cooled drum, or by passing the mixture 8 through an extruder.

The fluid mixing apparatus 10 is suitable for preparing mixtures for film formation, particularly edible films for use in the preparation of edible delivery systems. Typically the incompatible membrane components are placed in separate fluid feeds, and these non-interfering components meet immediately at the vapor injection interface within the mixing chamber 52 of the fluid mixing device. Although Figure 1 shows three inlets for vapor, first and second fluids, one or more additional inlets may be provided for one or more other fluids. The chambers 20, 40 and other components of the fluid mixing device 10 are preferably fabricated from high grade stainless steel.

Gel films can also be used to modify the dissolution properties of the dosage form. For example, the gel film of the present invention may incorporate components that produce a solid dosage form with immediate, enteric or sustained release capabilities. Definitions of "immediate release", "sustained release" and "enteric release" can be found in the United States Pharmacopoeia, which is incorporated herein by reference.

The present invention will be described in more detail by examples below, but it should be understood that the present invention is not limited to these examples. Unless otherwise indicated, all parts, percentages, ratios, etc. are by weight.

Example

Unless otherwise stated, the following procedures were used to prepare and test the materials and films of Examples 1-3. The Stephan UMC5 Processor is laboratory mixing equipment for proper high shear mixing, heating and degassing of formulations to be cast into films in the laboratory. A suitable batch size is 1500g.

Aqueous dispersions of starch are prepared by dissolving any salts/buffers and pH adjusters in deionized water, adding starch and/or maltodextrin (M100), mixing until they are dissolved/dispersed. Pure Cote ^(R) B760 starch is commercially available from Grain Processing Corporation, Muscatine, Iowa. Prepare the hydrocolloid mixture in a Stephan UMC5 processor: pre-mix the plasticizer until homogeneous, add the pre-mixed dry hydrocolloid in batches, stirring at 200 rpm for about 30 seconds after each addition. Sorbitol Special and glycerin were used as plasticizers. Sorbitol Special is an aqueous solution of sorbitol and sorbitan at 76% solids, manufactured by SPI Polyols, Inc. (New Castle, DE).

Add the starch dispersion into the anhydrous hydrocolloid mixture and stir for 5 minutes at a speed of 300 rpm. The mechanical stirring speed was increased to 2100 rpm and the mixture was heated to 85-95°C with stirring. When the target temperature was reached, the mixture was stirred for 30 minutes and then the sample was kept under vacuum (50-60 bar) for 45 minutes with continuous stirring.

After the hold time at vacuum and target temperature was complete, the samples were poured into preheated wide mouth 1 quart Mason glass jars. Record temperature and pH. The viscosity of the hot samples was measured with a Brookfield LVF viscometer.

A small aliquot of the sample was removed, refrigerated overnight, and gel/melt properties and solids content were determined with an Atago E-Series handheld refractometer (Gardco, Pompano Beach, FL). The melting temperature of the gel is determined by placing a small piece of refrigerated gel on a wire stand fixed in the test tube so that the gel piece does not touch the wall of the test tube. Cover the test tube with aluminum foil with a small hole for the temperature of the gel to be measured with a digital temperature probe. Submerge the test tube in a heating bath so that the gel mass is below the surface of the hot water bath at approximately 100°C. For samples with a melting temperature higher than 90 °C, use a silicone oil bath. When the gel sample appears wet, soft and stirrable, record the melting temperature (note the temperature range). Once the sample had melted, the tube was transferred to a second beaker filled with cold tap water (15°C). While the sample is cooling, measure the temperature with a temperature probe and check the surface of the sample to see if the sample is starting to gel. The gelation temperature is the temperature at which the sample no longer flows when cooled to fill the indentation made by the probe.

Next, the hot samples were cast with a squeegee with a 3 mm wide gap onto a 177 mm x 177 mm x 5 mm metal plate pre-sprayed with PAM (lecithin) to facilitate the movement of the membrane material. The gel-coated metal plate was covered to prevent water loss from the cast film and kept refrigerated (below 8°C) for at least half an hour before the film was removed for testing. Refrigeration is not required during film formation. The coated panels were dried in a 40°C blast oven to prepare dry film strips. The film was dried at 40°C for 2 hours to an average solids content of approximately 60%. Solids contents of 80% or more are generally obtained if the film is dried overnight at 40°C. Unless otherwise stated, sample properties were generally determined at room temperature (about 20°C). The percent solids of a dry film is determined by the weight difference between the cast film and the dry film of its solid formulation. The breaking force (BF) of cast and dry film strips was determined with a Texture Analyzer TA-108S Mini Film Test Rig.

Unless otherwise stated, Maltrin M100 was purchased from Grain Processing Corporation, PureCote B760 was purchased from Grain Processing Corporation, Sorbitol Special was purchased from SPI Polyols, and glycerin was purchased from VWR (EP/USP grade).

Example 1

Table I lists the composition and properties of gel films prepared with a mixture of sodium alginate and low viscosity guar gum Edicol ULV 50 produced by Indian Gum Industries Ltd. ^Protanal® LFR5/60, ^Protanal® LF20/40 and ^Protanal® SF120 RB are sodium alginate available from FMC Corporation, Philadelphia, PA.

Table I Example 1-1 Example 1-2 Example 1-3 Component (g) water 836.3 836.3 836.3 LFR5/60 40.5 0 0 LF20/40 0 40.5 0 SF120 RB 0 0 30 Guar gum ULV 50 49.5 49.5 45 Starch B760 220.8 220.8 220.8 M100 0 0 15.0 Sorbitol SP 264.4 264.4 264.4 glycerin 88.2 88.2 88.2 Gross weight (g) 1500.0 1500.0 1500.0 Temperature (°C*) 90 94 93 Viscosity (mPas*) 31650 >50000 >50000 Gelation temperature, ℃ 50 RT RT Melting temperature, °C 70-71 95* 87* pH 5.6 5.5 5.6 cast film Solids content (estimated) 40% 40% 40% BF(g) <40 102 110 Dry film (2 hours, 40°C) Solids content (estimated) 60% 64% 67% BF(g) 617 1250 1126 Dry film (16 hours, 40°C) Solids content (estimated) 80% 80% 94% Average film thickness (mm) 0.53 0.89 0.51 BF(g) 4780 7701 10850 *The temperature and viscosity of the melt before casting

Increasing the molecular weight of sodium alginate is beneficial to the structure of the whole membrane and can improve the strength of the membrane (Example 1-1, 1-2 and 1-3). The melting temperatures listed above were obtained by heating the gel film in an oil bath. When heated, they soften and can be stirred. Upon cooling, gels form at temperatures above room temperature.

Example 2

Two kinds of potassium alginates are used: KAHG is the potassium salt of alginic acid extracted from Laminaria hyperborean, which contains more guluronic acid (G) units; KAHM is the potassium salt of alginic acid extracted from Lessonia nigrescens, which contains more Polymannuronic acid (M) unit. The viscosities of KAHG and KAHM are 5 cps and 12 cps respectively when measured with 1% aqueous solution at 25°C.

Potassium cations bound to alginate are beneficial to initiate the process of homogeneous casting and curing film structure of kappa carrageenan and/or kappa-2 carrageenan and alginate. Kappa carrageenan is an alkaline-treated clarified extract from Kappaphycus alaverei (Eucheuma cottonii). All hydrocolloids used were low in divalent cation content, as shown in Table II.

Table II: Content of cations in hydrocolloids experiment KAHG KAHM κCgn viscosity Mg% 0.07 0.12 0.09 Ca% 0 0 0.06 K% 15.73 16.01 2.60 Na% 0.63 0.59 5.45

Table III lists the composition and properties of the films formed with mixtures of potassium alginate and other film formers such as kappa carrageenan and low viscosity guar gum Edicol ULV 50 produced by Indian Gum Industries.

Table III Films Prepared with Low Viscosity Guar Gum, Potassium Alginate and Carrageenan Example 2-1 Example 2-2 Example 2-3 Example 2-4 Example 2-5 Example 2-6 Component (g) water 836.3 836.3 836.3 836.3 836.3 836.3 KAHG 60 60 40.5 10.5 0 0 KAHM 0 0 0 0 60.0 10.5 κCgn 30.0 30.0 0 30.0 30.0 30.0 guar gum 0 0 49.5 49.5 0 49.5 Starch B760 220.8 220.8 220.8 220.8 220.8 220.8 Sorbitol SP 264.4 264.4 264.4 264.4 264.4 264.4 glycerin 88.2 88.2 88.2 88.2 88.2 88.2 Gross weight (g) 1500.0 1500.0 1500.0 1500.0 1500.0 1500.0 Temperature (°C*) 90 90 88 90 93 92 Viscosity (mPas*) 26500 28650 24800 28250 42650 31250 Gelation temperature, ℃ 42 41 50-51 53 39 55 Melting temperature, °C 60-65 62-67 60-61 70-74 60-63 65-69 pH 7.6 7.2 6.3 5.6 7.4 5.9 cast film Solids content (estimated) 40% 40% 40% 40% 38% 41% BF(g) <40 <40 <40 188 <40 185 Dry film (2 hours, 40°C) Solids content (estimated) 66% 62% 63% 64% 62% 66% BF(g) 370 248 445 1811 502 1265 Dry film (16 hours, 40°C) Solids content (estimated) 81% 79% 85% 80% 77% 80% Average film thickness (mm) 0.83 0.76 0.56 0.60 0.56 0.59 BF(g) 3826 4253 4144 7960 6918 8301 *The temperature and viscosity of the melt before casting

The results showed that the combination of potassium alginate with kappa carrageenan and guar gum, regardless of whether it contained more mannuronate, more guluronate, or both, formed a favorable interaction. effect. Further changing the weight ratio of alginate to the second film-forming agent and changing the process conditions can also be used to cast a high solid content (>80%) melt, and the formed and cooled gel film can also be further processed.

Example 3

Table IV lists the composition and properties of the gel films prepared with propylene glycol alginate and kappa carrageenan. Protanal ^(R) ester BV4830 is propylene glycol alginate available from FMC Corporation (Philadelphia, PA). HEC is hydroxyethylcellulose. Kappa carrageenan was as described in Example 2 above.

Table IV

Compositions based on propylene glycol alginate mixtures Example 3-1 Example 3-2 Example 3-3 Component (g) water 840.3 836.3 840.3 BV4830 91.2 49.5 66.0 HEC 1.9 κCgn twenty four 40.5 54.0 potassium citrate 2.9 Starch B760 207.8 220.8 207.8 Sorbitol SP 264.4 264.4 248.8 glycerin 88.2 88.2 83 Temperature (°C*) 91 87 89 Viscosity (mPa-s*) 24800 6550 12500 pH 4.2 3.8 3.9 Gelation temperature, ℃ 59 42-43 43-44 Melting temperature, °C 72-75 54-63 62-64 cast film Solids content (estimated) 45% 38% 36% BF(g) 136 89 113 Dry film (16 hours, 40°C) Solids content (estimated) 87% 79.8 86.6 Average film thickness (mm) 0.72 0.68 0.79 BF(g) 8838 5244 7638 *The temperature and viscosity of the melt before casting

Table V reports the composition and film properties of films prepared with kappa-2 carrageenan together with propylene glycol alginate and potassium alginate. Kappa-2 carrageenan is a clarified extract obtained by alkaline processing from Gigartina skottsbergii and Sarcothaliacrispata, a predominantly haploid (gametophytic) plant mixture. It also contains about 10-20% (equivalent to the total amount) of lambda- and theta-carrageenan from diploid (tetrasporocyte) plants.

Table V

Alginate membrane prepared with κ-2 carrageenan Example 3-4 Example 3-5 Component (g) water 834.7 834.7 κ-2 Cgn 40.5 54.0 KAHG 31.5 36 BV4830 18.0 36.0 M-100 227.3 227.3 Sorbitol SP 272.2 272.2 glycerin 90.8 90.8 Temperature (°C*) 87 84 Viscosity (mPas*) 4250 1050 solid content 40 37 Melting temperature, °C 77-78 74-79 Gelation temperature, ℃ 54 52 pH 4.8 5.5 Cast film (estimated 40% solids) BF(g) 142 168 Dry film (est. 80% solids, 16 hours, 40°C) Average film thickness (mm) 0.67 0.48 BF(g) 3409 4004 *The temperature and viscosity of the melt before casting

In Examples 3-4, potassium ions were provided by potassium alginate. At the temperature at which carrageenan can form a gel film structure, potassium ions can promote the formation of carrageenan double helix structure. In Examples 3-5, the increase in strength and decrease in processing viscosity is due to the higher content of propylene glycol alginate.

Table VI lists compositions and gel films formed from low viscosity guar gum Edicol ULV 50 with propylene glycol alginate and other hydrocolloids. ^Protanal® ester BV4830 and Protanal® ^ester SLF3 are propylene glycol alginate esters available from FMC Corporation (Philadelphia, PA) and Kibum, respectively. SLF-3 has a smaller molecular weight than BV-4830. HEC is hydroxyethylcellulose.

Table VI

Films prepared with propylene glycol alginate and guar gum Example 3-6 Example 3-7 Example 3-8 Example 3-9 Component (g) water 840.3 840.3 840.3 836.3 BV4830 0 0 91.2 12.0 SLF-3 114 85.5 0 0 HEC 2.4 1.8 1.9 0 κCgn 0 0 twenty four 40.5 Guar gum ULV 50 0 30 0 37.5 Starch B760 207.8 207.8 207.8 220.8 M-100 0 0 0 0 Sodium citrate 3.6 2.7 0 0 potassium citrate 0 0 2.9 0 KCl 0 0 2.4 0 Sorbitol SP 248.8 248.8 248.8 264.4 glycerin 83 83.0 83.0 88.2 Temperature (°C*) 91 87 90 90 Viscosity (mPas*) 3250 16500 25000 23100 Gelation temperature, ℃ 34-35 34-38 43-46 46 Melting temperature, °C 58-60 62-64 56-62 60-68 pH 4.4 4.5 4.3 4.6 cast film Solids content (estimated) 39% 41% 45% 41.5% BF(g) <40 <40 231 147 Dry film (2 hours, 40°C) Solids content (estimated) 74% 65% 55% 60% BF(g) 1877 355 842 592 Dry film (16 hours, 40°C) Solids content (estimated) 85% 77% 78% 80% Average film thickness (mm) 0.67 0.60 0.75 0.62 BF(g) 4677 3317 9599 7214 *The temperature and viscosity of the melt before casting

Example 4

The following examples illustrate membranes prepared using the fluid mixing apparatus shown in FIG. 3 . In these examples, Part A and Part B are pumped at room temperature from respective storage containers as two separate streams 4, 6 into two different inlets 42, 44 from which they are fed into the injection vapor In the fluid mixing device 10. The two separate streams 4 , 6 meet at the vapor interface in the mixing zone 52 of the fluid mixing device 10 . The respective solutions of Part A and Part B are readily pumped into the fluid mixing device 10 and mixed with the vapor 2 . Vapor 2 enters the mixing zone at a pressure of 120 psi. The resulting melt or mixed slurry 8 exits the outlet 56 of the fluid mixing device 10 . Pour the mixture 8 onto a smooth surface and pull down into a homogeneous film 9 .

To determine the viscosity of Mixture 8, a sample of about 500 ml of Mixture 8 was collected from outlet 56 and poured into a tank. The temperature, pH and viscosity of this sample were measured at 95°C. Viscosity was measured with a Brookfield LVF viscometer. Use the proper combination of speed and spindle so that readings can be taken. Convert reading on scale to dynamic viscosity (cP)

To determine film strength and solids content, the melt 8 was collected from outlet 56 and cast onto a stainless steel plate with a scraper set at a gap of 3 mm. Collect the initial membrane 9 or "fresh membrane". Several portions of fresh film 9 were placed in a 40°C ventilated oven to dry the fresh film 9 . The breaking force of cast and dried film strips was determined with a Texture Analyzer TA-108S Mini Film Test Rig. The initial weight of the fresh film and the final weight of the dried film were measured, and the percent solids was determined from the difference.

To determine the gelation temperature, a portion of the melt 8 is collected from the outlet 56 of the mixing device 10 and placed in a test tube, which is half empty. Insert a glass thermometer into the melt 8. Material 8 was allowed to cool at room temperature. Remove the thermometer from the material 8 every degree it cools. When a small temporary indentation was observed on the surface of material 8, the temperature was recorded. Reinsert the thermometer into the material 8 and allow the material to cool further. The thermometer is removed and reinserted every degree of cooling until a permanent indentation is formed in the material 8, ie the indentation will not be filled again. The temperature at which the permanent dent is formed is recorded. The reported gelation temperature is the range between the two temperatures recorded.

Table VII

Blend containing PGA Example number 4-1 4-2 4-3 4-4 4-5 Part A (%) Component (gms) carrageenan B kappa-2 2.7 3.2 3.2 4.0 0.0 Carrageenan A κ 0.0 0.0 0.0 0.0 4.0 PGA 3.3 3.9 3.9 4.9 4.9 glycerin 22.4 26.5 26.5 33.5 33.5 Part B (%) KOH 0.0 0.0 0.1 0.0 0.0 K2CO3 0.0 0.0 0.0 0.3 0.3 starch 13.9 16.4 16.4 20.7 20.7 water 57.8 50.0 49.9 36.6 36.6 Mixing chamber temperature (°C) 108 107 108 107 108 Outlet temperature (℃) 102 102 102 101 102 ViscositycP(95℃) 5500 4650 2200 12400 9400 pH 4.1 4.2 8.7 6.3 6.8 %solid 42 50 50 65 65 Gelation temperature (°C) 35-40 Untested Untested 58-66 63-71 Wet film strength (g) 60 117 3874 337 822 Dry Film Strength (grams) 2408 3069 4335 4561 4795

Table VII shows that the film former can be a hydrocolloid, such as a combination of carrageenan and PGA. In addition, salts can be added to alter membrane properties such as strength, gelation temperature, and pH.

Tables VIII and IX below further describe the components described in the above examples.

Table VIII

Description of the components name Product name supplier describe Propylene Glycol Alginate (PGA) Protanal BV 4830 FMC BioPolymer glycerin Callahan Chemical 99.70% starch Pure-Cote B790 Grain Processing Corporation

Table IX below describes the various carrageenans used in this example.

Table IX

Description of carrageenan mark carrageenan type describe supplier Carrageenan A kappa Alkali-treated clarified kappa carrageenan extract from Kappaphycus alverezii (Europa auricularis) with low divalent content FMC Corporation Carrageenan B kappa-2 A clarified low divalent extract often referred to as "κ-2 carrageenan" obtained by alkaline processing of a predominantly haploid (gametophyte) plant mixture of Sarcothia sp. and Sarcothalia crispata. Also contained about 10-20% (total) of lambda and theta carrageenans from diploid (tetrasporocyte) plants. Identified as a natural random block copolymer of kappa carrageenan and iota carrageenan in a ratio of 1.0 to 3.0:1, blended in the same ratio with separate natural polymers of kappa and iota carrageenan than, it has a distinctly different function. FMC Corporation

Example 5

The transport membranes of the present invention are prepared by dry mixing alginate and kappa carrageenan to form a gum mixture. KAHG and NAHG are the potassium and sodium salts of alginic acid extracted from Laminaria hyperborean, respectively, with high levels of guluronic acid (G) units. KAHM is a potassium alginate salt extracted from Lessonia nigrescens with a high level of mannuronic acid (M) units. In 1% aqueous solution, when measured at 25°C, the 1% aqueous solution viscosities of KAHG and KAHM are 5cP and 12cP, respectively. Maltodextrin Maltrin M 100 (Grain Processing Corporation, Muscatine, Iowa) was dry blended with the gum mixture. Deionized water and glycerol were dosed in a 1.2-liter stainless steel beaker. Add the dry premix to the water with good agitation, then heat to 90°C and hold at 90-95°C for 15 minutes to fully hydrate the gum. After replenishing the water lost due to evaporation, add the delivery ingredients and stir for 2 minutes to disperse. The delivery ingredients used in the experiments were: (1) natural and artificial strawberry flavor (Dragoco, 0.1%), (2) titanium dioxide, (3) caffeine. Quickly pour hot solution into container. The solution cast in a Petri dish was cooled to room temperature to form a film and then dried in a blast oven at 45°C overnight to achieve constant weight. Samples were cooled and then refrigerated (below 8°C) overnight before gel/melt properties and solids content were determined with an Atago E-Series handheld refractometer (Gardco, Pompano Beach, FL). The melting temperature of the gel is determined by placing a small piece of refrigerated gel on a wire stand fixed in the test tube so that the gel piece does not touch the wall of the test tube. Cover the test tube with aluminum foil with a small hole for the temperature of the gel to be measured with a digital temperature probe. Submerge the test tube in a heating bath so that the gel mass is below the surface of the hot water bath at approximately 100°C. For samples with a melting temperature higher than 90 °C, use a silicone oil bath. When the gel sample appears wet, soft and stirrable, record the melting temperature (note the temperature range). Once the sample had melted, the tube was transferred to a second beaker filled with cold tap water (15°C). While the sample is cooling, measure the temperature with a temperature probe and check the surface of the sample to see if the sample is starting to gel. The gelation temperature is the temperature at which the sample no longer flows and fills the dents poked with the probe during cooling. The breaking force (BF) and breakthrough values of cast and dry film strips were determined with the TextureAnalyzer TA-108S Mini Film Test Rig. The hardness is calculated by dividing the breaking force by the penetration value.

Table XI

Alginate delivery system Component (g) NAHG 1.65 0.00 1.65 0.00 0.00 0.00 KAHG 0.00 1.65 0.00 1.65 1.65 0.00 KAHM 0.00 0.00 0.00 0.00 0.00 1.65 κCgn 1.25 1.25 1.25 1.25 1.25 1.25 maltodextrin 7.00 7.00 7.00 7.00 10.00 10.00 water 80.00 80.00 80.00 80.00 80.00 80.00 glycerin 6.70 6.70 6.70 6.70 6.70 6.70 spices 3.30 3.30 0.00 0.00 0.00 0.00 TiO ₂ 0.00 0.00 3.30 3.30 0.00 0.00 caffeine 0.00 0.00 0.00 0.00 0.30 0.30 cast film solid content ~22% ~22% ~22% ~22% ~22% ~22% BF(g) 190 2075 197 1562 1986 1686 Penetration (cm) 0.4 0.3 0.4 0.3 0.4 0.3 hardness 476 6916 492 5036 4966 5620 dry film BF(g) 8775 14549 8926 7551 11600 9453 Penetration, cm 1.3 1.1 1.7 1.2 1.3 1.1

Although the present invention has been described in detail in conjunction with specific embodiments, it is easy for those skilled in the art to understand that various changes and improvements can be made without departing from the spirit and scope of the present invention.

claims

(Amended in accordance with Article 19 of the Treaty)

12. The delivery system of claim 1 having a breaking force strength of at least 2500 g.

13. The delivery system of claim 1 having a breaking force strength of at least 4000 g.

14. The delivery system of claim 1 having a breaking force strength of at least 5000 g.

15. The delivery system of claim 1 having a breaking force strength of at least 6000 g.

16. The method for preparing the homogeneous gel membrane delivery system of claims 1-15, comprising the steps of:

(i) carry out at least one of said alginate, and plasticizer, second film-forming agent, bulking agent and pH control agent in equipment providing sufficient shearing force, temperature and retention time heating, hydrating, mixing, dissolving and optionally degassing to form a homogeneous molten composition, wherein said temperature is equal to or higher than the dissolution temperature of said composition;

(ii) adding an effective amount of active material before or after forming the molten composition;

(iii) cooling said molten composition containing said active material to be at or below its gelling temperature to form said gel film containing said active material.

17. The method of claim 16, wherein the active substance is an oral care agent, a breath freshener, a medicament, a nutritional agent, a salivation stimulator, a vitamin, a mineral, a cosmetic ingredient, an agricultural active ingredient, At least one of coloring agent, sweetener, flavoring agent, spice or food.

18. The method of claim 16, wherein the equipment is a Ross mixer, extruder, Stephan processor, jet boiler or fluid mixing equipment.

19. The delivery system of claim 1 having a breaking force strength of at least 250 g.

20. The delivery system of claim 1 having a breaking force strength of at least 1000 g.

21. The delivery system of claim 1 further comprising a flavoring agent and having a solids content of at least 50%.

22. The delivery system of claim 1, wherein said second film former is a carrageenan in an amount of 1.5% said carrageenan based on the weight of all components of said solution. When measured in 0.10 mole sodium chloride aqueous solution, the viscosity of described carrageenan at 75 ℃ is less than 10 cp.

23. The delivery system of claim 1, wherein the gel film is free of plasticizers.

24. The delivery system of claim 1, consisting of said water-soluble thermoreversible alginate, a bulking agent, an active substance and water.

25. The delivery system of claim 24, wherein said bulking agent is corn syrup.

Claims (22)

1. the delivery system that comprises the gel film of homogeneous, thermoreversible, wherein said gel film comprises: (i) the reversible alginate water-soluble hot in nature of film forming amount, and choosing any one kind of them at least in plasticizer, second film former, extender and the pH controlling agent; (ii) active substance.

2. delivery system as claimed in claim 1, it is characterized in that described active substance is at least a in oral cavity nursing agent, breath freshener, medicament, nutrient, salivation stimulant, cosmetic composition, agricultural active composition, vitamin, mineral, coloring agent, sweeting agent, flavoring agent, spice or the food.

3. delivery system as claimed in claim 1 is characterized in that the content of described alginate accounts at least 0.25% of gel film dry weight.

4. delivery system as claimed in claim 1 is characterized in that the content of described alginate accounts for the 0.25%-25% of gel film dry weight.

5. delivery system as claimed in claim 1 is characterized in that, the content of described alginate accounts at least 10% of film former gross dry weight in the gel film.

6. delivery system as claimed in claim 1 is characterized in that, the content of described alginate accounts at least 40% of film former gross dry weight in the gel film.

7. delivery system as claimed in claim 1 is characterized in that, the content of described alginate accounts at least 60% of film former gross dry weight in the gel film.

8. delivery system as claimed in claim 1 is characterized in that, the content of described alginate accounts at least 80% of film former gross dry weight in the gel film.

9. delivery system as claimed in claim 1 is characterized in that, described alginate are the unique film former in the gel film.

10. delivery system as claimed in claim 1, it is characterized in that described second film former is selected from starch, starch derivatives, starch hydrolysate, cellulose gum, κ carrageenin, ι carrageenin, mannan glue, dextran, pulullan polysaccharide, gellan gum, pectin, alkyl cellulose ether and modification alkyl cellulose ether.

11. delivery system as claimed in claim 1, it is characterized in that, described plasticizer is selected from glycerol, Sorbitol, maltose alcohol, lactose, solubilisation oils and the poly alkylene glycol a kind of at least, and described second film former is selected from starch, starch derivatives, starch hydrolysate, cellulose gum, κ carrageenin, ι carrageenin, mannan glue, dextran, pulullan polysaccharide, gellan gum, pectin, alkyl cellulose ether and the modification alkyl cellulose ether a kind of at least; Described extender is selected from a kind of in microcrystalline Cellulose, Microcrystalline Starch, starch, starch derivatives, inulin and the starch hydrolysate at least.

12. delivery system as claimed in claim 1 is characterized in that, it has the disruptive force intensity of 2500g at least.

13. delivery system as claimed in claim 1 is characterized in that, it has the disruptive force intensity of 4000g at least.

14. delivery system as claimed in claim 1 is characterized in that, it has the disruptive force intensity of 5000g at least.

15. delivery system as claimed in claim 1 is characterized in that, it has the disruptive force intensity of 6000g at least.

16. prepare the method for the described homogeneous gel film of claim 1-15 delivery system, it comprises the steps:

(i) in the equipment that enough shearing forces, temperature and retention time are provided to described alginate, and heating of choosing any one kind of them at least in plasticizer, second film former, extender and the pH controlling agent, hydration, mixing, dissolving and the optional degassing, form the homogenizing melt composition, wherein said temperature is equal to or higher than the solution temperature of described compositions;

The active substance that (ii) before or after forming melt composition, adds effective dose;

(iii) cooling contain described active substance described melt composition to being equal to or less than its gelation temperature, form the described gel film that contains described active substance.

17. method as claimed in claim 16, it is characterized in that described active substance is at least a in oral cavity nursing agent, breath freshener, medicament, nutrient, salivation stimulant, vitamin, mineral, cosmetic composition, agricultural active composition, coloring agent, sweeting agent, flavoring agent, spice or the food.

18. method as claimed in claim 16 is characterized in that, described equipment is the Ross blender, extruding machine, Stephan datatron, jet boiler or fluid mixing apparatus.

19. delivery system as claimed in claim 1 is characterized in that, it has the disruptive force intensity of 250g at least.

20. delivery system as claimed in claim 1 is characterized in that, it has the disruptive force intensity of 1000g at least.

21. delivery system as claimed in claim 1, described system also comprises flavoring agent, and solids content is at least 50%.

22. delivery system as claimed in claim 1, it is characterized in that, described second film former is a kind of carrageenin, when in the 0.10 mole nacl aqueous solution that contains based on 1.5% described carrageenin of all components weight of described solution, measuring, described carrageenin 75 ℃ viscosity less than 10cp.

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