Title:  Effervescent granules and methods for their preparation

United States Patent:  6,649,186

Issued:  November 18, 2003

Inventors:  Robinson; Joseph R. (Madison, WI); McGinity; James William (Austin, TX); Delmas; Pascal (Outrenont, CA)

Assignee:  Ethypharm (Paris, FR)

Appl. No.:  553528

Filed:  April 20, 2000

Abstract

Disclosed here are effervescent granules having a controllable rate of effervescence. In some embodiments, the such granules comprise an acidic agent, an alkaline agent, a pharmacologically active agent, hot-melt extrudable binder capable of forming a eutectic mixture with the acidic agent and, optionally, a plasticizer. The effervescent granules are made by a hot-melt extrusion process. The present invention also provides a thermal heat process for preparing a pharmacologically active agent containing effervescent granule. In certain aspects, the granules contain pharmacologically active agents such as narcotics, antidiarrheal agents, antiviral agents, anxiolytic agents, a cholesterol lowering agent, an alpha adrenergic blocking agent, a phenanthrene derivative. By way of example, some of the narcotics that may be included in the granules and in the process of preparing the granules include, by way of example: phenanthrene derivatives (e.g., morphine sulfate), and morphine derivatives (e.g., hydromorphone hydrochloride).

SUMMARY OF THE INVENTION

The present invention provides an effervescent granule having a controllable rate of effervescence prepared by hot-melt extruding (i) an acidic agent, (ii) an alkaline-agent, and (iii) a hot-melt extrudable binder which melting or softening point temperature is less than about 150^oC. and which is capable of forming a eutectic mixture with the acidic agent. The acidic and alkaline agents should be able to effervesce when placed in an aqueous solution. A formulation according to this aspect of the invention can provide a rate of release of an active ingredient that ranges from immediate to a delayed or controlled release over a prolonged period of many hours.

One aspect of the present invention provides a solid pharmaceutical dosage form adapted for direct oral administration, i.e., for direct insertion into the mouth of a patient. A dosage form according to this aspect of the present invention includes a mixture incorporating a water and/or saliva activated effervescent granule having a controllable rate of effervescence and a therapeutic compound.

According to another aspect of the present invention, it has been found that combination of the effervescent granules with the other ingredients can provide effective taste masking of particularly poor tasting compounds. This aspect of the invention thus provides a dosage form which offers both immediate or extended release and effective taste masking.

The effervescent granules taught herein can be used in pharmaceutical, veterinary, horticultural, household, food, culinary, pesticidal, agricultural, cosmetic, herbicidal, industrial, cleansing, confectionery and flavoring applications.

Formulations incorporating the effervescent granules according to one aspect of the present invention can further include one or more additional adjuvants and/or active ingredients which can be chosen from those known in the art including flavors, diluents, colors, binders, filler, surfactant, disintegrant, stabilizer, compaction vehicles, and non-effervescent disintegrants. The effervescent granules themselves do, not generally include therapeutic compounds or other active ingredients.

The present invention also provides a method of preparing an effervescent granule having a controllable rate of effervescence where the method comprises mixing and hot melt extruding a hot-melt extrudable binder and an acidic agent to form a eutectic mixture which eutectic mixture is then mixed and hot-melt extruded with an alkaline agent to form the effervescent granule. The hot-melt extrusion process herein advantageously allows for extremely short exposure times of compounds to elevated temperatures as well as a higher throughput than batchwise hot-melt methods.

In particular embodiments, effervescent granules including a pharmacologically active agent are provided. In some aspects, by way of example, and while not intending to constitute an exclusive list, these pharmacologically active agents may comprise, in at least some embodiments, the following pharmacologically active agents: phenanthrene derivatives (e.g. morphine sulfate), synthetic and non-synthetic antidiarrheal agents (e.g. loperamide hydrochloride). In other embodiments, the pharmacologically active agent may comprise an antiviral agent (e.g. acyclovir), anxiolytic agents (e.g. buspirone), diuretic agents (e.g. hydrochlorthiazide), and morphine derivatives (e.g. hydromorphone hydrochloride). In yet other embodiments, the pharmacologically active agent may comprise antidepressants (e.g. fluoxetine hydrochloride), serotonin agonists (e.g. sumatriptan succinate), levorotatory isomers of thyroxine (e.g. levothyroxine sodium), cholesterol lowering agents (e.g. simvastatin) and alpha adrenergic blocking agents (e.g. ergotamine tartrate). Moreover, it is anticipated that other therapeutic, pharmacologically active and/or analgesic compounds may be used in conjunction with the present formulations of effervescent granules, as well as combinations of the various types and classes of pharmacologically active agents described here.

Additionally, the present invention provides a thermal heat process for preparing an effervescent granule formulation comprising a pharmacologically active agent. In some embodiments, the method comprises combining an acidic agent, a pharmacologically active agent, a hot-melt extrudable binder which can combine with said acidic agent, a pharmacologically active agent, and a plasticizer. The inclusion of a plasticizer in the formulation is optional. The acidic agent, alkaline agent, hot-melt extrudable binder and the optional plasticizer may then be dry blended to form a mixture. The mixture may then be hot-melt extruded to form a eutectic mixture. The effervescent mixture is then hot-melt extruded to form effervescent granules having a controllable rate of effervescence. The mixture is then screened and blended after which said mixture is subjected to compression until tablet form is achieved.

In particular embodiments, a thermal heat process for preparing effervescent granules including a pharmacologically active agent are provided. In some aspects, by way of example, and while not intending to constitute an exclusive list, the pharmacologically active agents that may comprise at least some embodiments of the effervescent granules prepared by the present thermal process include: phenanthrene derivatives (e.g. morphine sulfate), synthetic and non-synthetic antidiarrheal agents (e.g. loperamide hydrochloride). In other embodiments, the pharmacologically active agents may comprise antiviral agents (e.g. acyclovir), anxiolytic agents (e.g. buspirone), diuretic agents (e.g. hydrochlorthiazide), and morphine derivatives (e.g. hydromorphone hydrochloride). In yet other embodiments, pharmacologically active agents may comprise antidepressants (e.g. fluoxetine hydrochloride), serotonin agonists (e.g. sumatriptan succinate), levorotatory isomers of thyroxine (e.g. levothyroxine sodium), cholesterol lowering agents (e.g. simvastatin) and alpha adrenergic blocking agents (e.g. ergotamine tartrate). Moreover, it is anticipated that other therapeutic, pharmacologically active and/or analgesic compounds may be used in conjunction with the present formulations of effervescent granules or combinations thereof.

Other features, advantages and embodiments of the invention will be apparent to those skilled in the art from the following description, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "effervescent granules" means granules that consist of an effervescent couple and a suitable hot-melt extrudable binder and that are prepared by hot-melt extrusion. By "effervescent couple" is meant a combination of an acidic agent and an alkaline agent that when combined in the presence of water cause the formation of a gas such as carbon dioxide, oxygen or chlorine dioxide.

The effervescent granules of this invention can be in the state of powder or fine particles to increase the dissolution rate, and preferably a particle size such that 90% or more passes a 16 mesh (1,000 .mu.) screen, and more preferably a particle size such that more than 90% passes a 18 mesh (850 mu m) screen. Generally, the larger the effervescent granule, the longer it will take to completely disintegrate. This is particularly true when there are low levels of effervescent couple present in the granules.

Effervescent Granule Components

As used herein, "effervescence" means the evolution of bubbles of gas from a liquid as the result of a bubble or gas generating chemical reaction. The bubble or gas generating reaction of the effervescent couple in the effervescent granule is most often the result of the reaction of an acidic agent and an alkaline agent. The reaction of these two general classes of compounds produces a gas upon contact with water.

As used herein, the term "acidic agent" refers to any compound or material that can serve as a proton source and can react with the alkaline agent of the invention to form a gas causing a solution containing them to effervesce. The acidic agent can have more than one acid dissociation constant, i.e. more than one acid functional group. The acidic agent can be any organic or inorganic acid in the free acid, acid anhydride and acid salt form. An acidic agent which is in solid state at room temperatures and shows pH 4.5 or lower when saturated into water at room temperatures or its acid alkali metal salts (e.g. sodium salt, potassium salt, etc.) can be employed. As the acidic agent for the effervescent granule, a compound which is not harmful to animals including man is desirably employed. The acidic agent can be tartaric acid, citric acid, maleic acid, fumaric acid, malic acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha hydroxy acids, ascorbic acid, amino acids and their alkali hydrogen acid salts. And, even in the case of an acid substance such as phosphoric acid or pyrophosphoric acid or other inorganic acids which is liquid or in liquid state at room temperature, when their acid alkali metal salts are solid at room temperature, those acid alkali metal salts can be employed as acidic agents. Among the above-mentioned acidic agents, those having a relatively large acid dissociation constant (10³ or more) and a small hygroscopicity (critical humidity at 30^oC. is 40% RH or more) are preferably employed.

It is preferred if the acidic agent can form a eutectic mixture with a binder. Because these acids are directly ingested, their overall solubility in water is less important than it would be if the effervescent granules of the present invention were intended to be dissolved in a glass of water.

As used herein, the term "alkaline agent" means an alkaline compound that releases a gas, or causes a solution to effervesce, when exposed to a proton source such as an acidic agent or water. The alkaline agent can be a carbon dioxide gas precursor, an oxygen gas precursor or a chlorine dioxide gas precursor.

When the alkaline agent is a carbon dioxide precursor, compounds such as carbonate, sesquicarbonate and hydrogencarbonate salts (in this specification, carbonate and hydrogencarbonate, or bicarbonate, are generically referred to as carbonate) of potassium, lithium, sodium, calcium, ammonium, or L-lysine carbonate, arginine carbonate, sodium glycine carbonate, sodium amino acid carbonate can be used. When the alkaline agent is an oxygen gas precursor, compounds such as anhydrous sodium perborate, effervescent perborate, sodium perborate monohydrate, sodium percarbonate and sodium dichloroisocyannurate can be used. When the alkaline agent is a chlorine dioxide (ClO₂) precursor, compounds such as sodium hypochlorite and calcium hypochlorite can be used. ClO₂ can be used as a chemical sterilizer in cleansing operations.

Where the effervescent agent includes two mutually reactive components, such as an acidic agent and an alkaline agent, it is preferred, although not necessary, that both components react completely. Therefore, a ratio of components which provides for equal amounts of reaction equivalents is preferred. For example, if the acid used is diprotic, then either twice the amount of a mono-reactive carbonate alkaline agent, or an equal amount of a all-reactive alkaline agent should be used for complete neutralization to be realized. However, in other embodiments of the present invention, the amount of either the acidic agent or the alkaline agent can exceed the amount of the other component. This can be useful to enhance taste and/or performance of a tablet containing an overage of either component.

By controlling the relative ratio of acidic agent: alkaline agent, the effervescent granules can be used to regulate the pH of their environment. Thus, the present granules can be used to regulate the pH of body cavities such as the mouth, rectum or vagina.

The ratio of the above-mentioned acidic agent and alkaline agent can also be determined according to the pH required for dissolving an active ingredient included in a formulation containing effervescent granules or upon other conditions which a user can contemplate. When the solubility of the active ingredient increases at the acid side, the pH of the solution is lowered by adding the acidic agent in an amount more than equivalent to the alkaline agent. When the solubility of the active ingredient increases at the basic side, the pH of the solution is raised by adding the alkaline agent in an amount more than equivalent to the acidic agent. In either case, the pH near the acidic agent immediately after the dissolution is low, while the pH near an alkaline agent is high. In a case where the solubility of an active ingredient does not depend on pH, the ratio of an acidic agent and an alkaline agent can be optionally selected.

The amount of carbon dioxide precursor, i.e. alkaline agent, to be incorporated is proportional to the volume of carbon dioxide gas generated. When it is desired to increase the dissolution rate of an active ingredient included in a formulation containing effervescent granules, it can be advantageous to increase the amount of carbon dioxide precursor accordingly, and the amount is usually selected from the range of from about 3% to about 70%, preferably from about 10% to 70% by weight based on the effervescent granule.

An acidic agent and a carbon dioxide precursor are used respectively in a powdery or granular state, usually 90% or more of them being capable of passing through a 100 mesh (150 .mu.) screen. The particle size of the binder used will usually be about 100 mesh (150 .mu.). In any case, it is generally acceptable that the additional amount of either component can remain unreacted.

As used herein, the term "hot-melt extrudable" refers to a compound or formulation that can be hot-melt extruded. A hot-melt extrudable binder is one that is sufficiently rigid at standard ambient temperature and pressure but is capable of deformation or forming a semi-liquid state under elevated heat or pressure. Although the formulation of the invention need not contain a plasticizer to render it hot-melt extrudable, plasticizers of the type described herein can be included.

Examples of hot-melt extrudable binders which can be used in the effervescent granules include acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC F68, PLURONIC F127), collagen, albumin, gelatin, cellulosics in nonaqueous solvents, and combinations of the above and the like. Other binders include, for example, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide and the like.

Binders may be used in an amount of up to about 60 weight percent and preferably about 3 to about 8 weight percent of the total composition. All binders used in this invention are hot-melt extrudable. While the melting and/or softening point temperatures of these binders usually rise with increase of their molecular weights, preferable ones are those with a melting or softening point temperature less than about 150^oC. However, binders having melting or softening points greater than about 150^oC. can be used. Hot-melt extrudable binders having a melting or softening point temperature greater than about 150^oC. will require use of a plasticizer during hot-melt extrusion such that the binder melting or softening point temperature will be lowered below 150^oC. Among the above-mentioned binders, polyethylene glycol is preferable, and that having a molecular weight of about 1000 to 8000 Da is more preferable.

The binder can be used in any form such as powder, granules, flakes or heat-molten liquid. While the amount of binder to be added can be modified, it is usually present in an amount less than about 10% by weight and preferably in the range of about 3-8% by weight of the granule.

By "controllable rate of effervescence" is meant that the rate of effervescence can be controlled such that either a rapid, intermediate or slow rate of effervescence by an effervescent granule is achieved. The rate of effervescence by an effervescent granule is controlled as detailed below.

When referring to the rate of effervescence as "rapid", it is understood that the effervescent granules of the present invention should disintegrate in an aqueous solution in less than 10 minutes, and desirably between about 15 seconds and about 7 minutes. In a particularly preferred embodiment according to the present invention, the effervescent granules should dissolve in an aqueous solution in between about 8 seconds and about 5 minutes. Disintegration time can be approximated by observing the disintegration time of the effervescent granules immersed in water at about 37^oC. The disintegration time is the time from immersion to substantially complete the effervescent granules as determined by visual observation. As used in this disclosure the term "complete disintegration" of the effervescent granules refers to the dissolution or disintegration of the effervescent granules. Disintegration times referred to in this-disclosure should be understood as determined by the method used herein unless otherwise specified.

When referring to the rate of effervescence as "intermediate," it is understood that the effervescent granules of the invention should disintegrate in an aqueous solution in more than about 10 minutes and less than about 1 hour.

When referring to the rate of effervescence as "slow," it is understood that the effervescent granules of the present invention should disintegrate in an aqueous solution in about 1 hour to about 4 hours.

Control of the rate of effervescence can be achieved by varying the relative amounts of the components in the effervescent granule. Thus, by increasing the amount of hot-melt extrudable binder relative to the total weight of the effervescent granule, a less friable and stronger granule can be generally prepared. Conversely, by decreasing the amount of hot-melt extrudable binder relative to the total weight of the effervescent granule, a more friable or weaker granule can be generally prepared. Hydrophobic binders will generally tend to have a greater impact upon granule hardness than hydrophilic binders.

Generally, forming a eutectic mixture between the acidic agent and the hot-melt extrudable binder before hot-melting extruding with the alkaline agent will yield effervescent granules that are harder and thus slower dissolving than those prepared by hot-melt extruding the binder, acidic agent and alkaline agent components together simultaneously.

Having an excess of either the acidic agent or alkaline agent in the effervescent granule will generally result in increased rate of effervescence when compared to an effervescent granule having the same amounts, on an equivalent basis, of both agents. Regardless of whether either agent is in excess, the total amount of gas produced by an effervescent granule will not exceed the theoretical amount of gas produced by the agent serving as the limiting reagent.

It is possible that including a plasticizer in the present effervescent granules will alter its rate of effervescence. Generally, increasing the amount of plasticizer present will increase or prolong the time of effervescence.

The rate of effervescence can also be controlled by varying the hydrophilicity or hydrophobicity of the hot-melt extrudable binder. Generally, the more hydrophobic the binder, the slower the rate of effervescence. The solubility and rate of dissolution of a hydrophobic binder are important factors to consider as the level of binder in the effervescent granule is increased. For example, one can prepare an effervescent granule having a rapid rate of effervescence by a water soluble hot-melt extrudable binder such as an electrolyte or nonelectrolyte such as xylitol, which can form a eutectic mixture with an appropriate acidic agent during hot-melt extrusion.

Conversely, one can prepare an effervescent granule having a slow rate of effervescence by employing a poorly water soluble hot-melt extrudable binder such as hydrogenated castor oil, lipids, wax, cholesterol, fatty acids or mono-, di- or triglycerides. Additionally, an effervescent granule having an intermediate rate of effervescence can be prepared by employing a binder, or combination of binders, such as those just discussed and optionally a surface active agent or cosolvent that improves wetting or disintegration of the effervescent granule.

Thus, rate of effervescence of the effervescent granule can be controlled by: (1) varying the relative amounts of the components; (2) optionally forming a eutectic mixture between the acidic agent and hot-melt extrudable binder; (3) varying acidic agent: alkaline agent ratio; (4) hydrophilicity vs. hydrophobicity of hot-melt extrudable binder; (5) varying the effervescent couple: hot-melt extrudable binder ratio; and (6) varying the amount of plasticizer present.

It should also be noted that when the effervescent granules are included in a tablet form, the hardness of a tablet may also play a role in disintegration time. Specifically, increasing the hardness of a tablet can increase the disintegration time just as decreasing hardness may decrease disintegration time. The hardness of the tablet can be controlled by the pressure used on the punches to compress the effervescent granule-containing formulation and by the amount of effervescent granules, concentration of effervescent couple, and amounts of drug and other excipients present in the tablet composition.

The effervescent granules of the invention can be included in formulations containing active ingredients and particularly pharmacologically active agents. As used herein, the term "active ingredient" means a therapeutic compound, a flavoring agent, a sweetening agent, a vitamin, cleansing agent and other such compounds for pharmaceutical, veterinary, horticultural, household, food, culinary, pesticidal, agricultural, cosmetic, herbicidal, industrial, cleansing, confectionery and flavoring applications. When the effervescent granules are formulated into tablets, such tablets can also contain coloring agents, non-effervescent disintegrants, lubricants and the like. The effervescent granules of the invention can be formulated in a variety of forms such as a tablet, capsule, suspension, reconstitutable powder and suppository.

When a formulation including the effervescent granules and a therapeutic compound is included in a pharmaceutical tablet, the tablet's size and shape can be adapted for direct oral administration to a patient, such as a human patient. The pharmaceutical tablet is substantially completely disintegrable upon exposure to water and/or saliva. The effervescent granule is present in an amount effective to aid in disintegration of the tablet, and to provide a distinct sensation of effervescence when the tablet is placed in the mouth of a patient.

The effervescent sensation is not only pleasant to the patient but also tends to stimulate saliva production, thereby providing additional water to aid in further effervescent action. The patient should be able to perceive a distinct sensation of "fizzing" or bubbling as the tablet disintegrates in the mouth. To provide this sensation, the amount of effervescent granule in each tablet desirably is arranged to provide about 20 to about 60 cm³ of gas. The "fizzing" sensation substantially enhances the organoleptic effects of the tablet. Thus, the amount of effervescent granule useful in accordance with the present invention is also an amount effective to provide a positive organoleptic sensation to a patient. A "positive" organoleptic sensation is one which is pleasant or enjoyable and which can be perceived readily by a normal human being. Thus, once the tablet is placed in the patient's mouth, it will disintegrate substantially completely without any voluntary action by the patient. Even if the patient does not chew the tablet, disintegration will proceed. Upon disintegration of the tablet, the therapeutic compound, which itself can be particulate, is released and can be swallowed as a slurry or suspension.

The mass of each such pharmaceutical tablet generally should be less than about 2.0 g and preferably less than about 0.5 g. The tablet may include surface markings, cuttings, grooves, letters and or numerals for the purpose of decoration and/or identification. Preferably, the tablet is a compressed tablet. It includes effervescent granules, together with a therapeutic compound and other components. The size of the tablet is also dependent upon the amount of material used. Circular, disk-like tablets desirably have diameters of about 11/16 inch or less, whereas elongated tablets desirably have a long dimension of about 7/8 inch or less.

The amount of effervescent granules of the present invention useful for the formation of tablets, in general, according to the present invention should range from about 2 to about 90% by weight of the final tablet composition, and preferably between about 5 and about 40% by weight thereof. In a more preferred embodiment, the amount of effervescent granule according to the present invention ranges from between about 3 and about 8% by weight of the final tablet composition.

Non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin and tragacanth. Disintegrants can comprise up to about 20 weight percent and preferably between about 2 and about 10 percent of the total weight of the composition.

Coloring agents can include titanium dioxide, and dyes suitable for food such as those known as F.D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika, etc. The amount of coloring used can range from about 0.1 to about 3.5 weight percent of the total composition.

Flavors incorporated in the composition may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. Flavors which have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors may be present in an amount ranging from about 0.5 to about 3.0 by weight based upon the weight of the composition. Particularly preferred flavors are the grape and cherry flavors and citrus flavors such as orange.

Tablets according to this aspect of the present invention can be manufactured by well-known tableting procedures. In common tableting processes, material which is to be tableted is deposited into a cavity, and one or more punch members are then advanced into the cavity and brought into intimate contact with the material to be pressed, whereupon compressive force is applied. The material is thus forced into conformity with the shape of the punches and the cavity. Various tableting methods are well known to those skilled in the art and not detailed herein.

Materials to be incorporated in the tablets, other than the therapeutic compound and the effervescent granule can, be pretreated to form granules that readily lend themselves to tableting. This process is known as granulation. As commonly defined, "granulation" is any process of size enlargement whereby small particles are gathered together into larger, permanent aggregates to yield a free-flowing composition having a consistency suitable for tableting. Such granulated compositions may have consistency similar to that of dry sand. Granulation may be accomplished by agitation in mixing equipment or by compaction, extrusion or globulation.

As noted in Chapter 6 of Pharmaceutical Dosage Forms, supra, lubricants normally are used in manufacture of effervescent tablets. Without the use of an effective lubricant, tableting by use of high speed equipment would be difficult. Effervescent granulations are inherently difficult to lubricate due to both the nature of the raw materials and the requirement that the tablets disintegrate rapidly.

Lubricant, as used herein, means a material which can reduce the friction arising at the interface of the tablet and the die wall during compression and ejection thereof. Lubricants may also serve to prevent sticking to the punch and, to a lesser extent, the die wall as well. The term "antiadherents" is sometimes used to refer specifically to substances which function during ejection. As used in the present disclosure, however, the term "lubricant" is used generically and includes "antiadherents". Tablet sticking during formation and/or ejection may pose serious production problems such as reduced efficiency, irregularly formed tablets, and non-uniform distribution of intended agents or ingredients to be delivered thereby. These problems are particularly severe with high speed tableting approaches and methods.

Lubricants may be intrinsic or extrinsic. A lubricant which is directly applied to the tableting tool surface in the form of a film, as by spraying onto the die cavity and/or punch surfaces, is known as an extrinsic lubricant. Although extrinsic lubricants can provide effective lubrication, their use requires complex application equipment and methods which add cost and reduce productivity.

Intrinsic lubricants are incorporated in the material to be tableted. Magnesium, calcium and zinc salts of stearic acid have long been regarded as the most efficient intrinsic lubricants in common use. Concentrations of two percent or less are usually effective.

Other traditional intrinsic lubricants include hydrogenated and partially hydrogenated vegetable oils, animal fats, polyethyleneglycol, polyoxyethylene monostearate, talc, light mineral oils, sodium benzoate, sodium lauryl sulphate, magnesium oxide and the like. See European Patent Application No. 0,275,834, the disclosure of which is incorporated by reference. See also Leal, et al., U.S. Pat. No. 3,042,531.

Lubricants, according to the present invention, can be used in an amount of up to 1.5 weight percent and preferably between about 0.25 and about 1.0 weight percent of the total composition.

Intrinsic lubricants pose certain serious difficulties when used in conventional tablets. Many lubricants materially retard the disintegration of non-effervescent tablets. However, the effervescent granules used in the dosage form of the present invention overcome any such retardation. In dissolution of conventional effervescent tablets, the lubricant may cause "scumming" and/or agglomeration. Stearates, for example leave an objectionable "scum" when an effervescent tablet is placed in a glass of water. This "scum" reduces the aesthetic appeal of the solution made from an effervescent dosage form. However, because the tablets of the present invention dissolve in the mouth, the solution is never seen by the user. Therefore, the propensity of a lubricant to "scum" is of less importance. Thus, lubricants which can cause dissolution or scumming problems in other dosage forms can be used in dosage forms according to the present invention without material adverse effect.

The therapeutic compound included in a dosage form including the effervescent granules according to the invention can include at least one psychotropic drug such as a sedative, antidepressant, neuroleptic, or hypnotic. The present invention is especially valuable with psychotropic drugs in that a patient receiving such drugs, particularly a patient in a mental institution, often attempts to hold a conventional pharmaceutical tablet or capsule concealed within his mouth rather than swallow it. The patient may then surreptitiously remove the tablet or capsule when medical personnel are not present. The preferred dosage forms according to this aspect of the present invention are substantially resistant to such concealment, inasmuch as they will disintegrate rapidly even if they are concealed within the mouth.

As the therapeutic compound, use can be of synthetic antibacterial agents of hardly water-soluble pyridone-carboxylic acid type such as benofloxacin, nalidixic acid, enoxacin, ofloxacin, amifloxacin, flumequine, tosfloxacin, piromidic acid, pipemidic acid, miloxacin, oxolinic acid, cinoxacin, norfloxacin, ciprofloxacin, pefloxacin, lomefloxacin, enrofloxacin, danofloxacin, binfloxacin, sarafloxacin, ibafloxacin, difloxacin and salts thereof. Other therapeutic compounds which can be formulated along with the effervescent granules into an effervescent solid dosage form include penicillin, tetracycline, erythromycin, cephalosporins and other antibiotics.

The therapeutic compounds which can be formulated in suitable dosage forms along with the effervescent granules of the invention also include antibacterial substances, antihistamines and decongestants, anti-inflammatories, antiparasitics, antivirals, anxiolytic agents, morphine derivatives, serotonin agonists, levorotatory isomers of thyroxine, cholesterol lowering agents, alpha adrenergic blocking agents, local anesthetics, antifungal, amoebicidal, or trichomonocidal agents, analgesics, antiarthritics, antiasthmatics, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antineoplastics, antipsychotics, antihypertensives, phenanthrene derivatives, antidiarrheal agents, diuretics, and muscle relaxants.

Representative antibacterial substances are beta-lactam antibiotics, tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamides, aminoglycoside antibiotics, tobramycin, nitrofurazone, nalidixic acid and analogs and the antimicrobial combination of fludalanine/pentizidone. A representative phenanthrene derivative is morphine sulfate. A representative antidiarrheal agent is loperamide hydrochloride. A representative anxiolytic agent is buspirone. A representative diuretic agent is hydrochlorthiazide. A representative morphine derivative is hydromorphone hydrochloride. Representative antihistamines and decongestants are perilamine, chlorpheniramine, tetrahydrozoline and antazoline. Representative anti-inflammatory drugs are cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortolone, prednisolone, triamcinolone, indomethacin, sulindac and its salts and corresponding sulfide. A representative antiparasitic compound is ivermectin. Representative antiviral compounds are acyclovir and interferon. Representative analgesic drugs are diflunisal, aspirin or acetaminophen.

Representative antiarthritics are phenylbutazone, indomethacin, silindac, its salts and corresponding sulfide, dexamethasone, ibuprofen, allopurinol, oxyphenbutazone or probenecid. Representative antiasthma drugs are theophylline, ephedrine, beclomethasone dipropionate and epinephrine. Representative anticoagulants are heparin, bishydroxycoumarin, and warfarin. Representative anticonvulsants are diphenylhydantoin and diazepam. Representative antidepressants are amitriptyline, chlordiazepoxide perphenazine, fluoxetine hydrochloride, protriptyline, imipramine and doxepin. A representative cholesterol lowering agent is simvastatin. A representative alpha adrenergic blocking agent is ergotamine tartrate. A representative serotonin agonist is sumatropin succinate. A representative levorotatory isomer of thyroxine is levothyroxine sodium. Representative antidiabetics are insulin, somatostatin and its analogs, tolbutamide, tolazamide, acetchexamide and chlorpropamide. Representative antineoplastics are adriamycin, fluorouracil, methotrexate and asparaginase. Representative antipsychotics are prochlorperazine, lithium carbonate, lithium citrate, thioridazine, molindone, fluphenazine, trifluoperazine, perphenazine, amitriptyline and trifluopromazine. Representative antihypertensives are spironolactone, methyldopa, hydralazine, clonidine, chlorothiazide, deserpidine, timolol, propranolol, metoprolol, prazosin hydrochloride and reserpine. Representative muscle relaxants are succinylcholine-chloride, danbrolene, cyclobenzaprine, methocarbamol and diazepam.

The therapeutic compound(s) contained within a formulation containing effervescent granules can be formulated as its pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent pharmacologically active compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutarnic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, furnaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent therapeutic compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a predetermined amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used in this disclosure, the term vitamin refers to trace organic substances that are required in the diet. For the purposes of the present invention, the term vitamin(s) include, without limitation, thiamine riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E and vitamin K. Also included within the term vitamin are the coenzymes thereof. Coenzymes are specific chemical forms of vitamins. Coenzymes include thiamine pyrophosphates (TPP), flavin mononucleotide (FMM), flavin adenine dinucleotive (FAD), Nicotinamide adenine dinucleotide (AND), Nicotinamide adenine dinucleotide phosphate (NADP) Coenzyme A (CoA) pyridoxal phosphate, biocytin, tetrahydrofolic acid, coenzyme B12, lipoyllysine, 11-cis-retinal, and 1,25-dihydroxycholecalciferol. The term vitamin(s) also includes choline, carnitine, and alpha, beta, and gamma carotenes.

As used in this disclosure, the term "mineral" refers to inorganic substances, metals, and the like required in the human diet. Thus, the term "mineral" as used herein includes, without limitation, calcium, iron, zinc, selenium, copper, iodine, magnesium, phosphorus, chromium and the like, and mixtures thereof

The term "dietary supplement" as used herein means a substance which has an appreciable nutritional effect when administered in small amounts. Dietary supplements include, without limitation, such ingredients as bee pollen, bran, wheat germ, kelp, cod liver oil, ginseng, and fish oils, amino-acids, proteins and mixtures thereof. As will be appreciated, dietary supplements may incorporate vitamins and minerals.

The amount of therapeutic compound incorporated in each tablet may be selected according to known principles of pharmacy. An effective amount of therapeutic compound is specifically contemplated. By the term effective amount, it is understood that, with respect to for example pharmaceuticals, a pharmaceutically effective amount is contemplated. A pharmaceutically effective amount is the amount or quantity of a drug or pharmaceutically active substance which is sufficient to elicit the required or desired therapeutic response, or in other words, the amount which is sufficient to elicit an appreciable biological response when administered to a patient. As used with reference to a vitamin or mineral, the term "effective amount" means an amount at least about 10% of the United States Recommended Daily Allowance ("RDA") of that particular ingredient for a patient. For example, if an intended ingredient is vitamin C, then an effective amount of vitamin C would include an amount of vitamin C sufficient to provide 10% or more of the RDA. Typically, where the tablet includes a mineral or vitamin, it will incorporate higher amounts, preferably about 100% or more of the applicable RDA.

The therapeutic compound is used in finely divided form, i.e. powder or granulate so as to increase the dissolution rate. It is preferable to use a finely powdered therapeutic compound to increase the dissolution rate, more preferably, the therapeutic compound being capable of allowing not less than 80%, desirably not less than 90% of it to pass through a 100 mesh (150 mu m) screen. The amount of therapeutic compound to be incorporated ranges usually from about 0.1 to 50%, preferably about 1 to 25% by weight based on the effervescent composition, and the ratio may be suitably modified depending on the therapeutic compound then employed. When the therapeutic compound is an acid substance capable of effervescing by reaction with carbonate, the therapeutic compound itself may be used as the acidic agent, and, in this case, an acidic agent for use as set forth below may be optionally added further.

When the effervescent granules of the invention are formulated into a reconstitutable powder for a carbonated beverage, they can be prepared according to Example 4 or other suitable method known to those of skill in the art.

The effervescent granules formulated into a suppository can be used to treat vaginal infection and adjust vaginal pH. Such a formulation can be prepared according to example 5, or other method well known to those of skill in the art.

Suspensions containing the effervescent granules of the invention and a herbicide can be used in agricultural applications. Such formulations can comprise a reconstitute powder according to example 6, which is suspended in a liquid prior to use.

Hot Melt Extrusion

In one aspect of this invention, the effervescent granule is produced by a hot-melt extrusion method as described herein. An acidic agent and an alkaline agent, preferably a carbon dioxide precursor, and a hot-melt extrudable binder, all in a dry state, are placed into a mixer or hopper and agitated (blended) until thoroughly mixed to form an effervescent mixture. The effervescent mixture is then hot-melt extruded at a rate and temperature sufficient to melt or soften the binder, to minimize degradation of the components and to form an extrudant which is subsequently ground or chopped into effervescent granules.

In another aspect of the invention, the effervescent granule is produced by a hot melt extrusion process as follows. An acidic agent and a hot-melt extrudable binder, capable of forming a eutectic mixture with the acidic agent, are placed into a mixer and agitated until thoroughly mixed to form a mixture which is hot-melt extruded and ground to form a granular eutectic mixture. An alkaline agent, such as a carbon dioxide precursor, is added to the granular eutectic mixture and thoroughly blended to form an effervescent mixture. The effervescent mixture is then hot-melt extruded at a rate and temperature sufficient to melt or soften the eutectic mixture, to minimize degradation of the components, e.g. degradation of NaHCO₃ to Na₂ CO₃, and to form an extrudant which is subsequently ground or chopped into effervescent granules.

As used herein, the term "effervescent mixture" means a granular or particulate mixture comprising an acidic agent, an alkaline agent and a hot-melt extrudable binder which when placed in water will cause effervescence. As used herein, the term "eutectic mixture" means a mixture of an acidic agent and a hot-melt extrudable binder that has been hot-melt extruded and that melts or softens at a temperature lower than the melting or softening temperature of the hot-melt extrudable binder neat. The eutectic mixture can be a full or partial mixture and can be referred to as a "solid solution."

The rate at which the hot-melt extrusion is conducted can also vary widely. The rate will be such that degradation of the components of the mixture being extruded will be minimized. Such rate can be easily determined experimentally and will vary according to the particular mixture being extruded. Generally, the extrusion rate is such that the time of exposure of the components to the elevated temperature is less than 5 minutes and preferably less than 2 minutes.

The rate of effervescence can be controlled by varying the rate of hot-melt extrusion. Generally, increasing the rate of hot-melt extrusion of the effervescent granule will increase the rate of effervescence. This is especially true for hot-melt extrudable binders having melting or softening points greater than about 100 C. Conversely, decreasing the rate of hot-melt extrusion of effervescent granule will generally decrease the rate of effervescence.

The hot-melt extrusion process preferably employed is conducted at an elevated temperature, i.e. the heating zone(s) of the extruder is above room temperature (about 20^oC.). It is important to select an operating temperature range that will minimize the degradation or decomposition of the effervescent composition during processing. The operating temperature range is generally in the range of from about 50^oC. to about 150^oC. as determined by the setting for the extruder heating zone(s). The temperature of the mixture being hot-melt extruded will not exceed 150^oC. and preferably will not exceed 120^oC. The hot-melt extrusion is conducted employing a dry granular or powdered feed.

The extruder used to practice the invention can be any such commercially available model equipped to handle dry feed and having a solid conveying zone, one or multiple heating zones, and an extrusion die. A two stage single screw extruder, such as that manufactured by BRABENDER or KILLION are two such apparati. It is particularly advantageous for the extruder to possess multiple separate temperature controllable heating zones.

Many conditions can be varied during the extrusion process to arrive at a particularly advantageous formulation. Such conditions include, by way of example, formulation composition, feed rate, operating temperature, extruder screw RPM, residence time, die configuration, heating zone length and extruder torque and/or pressure. Methods for the optimization of such conditions are known to the skilled artisan.

When higher melting temperature, higher molecular weight or high softening temperature binders are employed, the hot-melt extrusion may require higher processing temperature, pressure and/or torque than when binders having a lower molecular weight, melting or softening temperature are employed. By including a plasticizer, and, optionally, an antioxidant, in a formulation, processing temperature, pressure and/or torque may be reduced. Plasticizers are not required in order to practice the invention. Their addition to the formulation is contemplated as being within the scope of the invention. Plasticizers are advantageously included in the effervescent granules when hot-melt extrudable binders having a melting or softening point temperature greater than 150^oC. are employed.

As used herein, the term "plasticizer" includes all compounds capable of plasticizing the hot-melt extrudable binder of the invention. The plasticizer should be able to lower the melting temperature or glass transition temperature (softening point temperature) of the hot-melt extrudable binder. Plasticizers, such as low molecular weight PEG, generally broaden the average molecular weight of the hot-melt extrudable binder thereby lowering its glass transition temperature or softening point. Plasticizers also generally reduce the viscosity of a polymer melt thereby allowing for lower processing temperature and extruder torque during hot-melt extrusion. It is possible the plasticizer will impart some particularly advantageous physical properties to the effervescent granules.

Plasticizers useful in the invention can include, by way of example and without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin.

Such plasticizers can also be ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. All such plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co.

It is contemplated and within the scope of the invention, that a combination of plasticizers may be used in the present formulation. One advantageous combination is that comprised of poly(ethylene glycol) and low molecular weight poly(ethylene oxide). The PEG based plasticizers are available commercially or may be made by a variety of methods, such as disclosed in Poly(ethylene glycol)Chemistry: Biotechnical and Biomedical Applications (J. M. Harris, Ed.; Plenum Press, NY) the teachings of which are hereby incorporated by reference.

The amount of plasticizer used in the effervescent granules will depend upon its composition, physical properties, effect upon the effervescent granules, interaction with other components of the granules and other such reasons. Generally, the plasticizer content will not exceed about 40% wt. of the formulation.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

One embodiment of the present invention provides an effervescent granule having a controllable rate of effervescence comprising:

a hot-melt extrudable binder present in the amount of about 3% to about 8% by weight of said effervescent granule, said binder being capable of forming a eutectic mixture with an acidic agent;

an acidic agent; and

an alkaline agent; said effervescent granule being made by a process comprising:

dry blending and hot-melt extruding said acidic agent and said hot-melt extrudable binder to form an acidic mixture; and

dry blending and hot-melt extruding the acidic mixture and said alkaline agent to form said effervescent granule.

Another embodiment of the present invention provides a hot-melt extrusion process for preparing an effervescent granule having a controllable rate of effervescence, said process comprising:

dry blending and hot-melt extruding an acidic agent, a hot-melt extrudable binder and a plasticizer to form a eutectic mixture; and

dry blending and hot-melt extruding the eutectic mixture and an alkaline agent to form said effervescent granule.

Claim 1 of 30 Claims

What is claimed is:

1. An effervescent granule having a controllable rate of effervescence comprising:

a mixture consisting essentially of an acidic agent, pharmacologically active agent, a hot-melt extrudable binder and optionally a plasticizer; and an alkaline agent;

the effervescent granule made by an essentially water free and essentially solvent free thermal heat process comprising:

dry blending said mixture; and

hot-melt extruding said blended mixture to form an effervescent granule.

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