HK1072548A - Orally administered liquid compositions comprising guaifenesin and a polyoxyalkylene block copolymer - Google Patents
Orally administered liquid compositions comprising guaifenesin and a polyoxyalkylene block copolymer Download PDFInfo
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- HK1072548A HK1072548A HK05105267.0A HK05105267A HK1072548A HK 1072548 A HK1072548 A HK 1072548A HK 05105267 A HK05105267 A HK 05105267A HK 1072548 A HK1072548 A HK 1072548A
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Description
Technical Field
The present invention relates to the field of oral liquid compositions for delivering pharmaceutically active substances to humans and animals.
Background
Pharmaceutical actives are typically delivered using a dosage form designed to promote ease of application while promoting maximum efficacy of the active. One of the difficulties in manufacturing oral dosage forms is formulating the product in a dosage form small enough to be easily swallowed.
When the desired dosage form is a liquid, the pharmaceutically active substance must be soluble in the excipient, wherein the composition is easy to use and maximizes therapeutic efficacy. One such composition is a pharmaceutical suspension. A suspension is one in which solid active particles are dispersed in a liquid vehicle. Although suspensions are a very useful method for concentrating active substances in small volumes, they also have some inherent disadvantages. One disadvantage is that over time the active particles settle to the bottom or float to the top of the liquid, resulting in a non-uniform suspension. Thus, patients using suspensions in such cases are prone to receive more or less than the target dose of active substance. In some cases, this may result in high and potentially dangerous doses being taken by the consumer, or conversely, the dose of active being taken by the consumer to a minimum level necessary to provide the targeted therapeutic benefit. Another disadvantage of suspensions relates to the absorption of the active substance. For absorption to occur, the pharmaceutically active substance must first be in a dissolved state. Therefore, suspensions containing pre-undissolved active substance must be dissolved in body fluids before absorption. Such a dissolution step may slow the onset of the desired therapeutic effect.
In view of the disadvantages of the suspensions described above, those skilled in the art have prepared solutions in the form of elixirs and syrups to deliver the active substance. These solutions can be easily and conveniently swallowed in different volumes of 5, 10 or even 50 ml. In some cases, however, it is desirable to deliver the active in a true solution having a small volume of less than about 3ml, even less than 1 ml. To date, achieving such small volumes has been a problem, and for some actives, this has been almost impossible. This problem is exacerbated when the dosage of active substance is required to be large, or where the active agent is particularly insoluble in conventional excipients used for pharmaceuticals.
To address this problem, liquid-filled soft gelatin capsules have been developed. However, the use of these capsules is somewhat limited. One limitation is that the desired amount of active cannot be contained in a small volume. To address the problems such as those described above, liquid-filled soft gelatin capsules containing acetaminophen have been the subject of much research. For example, U.S. patent 5,505,961 assigned to r.p. scherer recognizes that these problems associated with soft gelatin capsules have been solved, particularly where high doses of acetaminophen are required to provide therapeutic benefits. It is disclosed therein that acetaminophen, with or without other active substances, is soluble in solvents including polyethylene glycol, water, propylene glycol, solubilizing agents including potassium (or sodium) acetate and polyvinylpyrrolidone or PVP. It is disclosed therein that PVP is necessary to inhibit crystallization of these compositions. PCT application WO93/00072 to Coapman discloses a method of solubilizing a pharmaceutically active substance which is considered poorly soluble. This method requires PVP to help solubilize the active agent and prevent precipitation. Similar limitations to acetaminophen solutions are also disclosed and are described in Dhabhar's PCT application WO95/23595, wherein PVP is disclosed as the essential component of the composition which is the subject of this patent.
PVP is a high molecular weight polymer that not only inhibits crystallization, but also increases the viscosity of the components of the liquid composition. Such an increase in viscosity is not significant for products contained in capsules for swallowing. The high viscosity associated with such liquid compositions comprising PVP does not inhibit effective oral dosing of small volumes of product, particularly from precision dosing instruments such as medical droppers, oral syringes, dose cups and sachets. High viscosity liquid compositions are difficult to administer conveniently from these types of precision dosing tools and do not spread easily over large surface areas of the oral mucosal tissue.
While avoiding PVP and its associated problems, new problems associated with oral administration have arisen. For example, U.S. patent No. 5,360,615, assigned to r.p. scherer, discloses solubilizing an active by partially ionizing the active by the addition of an acid or base. However, it has been found that this approach is less than ideal for situations where liquid solutions are delivered to the oral cavity for absorption through the mucosa, as ionization of the active inhibits such absorption.
Thus, a very important consideration in selecting a product form is to determine the target site of delivery of the active substance in vivo. The prior art describing drug delivery to the stomach includes liquid filled gelatin capsules. The liquid contained within these capsules is not intended to contact the body until the gelatin shell is dissolved in the stomach. In such products it does not matter whether the liquid within the gelatin is highly viscous, or even whether it is a paste or a solid. However, for oral administration, the flowability of the composition is critical. The low viscosity liquid allows for precise administration from existing or developing precision dispensing or dosing devices to deliver the liquid composition to a user. The low viscosity liquid is easier to swallow and gives the composition a satisfactory mouthfeel. Such acceptance by consumers is very important and may encourage consumers to follow medication guidelines to achieve desired therapeutic benefits. In addition to aesthetic considerations, it is also desirable that the formulation diffuse over a large surface area of the mucosal tissue to enhance diffusion of the corresponding active within the formulation across the mucosal membrane.
Summary of The Invention
The present inventors have investigated to develop compositions comprising pharmaceutically active substances for delivery to the oral cavity, which are often difficult to solubilize at high concentrations. The basic relationship between a pharmaceutically active substance and an excipient comprising the active substance is: the active is maintained in solution, while the use of the composition is characterized as flowable and pourable, to enhance delivery of the pharmaceutical active to the oral cavity.
After intense research to try to arrive at such compositions, the present inventors have surprisingly found an important relationship of the components, including the excipients used to solubilize the active. When the excipient components have a specific content and ratio to each other, as shown in fig. 1, the pharmaceutically active substance remains in solution, is pourable and flowable at temperatures other than room temperature, such as body temperature.
Thus, the present invention is an oral liquid pharmaceutical composition that exhibits excellent physical stability while delivering concentrated levels of pharmaceutically active substances. In particular, these compositions do not precipitate the active in solution over an extended period of time. Other advantages of the present invention include uniform and accurate dosing of the patient. In addition, the composition remains liquid within the oral cavity, thereby allowing a large area of oral mucosal tissue to be contacted by the pharmaceutically active substance, which is intended to pass through the oral mucosal tissue. Thus, the compositions have efficacy and are also preferred by patients due to their improved palatability. The formulation also solubilizes lipophilic active agents simultaneously with hydrophilic excipients and formulation aids.
Brief description of the drawings
FIG. 1 is a ternary mixed phase diagram, which is a graphical representation of the three variables of the three major components of the excipients of the compositions of the present invention. The axes of the phase diagram correspond to these three components.
Definition of
The definition of terms that can be used in the present invention is as follows. In addition, The terminology used in The art and The common concepts are further described in Schramm, "The Language of Colloid and interface Science," American Chemical Society, (1993), which is incorporated herein by reference:
as used herein, "hydrophilic solvent" refers to polar, pharmaceutically acceptable solvents that are miscible with water and have a dielectric constant (. epsilon.) of about 20 or greater, as seen in "Martin's Physical Pharmacy", Fourth Edition, pages 213 to 214.
As used herein, a "small volume dose" refers to a dose of a liquid composition of less than about 3ml in which the pharmaceutically active substance is sufficiently concentrated to produce the desired therapeutic effect upon oral administration.
"optical density" or "OD" is a measure of the radiation absorption of a mixture of components that form a liquid or a layer of the liquid. OD is mathematically expressed as the negative common logarithm of the luminous transmittance (T) of the mixture. The optical density value was calculated using the following formula, OD ═ log10 (1/T).
As used herein, "orally administered" means that the composition is introduced into the oral cavity, contacted with tissues within the oral cavity, and then swallowed or absorbed.
"physical stability" as used in the present compositions refers to the resistance of the composition to variations in the number and relative amounts of the phases of matter present.
"pourable" as used herein refers to the property of a liquid to maintain a highly flowable state, regardless of the temperature of the liquid at normal atmospheric pressure from about 15 ℃ to about 40 ℃.
As used herein, "solution" refers to a uniformly dispersed mixture of one or more pharmaceutically active substances (solutes) at the molecular or ionic level in one or more other substances (solvents). Under normal ambient conditions, the physical state of the solution is such that it is readily dispensed from the container by pouring.
Detailed Description
The present invention is an oral liquid pharmaceutical composition having excellent physical stability while containing a concentrated amount of a pharmaceutically active substance. In addition to these pharmaceutical actives, these compositions also include excipients for solubilizing the active, wherein the excipients include a hydrophilic solvent, a polyoxyalkylene block copolymer and water mixed together in a certain amount and ratio with each other, wherein the active is solubilized and maintained in this state for a longer period of time. Hydrophilic solvents and water also aid in the inclusion of other compounds, such as sweeteners and stabilizers, into the compositions of the present invention. The compositions of the present invention provide accurate delivery of the active substance, particularly when the compositions are packaged in precision dosage measuring devices, including graduated tubes, dropper tubes, pipettes, single or unit dose packages of liquid elixirs, sprayers, liquid-filled edible capsules or drops, or other similar packaging. In addition, these solutions readily diffuse to large surface areas of mucosal tissue located within the mouth, throat, oropharynx, and combinations thereof, allowing some active substances to be rapidly absorbed.
Consumers prefer smaller administration volumes that contain a sufficiently high concentration of the pharmaceutically active substance to provide the desired therapeutic benefit of the active substance. As these studies meet the needs of consumers, the compositions of the present invention are useful for administration in small volumes. In the present invention, it is contemplated that the maximum volume of a single dose of the composition of the present invention does not exceed about 3ml, alternatively does not exceed 2.5 ml.
Herein, all percentages of components included in the present invention are by weight of the composition.
Pharmaceutically active substance：
The pharmaceutically active substances of the present invention are those which are particularly difficult to solubilize in small volumes of solvent, since the active substances are already close to their solubility limit. At such concentrations, these pharmaceutically active substances tend to be physically unstable and precipitate out of solution with small changes in the composition, including room temperature, the level of contaminants in the solution, or other factors commonly known to precipitate the active substance in solution. Precipitation may occur at any time from just after preparation and packaging of the composition to within the normal expected shelf life.
The composition of the invention comprises a pharmaceutically active substance soluble in a polyoxyalkylene block copolymer, a hydrophilic solvent and water, said polyoxyalkylene block copolymer, hydrophilic solvent and water comprising the excipient of the composition of the invention. The pharmaceutical active may comprise guaifenesin alone or in combination with other actives selected from antihistamines, antitussives, expectorants/mucolytics, bronchodilators, decongestants and mixtures thereof.
Guaifenesin is known to alleviate the symptoms of respiratory diseases, such as dry cough without phlegm and the presence of mucus in the respiratory tract. The guaifenesin has the function of improving the sputum-free dry cough by reducing the viscosity and difficulty of spitting and increasing the volume of sputum. (see "Remington The science and Practice of Pharmacy", third edition 20, page 1303, Philadelphia college of Pharmacy and Sciences, published therein; incorporated herein by reference). In addition, guaifenesin is believed to be a fertility aid in women to reduce the endogenous mucous membranes of the reproductive tract.
There are many active substances that can be combined with guaifenesin. These active substances are derived from suitable classes of agents, including, but not limited to, the following:
antihistaminic agent: including hydroxyzine, pyrilamine, phenindamine, dexchlorpheniramine, clemastine, diphenhydramine, azelastine, acrivastine, levocabastine, mequitazine, astemizole, ebastine, loratadine, cetirizine, terfenadine, procaine, dimenhydrinate, meclizine, tripelennamine, carbinoxamine, cyproheptadine, azatadine, brompheniramine, triprolidine, cyclizine, sonzilazine, pheniramine, and mixtures thereof.
Antitussive agent: including hydrocodone, narcotine, benzonatate, diphenhydramine, chlorodiphenylethamine, chlorobutamol, fosminobenzene, norpapaverine, focodine, ziprasidone, hydromorphone, tocrasil, caramiphen, levopropoxyphene, codeine, dextromethorphan, focodine, and mixtures thereof.
Expectorant/mucolytic: comprises ambroxol, bromhexine, terpineol and iodinePotassium, n-acetylcysteine, and mixtures thereof.
Bronchodilators: preferably for inhalation, comprising albuterol, epinephrine, ephedrine, diphenylol isopropylaminoethanol, terbutaline, theophylline, aminophylline (aminphyline) isottaline, terbutaline, isotaline, pirbuterol, bitolterol, fenoterol, rimiterol, ipratropium, and mixtures thereof.
Decongestant: including pseudoephedrine, phenylephrine, phenylpropanolamine and their salts and mixtures thereof.
The pharmaceutical active is present in the compositions of the present invention at a level of from about 2% to about 40%, alternatively from 3% to 40%, and also from 5% to 30% by weight of the composition. The amount of each active substance that makes up the aggregate or combination of pharmaceutically active substances may be determined by one skilled in the art, which may take into account various factors, including the physicochemical and bioavailability properties of the active substances, the dosing regimen and age, weight and physical condition of the patient, and the stability of the system in which they are contained. To this end, the inventors have expended much effort to determine whether such systems will maintain physical stability within the context of the components of the present compositions.
Excipient
In addition to the active substances mentioned above, the compositions of the invention also comprise excipients. The content of excipients may be 100% of the composition minus the active substance and optional ingredients described below. In the present invention, the excipient content of the composition is typically from about 40% to about 98%, alternatively from about 60% to about 90%. The excipient of the present invention comprises a mixture of three components of (a) a polyoxyalkylene block copolymer, (b) a hydrophilic solvent and (c) water, wherein the three components are present in a specific ratio to each other. These specific ratios are most easily represented using ternary (or three-component) mixed phase diagrams. These phase diagrams are well known in the art and are used to describe these mixtures, see "Experiments with mixtures", John A. Cornell, 1990, John Wiley and Sons, New York, pp.2-8; this document is incorporated herein by reference. For these mixtures, the total amount of the three components present represents 100% of the excipient, with each component being a proportion of this total. The excipients of the compositions of the present invention can be precisely described using a three-component mixed phase diagram, referred to herein as figure 1. Excipient refers to region 1 of fig. 1, defined by the line segments AB, BC, CD and DA connecting the vertices A, B, C and D of the parallelogram.
These vertices lie on the phase diagram, where the polyoxyalkylene block copolymer proportions account for 5% and 25% of the excipient, the hydrophilic solvent portion accounts for 30%, 50%, 70%, and 90% of the excipient, and the water portion accounts for 5% and 45% of the excipient. The vertices of the parallelogram are referred to the following four points:
| components | All components | |||
| Dot | Polyoxyalkylene block copolymers | Hydrophilic solvent | Water (W) | |
| A | 5 | 50 | 45 | 100 |
| B | 5 | 90 | 5 | 100 |
| C | 25 | 70 | 5 | 100 |
| D | 25 | 30 | 45 | 100 |
In determining the percentage of each component comprising an excipient, the components cannot be changed independently of each other. The ratio of one component depends on the ratio of the other two components. For example, if the proportion of water is in the range of 5 to 45% and the polyoxyalkylene block copolymer is in the range of 5 to 25%, the range of the hydrophilic solvent can be determined by the following formula:
100% - (polyoxyalkylene block copolymer% + water%);
in this example, the calculated range is about 30% to about 90%.
Polyoxyalkylene block copolymers, also referred to herein as "poloxamers", are nonionic block copolymers of ethylene oxide and propylene oxide having the formula:
polyoxyalkylene block copolymers useful in the present invention include those wherein x has a value of from about 1 to about 130, y has a value of from about 1 to about 72, and x has a value of from about 0 to about 130, wherein the average molecular weight of the copolymer is from about 3000 to about 15,000. Alternatively, the polyoxyalkylene block copolymer of the present invention is one wherein x equals 100, y equals 70, x' equals 100, said copolymer having an average molecular weight of about 12,600; alternatively, where x equals 76, y equals 31, and x' equals 76, the average molecular weight of the copolymer is 8400. The excipient of the present invention comprises from about 5% to about 25%, alternatively from about 5% to about 20%, of the poloxamer.
The poly (oxyethylene) segments are hydrophilic, while the poly (oxypropylene) segments are hydrophobic. Poloxamers are commercially available in which the number of blocks, the total average molecular weight and the percentage of hydrophilic molecules can be varied. By block is meant a single polyoxyethylene or polyoxypropylene segment. Diblock and triblock polymers have been described. For triblock copolymers, the blocks may be arranged in such a way that two polyoxyethylene blocks surround one polyoxypropylene block, which is the most common poloxamer structure, or alternatively, the blocks may be arranged in such a way that two polyoxypropylene blocks surround one polyoxyethylene block, which is sometimes referred to as a reverse poloxamer. Poloxamers are commercially available under the trade name Lutrol*、Monolan*Or Pluronic*. [ Poly (oxyethylene)/poly (oxypropylene)]The chemical structure, synthesis and properties of block copolymer surfactants have been described in Paschalis Alexandriis, "Current optics in Colloid and interface Science", Vol.2, pp.478-489 (1997); this document is incorporated herein by reference.
For the health care field, preferred poloxamers include Pluronic*F127、Pluronic*L1220 and Pluronic*F68. These specific polymers are all available from basf corporation.
In the present invention, it is contemplated that mixing a hydrophilic solvent with a poloxamer and water can provide an environment suitable for solubilizing a pharmaceutically active substance, wherein the composition has the physical stability previously discussed. The excipient of the present invention comprises from about 30% to about 90%, alternatively from about 35% to about 90%, and finally from about 40% to about 90% of a hydrophilic solvent.
Hydrophilic solvents of particular interest are selected from the group consisting of monohydric alcohols and polyhydric alcohols. Preferred monohydric alcohols of the present invention include ethanol and tetraethylene glycol. Anhydrous ethanol was obtained from Aaper Alcohol & Chemical Co., Shelbyville, KY. The polyols of the present invention are selected from the group consisting of diols, monosaccharides, oligosaccharides, and mixtures thereof. Glycols are particularly useful as hydrophilic solvents in the present invention. The glycol used in the present invention is selected from glycerol, propylene glycol and polyethylene glycol. The monosaccharide of the invention is selected from glyceraldehyde, ribose, glucose, fructose, invert sugar (e.g. honey) and mixtures thereof. The oligosaccharide of the invention is selected from maltose, sucrose, raffinose, lactose, cellobiose, ribose, sorbitol, mannitol, xylitol, inositol, galactose, mannose, xylose, rhamnose, glutaraldehyde and mixtures thereof.
In addition to the components previously discussed, the present invention also includes water. The water content in the vehicle of the present invention is from about 5% to about 45%, alternatively from about 5% to about 40%.
Optional ingredients
The compositions may include optional ingredients conventionally included in oral liquid compositions, which are typically used to improve the aesthetics of the composition. These optional ingredients include, but are not limited to, dyes, fragrances, preservatives, antioxidants, and similar types of compounds. Specific optional ingredients include, but are not limited to, surfactants including tyloxapol, polysorbate 80, lauranediol (lauroglycol)90, polyoxy (polyox/polyoxy)40 stearate, octanol 90; a polymer comprising polyvinylpyrrolidone, hydroxypropyl methylcellulose, beta-cyclodextrin; or solvents such as propylene carbonate, n-methyl pyrrolidone, ethoxydiglycol (transcutol), dimethyl isosorbide and mixtures thereof. These optional ingredients are included in the composition in sufficient amounts to perform their intended function without detriment to the benefits associated with the present invention.
Method
Methods of treating diseases
Drug delivery to the bloodstream can be achieved by placing a medicament into the mouth, and the delivery can be divided into two main sub-categories, depending on the desired effect. In one instance, where the drug is delivered to the blood by absorption after swallowing (i.e., from the stomach, small intestine or colon); in another instance, where the composition resides in the oral cavity prior to swallowing, it is absorbed or largely absorbed through the membranes of the oral cavity, either quickly or over an extended period of time. This route is commonly referred to as "buccal" or "oromucosal" absorption. In contrast, the former route is often referred to as oral administration of the active substance. Oral administration of active substances is by far the most common mode of use of all drugs and has been well studied and described in detail in: mayerson, M., Principles of Drug Absorption; "Modern pharmaceuticals", second edition, chapter ii, g.s.banker and c.t.rhodes, editors, Marcel dekker inc, New York, 1990; this document is incorporated herein by reference.
Oral mucosal Delivery in the Oral Cavity is generally considered to be directed to the sublingual area for rapid therapeutic effect, depending on the method of Delivery of the active, see d.harris and j.r.robinson, "Drug Delivery via the music Membranes of the Oral Cavity", Journal of Pharmaceutical Sciences 81: 1,1992. These agents are delivered sublingually to the floor of the mouth where they reside for a period of time. However, the present inventors have found that when the present composition is placed in any of the mucosa of the mouth, throat, tongue, oropharynx and combinations thereof and swallowed, a substantial increase in bioavailability can be achieved for a particular pharmaceutically active substance, with very rapid absorption; see PCT publication 00/41693 to Dobrozsi et al, published at 7/20/2000, which is incorporated herein by reference.
The present invention is in the form of a liquid or elixir for application to any mucosal membrane in the oral cavity. This can be accomplished using a medical dropper calibrated to show the appropriate dose to be administered, then spraying the elixir onto the tongue prior to swallowing. Elixirs can be sprayed into the mouth and throat and then swallowed. It may also be encapsulated in some edible and/or chewable shell that makes it portable and convenient to transport and take without the need to measure the amount of liquid elixir. Examples of encapsulating shells include hard candies, which are used in candy pieces, gelatin and starch based shells, and combinations thereof. Elixirs may be packaged as single-dose disposable vials for ease of opening, with the elixir being sprayed or poured into the mouth. Typical pharmaceutical volumes of the compositions of the present invention are no more than about 3ml, alternatively from about 0.2ml to about 3 ml.
Method for determining physical stability of the invention
The susceptibility of the composition to changes in morphology and appearance is an indication of the physical stability of the composition. In these tests for stability, the optical density of the liquid is measured. This method is thermochemical, wherein the method of preparing the composition samples and the control samples, which were packaged in 30ml amber glass bottles leaving only a minimal amount of headspace, is disclosed in the examples below. The bottles were placed in an insulated chamber at a constant temperature of less than 5 c until the bottles were removed for testing. The physical stability of the OD including the control sample and the inventive sample was evaluated by measuring the optical density of each sample. The experiment used a spectrophotometer such as Jenway Model 6405UV/VIS with a transmittance wavelength of 530 nm. Physical stability is a function of the light transmittance of the composition. The light transmittance of the composition is directly related to the turbidity of the liquid, sedimentation/precipitation, and/or the crystal content in the liquid.
The measurement of the samples was performed every 7 days. The values measured over the entire 3 month test period were averaged. Formulations with lower optical densities are believed to have higher overall physical stability. The Optical Density (OD) value of the composition of the present invention is required to be less than or equal to 0.05, which indicates that the composition has excellent physical stability.
Examples
Example 1:composition for treating cough with expectorant
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 15.39 |
| Memethaphenine base | 1.13 |
| Propylene glycol | 41.32 |
| Water (W) | 20.38 |
| Alcohol, 96% v/v | 10.65 |
| Poloxamers1 | 7.01 |
| Sucralose | 1.40 |
| Flavouring agent | 1.50 |
| Saccharin sodium salt | 0.40 |
| Tetrasulfamate | 0.40 |
| Sodium metabisulfite | 0.20 |
| Ethylenediaminetetraacetic acid disodium salt | 0.20 |
| Glycyrrhiza element monoammonium salt | 0.02 |
1Pluronic*F127, obtained from BASF Specialty Chemicals, mt.
Preparation of：
Propylene glycol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. In a separate container (alcohol premix) add alcohol, methamphetamine and monoammonium glycyrrhizinate and mix until uniform. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising an alcohol to a main mixing vessel comprising a poloxamer. Mix until homogeneous. The premix containing water is added to the main vessel with stirring, mixing is continued until homogeneous, and then the desired flavor components are added and mixed until homogeneous.
Example 2: composition for treating cough with expectorant
| Components | ％ (w/w) |
| Guaiacol glyceryl ether | 15.39 |
| Memethaphenine base | 1.13 |
| Propylene glycol | 25.77 |
| Poloxamers1 | 15.00 |
| Water (W) | 13.59 |
| Alcohol, (100%) | 10.00 |
| Ethoxy diethylene glycol | 10.00 |
| Tyloxapol | 5.00 |
| Sucralose | 1.40 |
| Flavouring agent | 1.50 |
| Saccharin sodium salt | 0.40 |
| Tetrasulfamate | 0.40 |
| Sodium metabisulfite | 0.20 |
| Ethylenediaminetetraacetic acid disodium salt | 0.20 |
| Glycyrrhiza element monoammonium salt | 0.02 |
1Pluronic*F127, obtained from BASF Specialty Chemicals, mt.
Preparation of：
Propylene glycol, tyloxapol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. In a separate container (alcohol premix) add alcohol, methamphetamine, ethoxydiglycol and monoammonium glycyrrhizinate and mix until homogeneous. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising an alcohol to a main mixing vessel comprising a poloxamer. Mix until homogeneous. The premix containing water was added to the main vessel with stirring and mixing continued until homogeneous. Subsequently, the desired flavor components are added and mixed until homogeneous.
Example 3: composition for treating cough with expectorant
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 15.39 |
| Memethaphenine base | 1.13 |
| Poloxamers1 | 15.56 |
| Water (W) | 20.81 |
| Propylene glycol | 34.24 |
| Alcohol, 96% v/v | 10.65 |
| Sucralose | 0.40 |
| Flavouring agent | 1.12 |
| Saccharin sodium salt | 0.20 |
| Tetrasulfamate | 0.10 |
| Sodium metabisulfite | 0.20 |
| Ethylenediaminetetraacetic acid disodium salt | 0.20 |
1Pluronic*F68, available from BASF Specialty Chemicals, Mt. Olive, NJ.
Preparation of：
Propylene glycol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. Add alcohol, methaphen base in a separate vessel (alcohol premix) and mix until homogeneous. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising water to a main mixing vessel comprising a poloxamer. Mix until homogeneous. Cool under agitation and add the alcohol containing premix to the main vessel and continue stirring until uniform. Subsequently, the desired flavor components are added and mixed until homogeneous.
Example 4: composition for treating cough with expectorant
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 15.40 |
| Memethaphenine base | 1.13 |
| Propylene glycol | 27.74 |
| Poloxamers1 | 18.52 |
| Water (W) | 18.09 |
| Alcohol, (100%) | 10.00 |
| Tyloxapol | 5.00 |
| Sucralose | 1.40 |
| Flavouring agent | 1.50 |
| Saccharin sodium salt | 0.40 |
| Tetrasulfamate | 0.40 |
| Sodium metabisulfite | 0.20 |
| Ethylenediaminetetraacetic acid disodium salt | 0.20 |
| Glycyrrhiza element monoammonium salt | 0.02 |
1Pluronic*F127, obtained from BASF Specialty Chemicals, mt.
Preparation of：
Propylene glycol, tyloxapol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. In a separate container (alcohol premix) add alcohol, methamphetamine and monoammonium glycyrrhizinate and mix until uniform. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising an alcohol to a main mixing vessel comprising a poloxamer. Mix until homogeneous. The premix containing water was added to the main vessel with stirring and mixing continued until homogeneous. Subsequently, the desired flavor components are added and mixed until homogeneous.
Example 5: composition for treating cough with expectorant
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 15.40 |
| Memethaphenine base | 1.13 |
| Propylene glycol | 29.67 |
| Water (W) | 17.81 |
| Poloxamers1 | 11.87 |
| Alcohol, (100%) | 10.00 |
| Ethoxy diethylene glycol | 10.00 |
| Sucralose | 1.40 |
| Flavouring agent | 1.50 |
| Saccharin sodium salt | 0.40 |
| T-shirtAmmonium sulfonate | 0.40 |
| Sodium metabisulfite | 0.20 |
| Ethylenediaminetetraacetic acid disodium salt | 0.20 |
| Glycyrrhiza element monoammonium salt | 0.02 |
1Pluronic*F127, obtained from BASF Specialty Chemicals, mt.
Preparation of：
Propylene glycol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. In a separate vessel (alcohol premix) add alcohol, methamphetamine, ethoxydiglycol and monoammonium glycyrrhizinate and mix until homogeneous. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising an alcohol to a main mixing vessel comprising a poloxamer. Mix until homogeneous. The premix containing water was added to the main vessel with stirring and mixing continued until homogeneous. Subsequently, the desired flavor components are added and mixed until homogeneous.
Example 6: composition for treating cough with expectorant
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 15.39 |
| Memethaphenine base | 1.13 |
| Propylene glycol | 52.82 |
| Water (W) | 20.38 |
| Alcohol (96% v/v) | 0.44 |
| Poloxamers1 | 7.01 |
| Sucralose | 0.40 |
| Flavouring agent | 1.12 |
| Saccharin sodium salt | 0.10 |
| Tetrasulfamate | 0.10 |
| Sodium metabisulfite | 0.20 |
| Ethylenediaminetetraacetic acid disodium salt | 0.91 |
1Pluronic*L1220 from BASF Specialty Chemicals, mt. olive, NJ.
Preparation of：
Propylene glycol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently dissolve the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. In a separate vessel (alcohol premix), add alcohol, methamphetamine base, mix until homogeneous. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising water to a main mixing vessel comprising a poloxamer. Mix until homogeneous. Cooling under stirring while adding the alcohol-containing premix to the main vessel, continuing stirring until homogeneous, and subsequently adding the desired flavor components and mixing until homogeneous.
Example 7:composition for treating cough with expectorant
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 15.38 |
| Memethaphenine base | 1.12 |
| Poloxamers1 | 14.00 |
| Propylene glycol | 30.00 |
| Water (W) | 17.00 |
| Alcohol (96% v/v) | 10.00 |
| Ethoxy diethylene glycol | 10.00 |
| Flavouring agent | 1.00 |
| Sucralose | 0.90 |
| Saccharin sodium salt | 0.20 |
| Tetrasulfamate | 0.20 |
| Sodium metabisulfite | 0.10 |
| Ethylenediaminetetraacetic acid disodium salt | 0.10 |
1Pluronic*F127, obtained from BASF Specialty Chemicals, mt.
Preparation of：
Propylene glycol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. In a separate vessel (alcohol premix), add alcohol, methallyl base, and ethoxydiglycol, mix until homogeneous. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising an alcohol to a main mixing vessel comprising a poloxamer. Mix until homogeneous. The premix containing water was added to the main vessel with stirring and mixing continued until homogeneous. Subsequently, the desired flavor components are added and mixed until homogeneous.
Example 8: composition for treating cough with expectorant
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 15.39 |
| Memethaphenine base | 1.13 |
| Tetraglycol | 25.25 |
| Propylene glycol | 20.21 |
| Poloxamers1 | 14.03 |
| Water (W) | 10.00 |
| Alcohol (96% v/v) | 10.65 |
| Sucralose | 1.40 |
| Saccharin sodium salt | 0.44 |
| Tetrasulfamate | 0.40 |
| Sodium metabisulfite | 0.10 |
| Ethylenediaminetetraacetic acid disodium salt | 0.10 |
| Flavouring agent | 0.90 |
1Pluronic*F127, obtained from BASF Specialty Chemicals, mt.
Preparation of：
Propylene glycol, tetraethylene glycol and poloxamer are added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. Add alcohol, methaphen base in a separate vessel (alcohol premix) and mix until homogeneous. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising an alcohol to a main mixing vessel comprising a poloxamer. Mix until homogeneous. The premix containing water was added to the main vessel with stirring and mixing continued until homogeneous. Subsequently, the desired flavor components are added and mixed until homogeneous.
Example 9: composition for treating cough with expectorant
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 25.00 |
| Memethaphenine base | 1.83 |
| Poloxamers1 | 16.36 |
| Water (W) | 20.50 |
| Propylene glycol | 24.34 |
| Alcohol, 96% v/v | 10.65 |
| Sucralose | 0.40 |
| Flavouring agent | 0.40 |
| Saccharin sodium salt | 0.20 |
| Tetrasulfamate | 0.20 |
| Sodium metabisulfite | 0.10 |
| Ethylenediaminetetraacetic acid disodium salt | 0.02 |
1Pluronic*F68, available from BASF Specialty Chemicals, Mt. Olive, NJ.
Preparation of：
Propylene glycol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. Add alcohol, methaphen base in a separate vessel (alcohol premix) and mix until homogeneous. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising an alcohol to a main mixing vessel comprising a poloxamer. Mix until homogeneous. The premix containing water was added to the main vessel with stirring, and stirring was continued until homogeneous. Subsequently, the desired flavor components are added and mixed until homogeneous.
Example 10: composition for treating cough with expectorant
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 20.00 |
| Memethaphenine base | 1.47 |
| Propylene glycol | 19.75 |
| Poloxamers1 | 16.07 |
| Water (W) | 13.59 |
| Alcohol, (100%) | 10.00 |
| Ethoxy diethylene glycol | 10.00 |
| Tetraglycol | 5.00 |
| Sucralose | 1.40 |
| Flavouring agent | 1.52 |
| Saccharin sodium salt | 0.40 |
| Tetrasulfamate | 0.40 |
| Sodium metabisulfite | 0.20 |
| Ethylenediaminetetraacetic acid disodium salt | 0.20 |
1Pluronic*F127, obtained from BASF Specialty Chemicals, mt.
Preparation of：
Propylene glycol, tetraethylene glycol and poloxamer are added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. In a separate vessel (alcohol premix), add alcohol, methadone base and ethoxydiglycol and mix until homogeneous. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising an alcohol to a main mixing vessel comprising a poloxamer. Mix until homogeneous. The premix containing water was added to the main vessel with stirring and mixing continued until homogeneous. Subsequently, the desired flavor components are added and mixed until homogeneous.
Example 11: composition for treating bronchitis with expectorant
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 15.26 |
| Ambroxol | 2.36 |
| Propylene glycol | 47.27 |
| Water (W) | 17.94 |
| Alcohol, 100% | 10.00 |
| Poloxamers1 | 7.17 |
1Pluronic*F127, obtained from BASF Specialty Chemicals, mt.
Preparation of：
Propylene glycol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaiacol glyceryl ether and ambroxol were added with stirring. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. Finally, alcohol and water were added to the vessel and mixed until homogeneous.
Example 12: liquid cough medicine sugar block
| Material | ％(w/w) |
| Memethaphenine base | 2.05 |
| Guaiacol glyceryl ether | 20.00 |
| Poloxamers1 | 15.50 |
| Propylene glycol | 46.71 |
| Water (W) | 13.44 |
| Alcohol (96% v/v) | 0.40 |
| Sucralose | 0.40 |
| Saccharin sodium salt | 0.15 |
| Tetrasulfamate | 0.15 |
| Sodium metabisulfite | 0.15 |
| Ethylenediaminetetraacetic acid disodium salt | 0.15 |
| Flavouring agent | 0.90 |
1Pluronic*L1220 from BASF Specialty Chemicals, mt. olive, NJ.
Preparation of：
Propylene glycol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. Add alcohol, methaphen base in a separate vessel (alcohol premix) and mix until homogeneous. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising an alcohol to a main mixing vessel comprising a poloxamer. Mix until homogeneous. The premix containing water was added to the main vessel with stirring and mixing continued until homogeneous. The desired flavor components are then added and mixed until homogeneous. Individual filled pieces of candy, each containing about 1.0ml of liquid, are prepared by conventional methods of use, such as extrusion.
Example 13: chewable soft gelatin capsule
| Components | ％(w/w) |
| Memethaphenine base | 2.05 |
| Poloxamers1 | 12.25 |
| Propylene glycol | 47.56 |
| Water (W) | 10.44 |
| Alcohol (96% v/v) | 10.46 |
| Sucralose | 0.40 |
| Saccharin sodium salt | 0.10 |
| Tetrasulfamate | 0.10 |
| Sodium metabisulfite | 0.20 |
| Ethylenediaminetetraacetic acid disodium salt | 0.15 |
| Guaiacol glyceryl ether | 15.39 |
| Flavouring agent | 0.90 |
1Pluronic*F127, obtained from BASF Specialty Chemicals, mt.
Preparation of：
Propylene glycol and poloxamer were added to the clean vessel (main mixture). The mixture is suitably heated with stirring to sufficiently melt and dissolve the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. The alcohol and methamphetamine base were added in separate containers (alcohol premix) and mixed until homogeneous. In another vessel (water premix), water, EDTA, sodium saccharin, acesulfame, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
Adding a premix comprising an alcohol to a main mixing vessel comprising a poloxamer. Mix until homogeneous. The premix containing water was added to the main vessel with stirring and mixing continued until homogeneous. Subsequently, the desired flavor components are added and mixed until homogeneous. Single filled soft gelatin capsules containing about 1.0ml of liquid were prepared.
Example 14: composition for treating sinusitis or allergic rhinitis symptoms
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 15.37 |
| Bromhexine | 0.67 |
| Propylene glycol | 48.00 |
| Water (W) | 18.46 |
| Alcohol, 100% | 10.00 |
| Poloxamers1 | 7.50 |
1Pluronic*F127, obtained from BASF Specialty Chemicals, mt.
Preparation of：
Propylene glycol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin and bromhexine were added with stirring. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. Finally, the alcohol and water are added to the vessel and mixed until homogeneous.
Example 15: composition for treating bronchitis with expectorant
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 15.37 |
| Bromhexine | 0.67 |
| Ambroxol | 2.30 |
| Propylene glycol | 46.70 |
| Water (W) | 17.46 |
| Poloxamers1 | 7.50 |
| Alcohol, 100% | 10.00 |
1Pluronic*F127 from BASF Specialty Chemicals，Mt.Olive，NJ。
Preparation of：
Propylene glycol and poloxamer were added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. With stirring, guaifenesin, bromhexine and ambroxol are added. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. Finally, the alcohol and water are added to the vessel and mixed until homogeneous.
Example 16: composition for treating infertility
| Components | ％(w/w) |
| Guaiacol glyceryl ether | 18.50 |
| Propylene glycol | 26.75 |
| Poloxamers1 | 19.00 |
| Water (W) | 16.50 |
| Alcohol, (100%) | 10.00 |
| Flavouring agent | 1.40 |
| Tetraglycol | 5.00 |
| Sucralose | 1.20 |
| Flavouring agent | 1.20 |
| Saccharin sodium salt | 0.25 |
| Sodium metabisulfite | 0.10 |
| Ethylenediaminetetraacetic acid disodium salt | 0.10 |
1Pluronic*F127, obtained from BASF Specialty Chemicals, mt.
Preparation of：
Propylene glycol, tetraethylene glycol and poloxamer are added to the clean vessel (main mixture). The mixture was appropriately heated under stirring to sufficiently melt the poloxamer. Guaifenesin was added and stirring was continued. Once a homogeneous solution was obtained, the heat source was removed and stirring was continued. Alcohol was added and stirring was continued. In another vessel (water premix), water, EDTA, sodium saccharin, sucralose, and sodium metabisulfite were added. Mix until all materials are dissolved.
The premix comprising alcohol is added to the main mixing vessel comprising poloxamer and mixed until homogeneous. The premix containing water was added to the main vessel with stirring and mixing continued until homogeneous. Subsequently, the desired flavor components are added and mixed until homogeneous.
Claims (10)
1. An oral liquid composition comprising from 2% to 40% guaifenesin and excipients comprising:
from 5% to 25% of a polyoxyalkylene block copolymer wherein said polyoxyalkylene block copolymer has the formula:
x has a value of 1 to 130, y has a value of 1 to 72, and x has a value of 0 to 130;
30% to 90% of a hydrophilic solvent; and
c.5% to 45% water;
wherein the polyoxyalkylene block copolymer, hydrophilic solvent and water are in proportions such that the excipient is located in the region defined by line segments AB, BC, CD and DA in FIG. 1.
2. The oral composition of claim 1, wherein the polyoxyalkylene block copolymer is present in an amount of 5% to 25%, the hydrophilic solvent is present in an amount of 35% to 90%, and wherein the water is present in an amount of 5% to 40% of the excipient.
3. The oral composition of claim 1 or 2, wherein the hydrophilic solvent is selected from the group consisting of monohydric alcohols and polyhydric alcohols, wherein the polyhydric alcohols are selected from the group consisting of glycols, monosaccharides, oligosaccharides, and mixtures thereof.
4. The oral composition according to any one of the preceding claims wherein the hydrophilic solvent is a glycol selected from the group consisting of glycerol, propylene glycol, polyethylene glycol, and mixtures thereof.
5. A method of treating a respiratory disease using the composition of claim 1, wherein the method comprises orally administering a total dose volume of equal to or less than 3.0ml of the composition.
6. The method of claim 5, wherein the composition is placed in close proximity to any of the mucosa of the oral cavity, throat, tongue, oropharynx, and combinations thereof.
7. An oral liquid composition comprising 5% to 30% guaifenesin and excipients comprising:
from 5% to 20% of a polyoxyalkylene block copolymer wherein said polyoxyalkylene block copolymer has the formula:
x equals 100, y equals 70, x' equals 100, and has an average molecular weight of about 12,600;
c, 40% to 90% of propylene glycol and ethanol hydrophilic solvent; and
5% to 40% water;
wherein the polyoxyalkylene block copolymer, hydrophilic solvent and water are in proportions such that the excipient is located in the region defined by line segments AB, BC, CD and DA in FIG. 1.
8. The oral composition of claim 7, further comprising ambroxol, bromhexine, methamphetamine, or combinations thereof.
9. A method of treating a respiratory disease using the composition of claim 7, wherein the method comprises orally administering a total dose volume of no more than 3.0ml of the composition.
10. The method of claim 9, wherein the composition contacts the mucosa of the oral cavity.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/974,347 | 2001-10-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1072548A true HK1072548A (en) | 2005-09-02 |
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