METHODS FOR PRODUCING AN ORALSUSPENSION OF TEICHOPLANIN OR TEICHOPLANIN ANALOGS
A stable suspension of teicoplanin and one or more pharmaceutically acceptable additives and method for preparation wherein the teicoplanin is mixed with an aqueous or non aqueous suspension base and pharmaceutically acceptable additives and wherein the teicoplanin is milled to obtain a homogeneously dispersed suspension.
This application claims priority to U.S. Provisional Application No. 62/215,425 filed Apr. 30, 2015. The entire contents of the above application are hereby incorporated by reference as though fully set forth herein.
FIELDThe present invention relates to the field of medicinal preparations containing peptides. More specifically, the present invention relates to preparations of teicoplanin, which is an antibiotic of the glycopeptide family, more particularly of the ristocetin type.
BACKGROUNDTeicoplanin is an antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, Enterococcus faecalis and Clostridium. It is a semisynthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Its mechanism of action is to inhibit the polymerization of cell wall components in bacterial cell wall synthesis.
Teicoplanin is complex glycoprotein mixture of several compounds, five major (named teicoplanin A2-1 through A2-5) and four minor (named teicoplanin RS-1 through RS-4). (See De Lalla F, Nicolin R, Rinaldi E, Scarpellini P, Rigoli R, Manfrin V, Tramarin A (1992). “Prospective study of oral teicoplanin versus oral vancomycin for therapy of pseudomembranous colitis and Clostridium difficile-associated diarrhea”. Antimicrob Agents Chemother 36 (10): 2192-2196 All teicoplanins share a same glycopeptide core, termed teicoplanin A3-1—a fused ring structure to which two carbohydrates (mannose and N-acetylglucosamine) are attached. The major and minor components also contain a third carbohydrate moiety—β-D-glucosamine—and differ only by the length and conformation of a side-chain attached to it.
Teicoplanin is marketed by Sanofi-Aventis under the trade name Targocid and is used in the treatment of Clostridium difficile infection-associated diarrhea and colitis by oral administration. The recommended dose is 100-400 mg administered orally twice a day for 7 to 14 days. Its strength is attributed to the length of its hydrocarbon chain. (See Gilpin M, Milner P (1997). “Resisting changes—Over the past 40 years the glycopeptide antibiotics have played a crucial role in treating bacterial infections. But how long can it continue?”. Royal Society of Chemistry. Retrieved 2006 Oct. 15—includes picture of Teicoplanin's structure).
Oral teicoplanin has been demonstrated to be effective in the treatment of pseudomembranous colitis and Clostridium difficile-associated diarrhea, with comparable efficacy with vancomycin (See Bernareggi A, Borghi A, Borgonovi M, Cavenaghi L, Ferrari P, Vékey K, Zanol M, Zerilli L (1992). “Teicoplanin metabolism in humans”. Antimicrob Agents Chemother 36 (8): 1744-1749).
The systematic IUPAC name and synonyms for teicoplanin may include: (1 S,2R,19R,22R,34S,37R,40R,52S)-2-[(2-Acetamido-2-desoxy-β-D-glucopyranosyl)oxy]-22-amino-5,15-dichlor-64-{[2-(decanoylamino)-2-desoxy-β-D-glucopyranosyl]oxy}-26,31,44,49-tetrahydroxy-47-(α-D-mannopyranosyloxy)-21,35,38,54,56,59-hexaoxo-7,13,28-trioxa-20,36,39,53,55,58-hexaazaundecacyclo[38.14.2.23,6.214,17.219,34.18,12.123,27.129,33.141,45.010,37.046,51]hexahexaconta-3,5,8(64),9,11,14,16,23(61),24,26,29(60),30,3 [German] [ACD/IUPAC Name]. Acide(1S,2R,19R,22R,34S,37R,40R,52S)-2-[(2-acétamido-2-désoxy-β-D-glucopyranosyl)oxy]-22-amino-5,15-dichloro-64-{[2-(decanoylamino)-2-désoxy-β-D-glucopyranosyl]oxy}-26,31,44,49-tétrahydroxy-47-(α-D-mannopyranosyloxy)-21,35,38,54,56,59-hexaoxo-7,13,28-trioxa-20,36,39,53,55,58-hexaazaundécacyclo[38.14.2.23,6.214,17.219,34.18,12.123,27.129,33.141,45.010,37.046,51] hexahexa conta-3,5,8(64),9,11,14,16,23(61),24,26,29(6 [French] [ACD/IUPAC Name]
Teicoplanin refers to a complex of related natural products isolated from the fermentation broth of a strain of Actinoplanes teichomyceticus (See Jung H M, Jeya M, Kim S Y, Moon H J, Kumar Singh R, Zhang Y W, Lee J K. (2009) Appl Microbiol Biotechnol. 2009 September; 84(3):417-428) consisting of a group of five structures. These structures possess a common aglycone, or core, consisting of seven amino acids bound by peptide and ether bonds to form a four-ring system. These five structures differ by the identity of the fatty acyl side-chain attached to the sugar. The origin of these seven amino acids in the biosynthesis of teicoplanin was studied by 1H and 13C nuclear magnetic resonance (See Heydorn, A.; Peterson, B. O.; Duus, J.; Bergmann, S.; Suhr-Jessen, T.; Nielson, J. Journal of Biological Chemistry. 2000, 275, 6201-6206). The studies indicate amino acids AA1, AA2, AA4, AA5, and AA6 are derived from tyrosine, and amino acids AA3 and AA7 are derived from acetate. To be specific, teicoplanin contains 4-hydroxyphenylglycine and 3,5-dihydroxyphenylglycine residues, a chlorine atom attached on each of the tyrosine residues, and three sugar moieties, N-fatty acyl-β-D-glucosamine, N-acetyl-β-D-glucosamine, and D-mannose (id.)
The most common dosage forms employed for oral administration of active substances are solid oral dosage forms such as tablets and capsules. Solid oral dosage forms are often not favorable for pediatric, geriatric and others with conditions that make swallowing difficult (stricture, post-stroke, feeding tubes, etc.). For these patients, tablets or capsules are difficult to ingest and carry a higher risk of choking. In some cases, patients are required to ingest multiple large tablets or capsules at a single time or frequently. All of these aforementioned common situations may result in poor patient compliance, incomplete treatment and suboptimal therapeutic outcomes. In such situations, oral liquid dosage forms maybe a preferred choice.
Oral liquid dosage forms may lead to a exposure of the active drug ingredient to the taste buds, and in cases where the drug has a bitter or unpleasant taste, decrease compliance. An unpleasant taste of a drug can cause difficulties in swallowing or medication avoidance. Therefore, taste-masking technologies are important as taste often impacts compliance.
Solubility, directly impacts a drug's dissolution rate, potency and time to onset. Low solubility can be a hurdle for active substance to be properly formulated.
To overcome problems of administering active drug from capsules or tablets, liquid oral dosage forms can be reconstituted from powders or granules and mixed with a liquid in a container or glass prior to administration. In certain cases, active substance does not completely dissolve in the liquid, which results in particles or granules adhering to the sides of the container or sinking to the bottom and causes an unacceptable variation in the dose of the active substance or drug that the patient receives. The granules or particles may have an unpleasant feel in the mouth, typically have an irregular shape, often adhere to oral mucosa, and have a gritty texture that is unpleasant and may act to reduce patient compliance.
PRIOR ARTThe prior art in Coronelli U.S. Pat. No. 4,239,751 teaches the production of teichomycin by cultivation of strain Actinoplanes teichomyceticus nov. sp. ATCC 31121. The prior art in Borghi in U.S. Pat. No. 4,542,018 teaches cultivation of teicoplanins A21-5 and methods for analysis and isolation, Corti in European patent 0122969 teaches a scalable method for production of teicoplanin suitable for commercial manufacture.
Purification of teicoplanin can be achieved by methods disclosed in the art. For example, Tang in U.S. Pat. No. 7,405,267 teaches a method for purification of teicoplanin including a final lyophilisation step. Lyophilisation is a well-known method to those skilled in the art of manufacture of sterile drug powder formulations (for example Rey, L & May, J C in Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products, Informa Healthcare, 2010 ISBN-13:9781439825754).
Targocid and other teicoplanin analogs and/or formulations are sold as lyophilized powders. Targocid also contains sodium chloride and sodium hydroxide as excipients.
Targocid requires reconstitution in WFI grade water according to instructions provided in the patient information leaflet prior to oral administration. The reconstitution process is inconvenient for both the pharmacist and the patient in need of teicoplanin treatment due to the foaming of the lyophilized powder on addition of water, as taught in the prior art by Vecchio EP1806150 and Kruchek (Anaesthesia, 2010, 65, 1047). Foaming of the teicoplanin solution can result in incomplete administration of the dose if administered orally before the foaming has subsided. Solutions to overcome the inconveniencing of foaming during reconstitution of teicoplanin powders rely on modifications of the lyophilized teicoplanin powder pre-reconstitution. For example, Vecchio in EP1806150 teaches the combination of antifoaming agents with the pre-reconstituted teicoplanin powder. Additionally, the formulation is not flavored to mask the unpalatable bitterness of teicoplanin; thus this can significantly led to a decrease in patient compliance. Furthermore, sterile water for injection is typically the vehicle for compounding this preparation and it lacks preservatives increasing the risk of contamination and exposure to pathogens (bacteria, viruses, fungi/yeast, and/or mold spores). For patients already infected with staphylococci or clostridium difficile any exposure to additional pathogens due to a contaminant can worsen their outcome.
Therefore there exists a need for a teicoplanin suspension without the need for reconstitution immediately prior to administration.
BRIEF SUMMARY OF THE INVENTIONIt is the object of the present invention to address several challenges in previous attempts to develop an oral suspension of teicoplanin. The present invention formulates teicoplanin in the form of a suspension (aqueous and non-aqueous vehicle), with an improved taste, stability and solubility by careful manipulation of the flavouring agent, sweetening agent and particle size. Such formulations are envisaged to fulfill the existing need of patient friendly dosage forms especially for the pediatric, geriatric and others with the decreased ability to swallow oral solid dose forms. Further, this suspension has many advantages over the reconstituted API in that it provides for better patient compliance, improved stability and does not have issues with dose variation.
An object of the invention is to provide a stable, taste-masked, suspension of teicoplanin and one or more pharmaceutically acceptable additives.
Another object of the invention is to provide a stable, taste-masked, suspension of teicoplanin, comprising a particle size such that d90 is less than about 170 μητ.
Yet another object of the invention is to provide a process for preparing a stable, taste-masked, suspension of teicoplanin comprising the steps of mixing teicoplanin with the suspension base (aqueous and non-aqueous) and further sizing the particles of teicoplanin by milling the suspension to obtain a homogenously dispersed teicoplanin suspension.
The present invention is an oral, stable, pharmaceutical suspension of teicoplanin. The suspension dosage form is taste masked and uniformally dispersed and/or dissolved, improving patient compliance, especially for children, elderly and those unable to swallow pills or digest oral solid dosage forms. The term “teicoplanin” as used is the invention is meant to cover crystalline teicoplanin in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. The term also includes all isomers or polymorphic forms not limited to pure or mixtures thereof. Teicoplanin may be used as a single active agent, or may be combined with other active agents, vitamins, minerals, dietary supplements, oils, including sunflower oil, coconut oil, etc.
The phrase ‘pharmaceutically acceptable’ as used in the invention is meant to refer to those compounds, materials compositions, or other dosage forms that are, within the scope of medical judgment, suitable for use in contact with tissues of human beings and animals and without excessive toxicity, irritation, allergic response, or any other problem or complication.
The term ‘taste masking’ as used in the invention is meant to refer as reduction of unpleasant taste associated with Teicoplanin in the pharmaceutical composition and/or after stability.
The term ‘stable’ as used in the present invention relates to both chemical (shelf-life) and physical stability (suspension uniformity). Improved uniformity results in an improved product because less shaking is required before dosing and imparts a longer shelf-life because the drug in the product will not settle out.
In the present invention, teicoplanin is milled or micronized to a desired particle size. The suspension may be milled by various techniques for example air-jet milling, impact milling, ball milling, dry milling, wet milling, or any other approved method to decrease particle size. Using the above techniques helps in obtaining the desired particle size with increased wettability, solubility, dissolution and dispersion of Teicoplanin. In the case of small particles, the active surface area is increased along with the dissolution time. Small sized particles slow the rate of sedimentation, dissolve faster, and are usually less gritty. There is therefore a need for a suspension containing fine particles, hereafter referring to d90 less than about 170 μητ, which will not cake but instead maintain homogeneity on prolonged storage.
The term ‘d90 as used herein means that “90% particles is less than about 170 μητ”. It is noted that the notation dx means that X % of particles have—a diameter less than the specified diameter d. The d90 of the teicoplanin dispersed or suspended in the suspension is less than about 170 μπτ and more preferably of less than about 70 μη. The size of the particles may be measured using a light scattering device, sedimentation methods, or other methods known to a skilled person. For example, Matersizer 2000 manufactured by Malvern instruments Ltd., Malvern UK may be used to measure the teicoplanin particles measured for the purpose of this invention.
Viscosity is a property of the suspension that imparts stability and helps to slow the sedimentation rate. The viscosity of the suspension determines the pourable consistency. The suspension may have a viscosity of in the range of about 20 cps to about 500 cps and in the non-aqueous or oil based suspension of 500 cps to 1500 cps when measured by Brookfield Viscometer, Brookfield Engineering Laboratories, Inc., Middleboro, Mass.
The taste-masked, suspension according to the invention has a suspension base with the active ingredient dispersed in the suspension base. The pharmaceutically acceptable suspension base may be, for example, an aqueous solvent such as water, with the suspending/viscosity-enhancing agent dispersed throughout the medium or a non-aqueous suspension base, which includes but is not limited to, sunflower oil, coconut oil, castor oil and mixtures thereof. The pharmaceutically acceptable suspension base may contain various additive(s), which are known to a person skilled in art.
The suspension of teicoplanin, or a pharmaceutically acceptable salt(s) according to the present invention comprises teicoplanin dispersed in an aqueous base; at least one dispersing agent; at least one buffering agent; and at least one suspension vehicle. The suspension may further comprise at least one or more other pharmaceutically acceptable additive(s) selected from group comprising but not limited to flavoring agent(s), sweetening agents(s), buffering agents(s), preservative(s), suspending agents(s), antioxidant(s), wetting agent(s), pH stabilizing agent(s), taste enhancing agent(s), antifoaming agent(s) and mixtures thereof.
In another embodiment, the suspension of teicoplanin, or a pharmaceutically acceptable salt(s) according to the present invention comprises teicoplanin dispersed in a non aqueous base; at least one dispersing agent and at least one suspension vehicle. The suspension may further comprise at least one or more other pharmaceutically acceptable additive(s) selected from group comprising but not limited to flavoring agent(s), sweetening agents(s), buffering agents(s), preservative(s), suspending agents(s), antioxidant(s), wetting agent(s), pH stabilizing agent(s), taste enhancing agent(s), antifoaming agent(s) and mixtures thereof.
An additive can have multiple functions. Flavoring agent(s) or flavorants are used in the invention to improve the taste or aroma and/or impart a pleasant flavor and/or odor to a pharmaceutical composition. Flavoring agents include but are not limited to natural and artificial flavors, such as synthetic flavor oils and flavoring aromatics and/or natural oils, such as sunflower or coconut oil, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. Representative suitable flavoring agents may be for example, without limitation, menthol, cinnamon, wintergreen, clove, bay, anise, eucalyptus, thyme, cedar leave, nutmeg, sage, almonds, cassia, vanilla, artificial vanilla, chocolate, artificial chocolate, bubble gum, both natural and artificial fruit flavors, such as cherry flavor, grape flavor, orange flavor, banana flavor, strawberry flavor, lemon flavor, grapefruit flavor and “mint” flavors such as peppermint flavor and spearmint flavor, lime flavor, apple flavor, pear flavor, peach flavor, raspberry flavor, plum flavor, pineapple flavor, apricot flavor and so forth, including combinations of two or more thereof. The amount of flavoring agent may depend on a number of factors, including the desired organoleptic effect. The precise amount of sweetening and/or flavoring agent(s) depends on the properties of the agent(s) used, however generally in an amount that is sufficient to mask the unpleasant taste and/or odor associated with teicoplanin as determinable by one skilled in the art. However, flavoring agents generally present is in a pharmaceutically acceptable range.
Sweeteners or sweetening agents include any compound that provides a sweet taste to make the product more palatable. Sweeteners suitable for inclusion in the present invention may be determined by one skilled in the art including, for example without limitation, natural, synthetic sugars, artificial sweeteners, natural extracts and any material that imitates a sweet sensation in a patient. Sweeteners such as the representative sweetening agents of intense sweeteners such as sorbitol, sucrose, saccharins such as sodium saccharin, cyclamates such as sodium cyclamates, aspartame, sucralose, thaumatin, acesulfam K, steviol glycosides such as stevioside and the like, and sugars such as monosaccharides, disaccharides and polysaccharides. Representative sugars useful in the present invention include, without limitation, xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch or corn syrup, and sugar alcohols such as sorbitol, xylitol, mannitol, glycerin, etc. and combination thereof. Sugar sweeteners may be replaced or augmented by water-soluble artificial sweeteners, such as the suitable artificial sweeteners previously listed and mixtures thereof. The amount of artificial sweetener used in the composition may vary to provide an appropriate amount of sweetness as determinable by one skilled in the art. Mixtures of sweetening and/or flavoring agents are preferably used. By suitable combination of sweetener and flavoring agents the unpleasant taste of the teicoplanin can be improved.
The pharmaceutical composition may also comprise antioxidant(s), which are agents or mixtures of agents that are capable of slowing or preventing oxidation of molecules or substances. Representative examples include, but are not limited to, ascorbic acid, butylated hydroxy anisole, butylated hydroxyl toluene, gallic acid, maleic acid, propyl gallate, sodium bisulphate, sodium metabisulphite, tocopherols and mixtures thereof.
The pharmaceutical composition may also comprise preservatives and agents that protect the suspension against microbes (e.g., yeast, mold, bacteria, etc.) and microbial growth. Representative preservatives include, but are not limited to, one or more alkyl hydroxybenzoates, such as methyl hydroxybenzoates, ethyl hydroxybenzoates, propyl hydroxybenzoates, butyl hydroxybenzoates and the like. Additional preservatives useful in the present invention include, but are not limited to, sodium benzoate, potassium sorbate, salts of edetate (also known as salts of ethylenediaminetetraacetic acid, or EDTA, such as disodium edetate) and antimicrobial agents including parabens (p-hydroxybenzoic acids esters) such as methyl paraben, ethylparaben, propylparaben, butylparaben and the like, and combinations thereof. Preservative(s) as used in the composition are in a pharmaceutically acceptable range.
The pharmaceutical composition may also comprise a suspending or viscosity enhancing agent or mixture of agents. Suspending/viscosity enhancing refers to agents or mixtures of agents that increases the viscosity or thickness of the liquid and slowing particle sedimentation. For example, in a suspension these agents help to keep the active substance suspended to allow accurate dosing. Representative suspending agents or viscosity enhancers include but are not limited to, to gums; sorbitol; glycerol; polyvinyl alcohol; polyvinyl pyrrolidone; polyethylene oxide; cellulose derivatives, such as hydroxypropylmethylcellulose or a salt thereof, alkyl ether of cellulose, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellose, hydroxypropylmethylcellulose (e.g. HPMC K4M, HPMC K100 LVP; HPMC K15 MP; HPMC E4 MP; HPMC E10 MP CR) and mixtures thereof. In cases where the suspension is non-aqueous or lipid based, sunflower oil, coconut oil, castor oil and other oil or lipid base agents or mixtures thereof may be preferable.
The pharmaceutical composition may also comprise a dispersing agent(s), which include but are not limited to, colloidal silicon dioxide and surfactants, wherein the surfactant is used alone or as an admixture with one or more surfactant. Combinations of colloidal silicon dioxide with one or more surfactants can also be used and other pharmaceutically accepted dispersing agents.
The pharmaceutical composition may also comprise a buffering agent or pH-stabilizing agent that can maintain a desired pH of the aqueous based suspension. The term “pH stabilizing agent” encompasses buffers, suitable pH stabilizing agents include but not limited to sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, tribasic sodium phosphate, anhydrous sodium carbonate, glycine, citric acid, sodium citrate, sodium tartarate, sodium acetate, sodium polyphosphate, potassium polyphosphate, magnesium oxide, magnesium carbonate, magnesium silicate, calcium salts, lactates, phosphates, tartrates, or mixtures thereof.
Preferably, the pH of the composition is in range of about 2.0 about 8.0. Most preferably the pH of composition is in range from about 4.5 to about 6.5.
The pharmaceutical composition may also comprise wetting agent(s), which refers to a surface active agent or mixture of agents that lowers the interfacial tension between a solid and liquid or liquid and liquid. They help to crate a homogenous dispersion of solid particles in a liquid vehicle and include, but are not limited to acacia, poloxamers, polysorbates such as sorbitan monolaurate, polysorbate 80, and sodium lauryl sulfate and mixtures thereof.
The pharmaceutical composition may also comprise suitable coloring agent(s) both natural and synthetic to provide an appealing color to the pharmaceutical composition, which include, but are not limited to US Food and Drug Administration (FDA) approved coloring agents; FD&C Red No. 3, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Yellow No. 10, titanium dioxide pigments, amaranth carmine, lake colors, iron oxide pigments and mixtures thereof.
The pharmaceutical suspension composition may also comprise suitable antifoaming agents, which include, but are not limited to simethicone emulsion, dimethicone, lutrol and the like.
All these additive(s) can be used at levels well known to the persons skilled in the art. The suspension of teicoplanin can be prepared by a process comprising the steps of (1) dispersing teicoplanin in an aqueous or non aqueous base comprising (a) at least one dispersing agent; (b) at least one buffering agent (in the case of an aqueous base) and (c) at least one suspension vehicle and (2) further milling the suspension to obtain a homogenously dispersed teicoplanin suspension. The suspension may further comprise at least one additive selected from the group comprising sweetening agents, antioxidants, taste enhancing agents, antifoaming agents, coloring agents, wetting agents, thickening agents, preservative or mixtures thereof.
The above-mentioned pharmaceutically acceptable additive(s) are intended to be exemplary, not exhaustive; other additives may also be used in the practice of the disclosed invention. It is further understood that more than one of any particular type of additive may be used in the compositions described herein. For example, the compositions may include more than one flavorant, colorant, etc.
The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure, and the accompanying claims:
EXAMPLES Suspensions—Aqueous Based Example 1 Teicoplanin 20 mg/mL Oral Suspension
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- 1. Calculate the required quantity of each ingredient for the total amount to be prepared.
- 2. Accurately weigh and/or measure each ingredient.
- 3. Prepare the suspension using 2 (two) separate Beakers.
- 4. Beaker 1: levigate teicoplanin (item 1) and colloidal silicon dioxide (item 2) in 30% sorbitol (item 8) (30 ml).
- 5. Beaker 2: Dissolve citric acid (item 3), strawberry flavor (item 5) and FD&C Red #3 (item 4) in purified water (item 7).
- 6. Add Beaker 2 to Beaker 1 while stirring then add propylene glycol (item 6) and stir well.
- 7. Complete to the final volume with sorbitol (item 8) and mix well.
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- 1. Calculate the required quantity of each ingredient for the total amount to be prepared.
- 2. Accurately weigh and/or measure each ingredient.
- 3. Prepare the suspension using 2 (two) separate Beakers.
- 4. Beaker 1: levigate teicoplanin (item 1) and colloidal silicon dioxide (item 2) in 30% sorbitol (item 8) (30 ml).
- 5. Beaker 2: Dissolve sodium Citrate (item 3), strawberry flavor (item 5) and FD&C Red #3 (item 4) in purified water (item 7).
- 6. Add Beaker 2 to Beaker 1 while stirring then add propylene glycol (item 6) and stir well.
- 7. Complete to the final volume with sorbitol (item 8) and mix well.
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- 1. Calculate the required quantity of each ingredient for the total amount to be prepared.
- 2. Accurately weigh and/or measure each ingredient.
- 3. Prepare the suspension using 2 (two) separate Beakers.
- 4. Beaker 1: levigate teicoplanin (item 1) in 30% sorbitol (item 9) (30 ml), then add ethanol (item 7) and stir well.
- 5. Beaker 2: dissolve citric acid (item 3), poloxamer 407 (item 2), strawberry flavor (item 5) and FD&C Red #3 (item 4) in purified water.
- 6. Add Beaker 2 to Beaker 1 while stirring then add propylene glycol (item 6) and stir well.
- 7. Complete to the final volume with sorbitol (item 8) and mix well.
Procedure
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- 1. Calculate the required quantity of each ingredient for the total amount to be prepared.
- 2. Accurately weigh and/or measure each ingredient.
- 3. Prepare the suspension using 2 (two) separate Beakers.
- 4. Beaker 1: levigate teicoplanin (item 1) in 30% sorbitol (item 9) (30 ml), then add ethanol (item 7) and stir well.
- 5. Beaker 2: dissolve sodium citrate (item 3), poloxamer 407 (item 2), strawberry flavor (item 5) and FD&C Red #3 (item 4) in purified water (item 8).
- 6. Add Beaker 2 to Beaker 1 while stirring then add propylene glycol (item 6) and stir well.
- 7. Complete to the final volume with sorbitol (item 9) and mix well.
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- 1. Heat the sunflower oil (item 1) to 45° C. in the 200 ml beaker.
- 2. Add the butyl paraben (item 2) and the alpha tocopherol (item 3). Stir vigorously until complete dispersion.
- 3. To the previously obtained mixture add the colloidal silicon dioxide (item 4), again stirring vigorously, keeping the temperature at 45° C.
- 4. Add the sodium saccharin (item 5) and sodium chloride (item 6) and again stir vigorously until complete dispersion.
- 5. Allow cooling to room temperature, stirring continuously.
- 6. Add the raspberry flavor (item 7), stir to complete dispersion and then add teicoplanin (item 8) again stirring to complete dispersion.
- 7. Pass mixture through colloidal mill.
- 8. Transfer to the 100 ml lidded graduated cylinder.
- 9. To the previously obtained mixture, add the fractionated coconut oil (item 10) up to 100 ml.
- 10. Shake until a homogenous mixture is obtained.
For the purposes of promoting an understanding of the principles of the invention, reference has been made to the preferred embodiments illustrated in the drawings, and specific language has been used to describe these embodiments. However, this specific language intends no limitation of the scope of the invention, and the invention should be construed to encompass all embodiments that would normally occur to one of ordinary skill in the art. The particular implementations shown and described herein are illustrative examples of the invention and are not intended to otherwise limit the scope of the invention in any way. For the sake of brevity, conventional aspects of the method (and components of the individual operating components of the method) may not be described in detail. Furthermore, the connecting lines, or connectors shown in the various figures presented are intended to represent exemplary functional relationships and/or physical or logical couplings between the various elements. It should be noted that many alternative or additional functional relationships, physical connections or logical connections might be present in a practical device. Moreover, no item or component is essential to the practice of the invention unless the element is specifically described as “essential” or “critical”. Numerous modifications and adaptations will be readily apparent to those skilled in this art without departing from the spirit and scope of the present invention.
Claims
1. A suspension comprising: (1) teicoplanin dispersed in an aqueous base; (2) at least one dispersing agent selected from the group comprising colloidal silicon dioxide, polyoxamer 407 or combinations thereof, (3) at least one buffering agent selected from the group comprising sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, tribasic sodium phosphate, anhydrous sodium carbonate, glycine, citric acid, sodium citrate, sodium tartarate, sodium acetate, sodium polyphosphate, potassium polyphosphate, magnesium oxide, magnesium carbonate, magnesium silicate, calcium salts, lactates, phosphates, tartrates or combinations thereof, and (4) at least one suspension vehicle selected from the group comprising sorbitol, glycerol polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellose, hydroxypropylmethylcellulose or combinations thereof.
2. The suspension of claim 1 further comprising at least one additive selected from the group comprising sorbitol, sucrose, sodium saccharin, sodium cyclamate, aspartame, sucralose, thaumatin, acesulfam K, stevioside, monosaccharides, disaccharides, polysaccharides xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch, corn syrup, sorbitol, xylitol, mannitol, glycerin, synthetic flavor oil, aromatic plant extract, sunflower oil, coconut oil or combinations thereof.
3. The suspension of claim 1 wherein the pH of the suspension is from about 2 to about 8.
4. The suspension of claim 1 wherein the viscosity of the suspension is from about 20 Cps to about 500 Cps.
5. The suspension of claim 1 wherein the d90 of teicoplanin is less than about 170 μm.
6. A suspension comprising: (1) teicoplanin dispersed in a non aqueous base; (2) at least one dispersing agent selected from the group comprising colloidal silicon dioxide, polyoxamer 407 or combinations thereof; and (3) at least one suspension vehicle selected from the group comprising sorbitol, glycerol, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellose, hydroxypropylmethylcellulose or combinations thereof.
7. The suspension of claim 6 further comprising at least one additive selected from the group comprising sorbitol, sucrose, sodium saccharin, sodium cyclamate, aspartame, sucralose, thaumatin, acesulfam K, stevioside, monosaccharides, disaccharides, polysaccharides xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch, corn syrup, sorbitol, xylitol, mannitol, glycerin, synthetic flavor oil, aromatic plant extract, sunflower oil, coconut oil or combinations thereof.
8. The suspension of claim 6 wherein the pH of the suspension is from about 2 to about 8.
9. The suspension of claim 6 wherein the viscosity of the suspension is from about 500 Cps to about 1500 Cps.
10. The suspension of claim 6 wherein the d90 of teicoplanin is less than about 170 μm.
11. A method for preparing a stable, taste-masked, ready-to-use suspension of teicoplanin wherein the said process comprises the steps of (1) dispersing teicoplanin in an aqueous base comprising (a) at least one dispersing agent selected from the group comprising colloidal silicon dioxide, polyoxamer 407 or combinations thereof, (b) at least one buffering agent selected from the group comprising sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, tribasic sodium phosphate, anhydrous sodium carbonate, glycine, citric acid, sodium citrate, sodium tartarate, sodium acetate, sodium polyphosphate, potassium polyphosphate, magnesium oxide, magnesium carbonate, magnesium silicate, calcium salts, lactates, phosphates, tartrates, or combinations thereof, and (c) at least one suspension vehicle selected from the group comprising sorbitol, glycerol polyvinyl alcohol polyvinyl pyrrolidone, polyethylene oxide, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellose, hydroxypropylmethylcellulose or combinations thereof; and (2) further milling the suspension to obtain a homogenously dispersed teicoplanin suspension.
12. The method of claim 11 wherein the suspension further comprises at least one additive selected from the group comprising sorbitol, sucrose, sodium saccharin, sodium cyclamate, aspartame, sucralose, thaumatin, acesulfam K, stevioside, monosaccharides, disaccharides, polysaccharides xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch, corn syrup, sorbitol, xylitol, mannitol, glycerin, synthetic flavor oil, aromatic plant extract, sunflower oil, coconut oil or combinations thereof.
13. The method of claim 11 wherein the pH of the suspension is from about 2 to about 8.
14. The method of claim 11 wherein the viscosity of the suspension is from about 20 Cps to about 500 Cps.
15. The method of claim 11 wherein the d90 of teicoplanin is less than about 170 μm.
16. A method for preparing a stable, taste-masked, ready-to-use suspension of teicoplanin wherein the said process comprises the steps of (1) dispersing teicoplanin in a non aqueous base comprising at least one dispersing agent selected from the group comprising colloidal silicon dioxide, polyoxamer 407 or combinations thereof and (2) further milling the suspension to obtain a homogenously dispersed teicoplanin suspension.
17. The method of claim 16 wherein the suspension further comprises at least one additive selected from the group comprising sorbitol, sucrose, sodium saccharin, sodium cyclamate, aspartame, sucralose, thaumatin, acesulfam K, stevioside, monosaccharides, disaccharides, polysaccharides xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch, corn syrup, sorbitol, xylitol, mannitol, glycerin, synthetic flavor oil, aromatic plant extract, sunflower oil, coconut oil or combinations thereof.
18. The method of claim 16 wherein the pH of the suspension is from about 2 to about 8.
19. The method of claim 16 wherein the viscosity of the suspension is from about 500 Cps to about 1500 Cps.
20. The method of claim 16 wherein the d90 of teicoplanin is less than about 170 μm.
Type: Application
Filed: Dec 3, 2015
Publication Date: Mar 9, 2017
Inventor: Illya Keith Maher (Great Neck, NY)
Application Number: 14/957,810
