WO2022234036A1 - Oral liquid vancomycin formulations - Google Patents

Oral liquid vancomycin formulations Download PDF

Info

Publication number
WO2022234036A1
WO2022234036A1 PCT/EP2022/062191 EP2022062191W WO2022234036A1 WO 2022234036 A1 WO2022234036 A1 WO 2022234036A1 EP 2022062191 W EP2022062191 W EP 2022062191W WO 2022234036 A1 WO2022234036 A1 WO 2022234036A1
Authority
WO
WIPO (PCT)
Prior art keywords
oral liquid
dosage form
unit dosage
liquid unit
vancomycin
Prior art date
Application number
PCT/EP2022/062191
Other languages
French (fr)
Inventor
Ivona JASPRICA
Anita BEVETEK MOCNIK
Katarina ALILOVIC
Jurica CEBIN
Gabrijela ERGOVIC
Lidija HERCEG HARJACEK
Jerome LE CUNFF
Original Assignee
Xellia Pharmaceuticals Aps
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xellia Pharmaceuticals Aps filed Critical Xellia Pharmaceuticals Aps
Publication of WO2022234036A1 publication Critical patent/WO2022234036A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Definitions

  • the present disclosure is related to taste masked oral liquid vancomycin formulations.
  • Vancomycin is a tricyclic glycopeptide antibiotic derived from Amycolatopsis orientalis (formerly Nocardia orientalis) . Vancomycin hydrochloride is indicated for the treatment of serious or severe infections caused by susceptible strains of methicillin-resistant (beta-lactam-resistant) staphylococci. Vancomycin oral solutions are indicated for use to treat enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) and antibiotic- associated pseudomembranous colitis caused by Clostridium difficile. [0003] As evidenced by U.S. Patent No.
  • antibiotics typically have an unpleasant and/or bitter taste which is usually masked by sweeteners such as sugar sweeteners and sucralose and flavoring agents such as fruit flavors, mint flavors and bubblegum flavors.
  • the commercially available FIRVANQ® oral vancomycin product for example, includes vancomycin powder in one bottle and a grape- flavored diluent in a second bottle. The vancomycin powder must be reconstituted in the grape-flavored diluent prior to administration.
  • vancomycin hydrochloride is known to have limited stability in aqueous solution.
  • amino acid derivatives such as N- acetyl-glycine and N-acetyl-D-alanine stabilize glycopeptide antibiotics such as vancomycin at low concentrations in aqueous solutions for injection.
  • a ready to use oral liquid dosage form comprising
  • a ready to use oral liquid unit dosage form comprises, consists essentially of, or consists of: 1.5 to 7.5 % w/V vancomycin or a salt thereof,
  • a polyethylene glycol optionally a pH adjusting agent, optionally a preservative, and water
  • the molar ratio of vancomycin to N-acetyl-D-alanine is 1:2 to 1: 44
  • the molar ratio of vancomycin to amino acid is 1 :0.5 to 1:40
  • the oral liquid unit dosage form has a pH of 3.8 to 4.4
  • the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
  • a ready to use oral liquid unit dosage form comprises, consists of, or consists essentially of:
  • a ready to use oral liquid unit dosage form comprises, consists essentially of, or consists of
  • a polyethylene glycol optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to amino acid is 1:0.5 to 1:40, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
  • the ready to use oral liquid unit dosage form is in a single-use container.
  • a method of improving patient compliance comprises administering to a patient in need thereof the ready to use oral liquid unit dosage forms described herein.
  • a method of improving palatability of a vancomycin oral liquid dosage form in the absence of added sweeteners and flavoring agents comprises combining N-acetyl-D-alanine with the vancomycin, wherein the molar ratio of vancomycin to N-acetyl-D-alanine is 1:2 to 1:44.
  • a method of improving palatability of a vancomycin oral liquid dosage form in the absence of added sweeteners and flavoring agents comprises combining an amino acid and polyethylene glycol with the vancomycin, wherein the molar ratio of vancomycin to amino acid is 1 :0.5 to 1:40, and wherein the polyethylene glycol is in an amount of 0.0, 0.1, 0.5 or 1.0 to 15% w/V.
  • oral liquid unit dosage forms described herein for use as a medicament improving compliance in patient in need of vancomycin administration.
  • the oral liquid unit dosage forms described herein for use as a medicament in treatment of antimicrobial infection.
  • Figure 1 shows a taste map based on principal component analysis (PC A) of samples for EXAMPLE 1.
  • Figure 2 shows the distance between formulations for EXAMPLE 1.
  • Figure 3 shows a taste map based on principal component analysis (PC A) of samples for EXAMPLE 2.
  • Figure 4 shows the distance between formulations for EXAMPLE 2.
  • Taste is a crucial factor that determines both the palatability of oral dosage forms and patient compliance.
  • Pediatric and geriatric populations are the most sensitive to the bad taste of medicaments.
  • Taste-masking is defined as a perceived reduction of an unpleasant taste that would otherwise exist in a formulation.
  • vancomycin has an unpleasant taste which is typically masked by strong flavoring agents. It would be advantageous to provide stable, oral liquid vancomycin formulations, particularly ready to use oral liquid unit dosage forms, that do not require added sweeteners or flavoring agents.
  • N-acetyl-D- alanine and/or an amino acid and optionally polyethylene glycol to a vancomycin oral liquid formulation effectively masks the unpleasant taste of vancomycin.
  • Schiffmann et al. (“Taste of Acetylated Amino Acids”, Chemical Senses and Flavor 1, pp. 387-401, 1975) concluded that, when compared to their amino acid counterparts, the N-acetylated amino acids have different taste properties.
  • alanine has a sweet taste
  • both the D- and L- acetylated forms of alanine were disclosed to have a sour taste.
  • N-acetyl-D-alanine for example, to effectively mask the unpleasant taste of vancomycin.
  • a ready to use oral liquid unit dosage form comprises, consists of, or consists essentially of: 1.5 to 7.5 % w/V vancomycin or a salt thereof,
  • a polyethylene glycol optionally a pH adjusting agent, optionally a preservative, and water
  • the molar ratio of vancomycin to N-acetyl-D-alanine is 1:2 to 1: 44
  • the molar ratio of vancomycin to amino acid is 1 :0.5 to 1:40
  • the oral liquid unit dosage form has a pH of 3.8 to 4.4
  • the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
  • N-acetyl-D-alanine an amino acid and polyethylene glycol
  • either N-acetyl-D-alanine or an amino acid and polyethylene glycol also taste-masked vancomycin compared to a control containing only vancomycin and water.
  • a ready to use oral liquid unit dosage form comprises, consists of, or consists essentially of:
  • a ready to use oral liquid unit dosage form comprises, consist essentially of, or consists of
  • a polyethylene glycol optionally a pH adjusting agent, optionally a preservative, and water
  • the molar ratio of vancomycin to amino acid is 1 :0.5 to 1:40
  • the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
  • a ready to use oral liquid unit dosage form is a single unit dose in the form marketed for use, that is, an oral liquid dosage form meant for oral administration without dilution or the addition of any component not found in the oral liquid unit dosage form.
  • a ready to use oral liquid unit dosage form is to be administered completely at one time, not divided up into multiple administrations.
  • a ready to use oral liquid unit dosage form may be in a single use container, specifically a non-reusable container.
  • An exemplary non-reusable container is a sealed plastic cup, wherein removal of the seal allows a patient to consume the entire contents of the cup.
  • Other containers include plastic blow fill sealed pouches, sealed ampoules, or any other non-reusable container known in the art.
  • Vancomycin is a tricyclic glycopeptide antibiotic. Its structure is represented in Formula 1. Its purity in the formulation can be assessed by the content of Vancomycin B.
  • Vancomycin as used herein means the compound represented in Formula 1 and also pharmaceutically acceptable salts thereof, for example vancomycin hydrochloride.
  • the vancomycin or a salt thereof in the oral liquid unit dosage form is present in an amount of 1.5 to 7.5 % w/V, specifically 3.0 to 6.0 % w/V, and most specifically 5.0% w/V.
  • N-acetyl-D-Alanine or NAD A is a compound represented by the following structure: or the compound as indicated by the CAS registry number: 19436-52-3. It can exist as an acid or in deprotonated form.
  • N-acetyl-D-Alanine is also meant to cover any salt thereof, especially pharmaceutically acceptable salts.
  • the N-acetyl-D-Alanine in the oral liquid unit dosage form is present in an amount of 1.4 to 6.0 % w/V, specifically 3.0-6.0 % w/V, more specifically 3.0 to 5.0 %w/V and most specifically about 4.5 % w/V.
  • the N-acetyl-D-Alanine in the oral liquid unit dosage form is present in an amount of 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 or 6.0 %w/V.
  • the molar ratio of vancomycin to N-acetyl-D-alanine is 1:2 to 1:44, specifically 1:4 to 1:20, more specifically 1: 10 to 1:15, and most specifically 1:10. In an aspect, the molar ratio of vancomycin to N-acetyl-D-alanine is 1 :4, 1 :5,
  • amino acid means any amino acid, including, but not limited to the 20 amino acids naturally occurring in peptides in both D and L-form and is also meant to cover any salt thereof, especially pharmaceutically acceptable salts.
  • amino acid includes alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine and ornithine, and any conformations thereof.
  • amino acid includes L-alanine, L-arginine, L-asparagine, L- aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-Phenylalanine, L-Proline, L-Serine, L- Threonine, L-Tryptophan, L-Tyrosine, L-Valine and L-Ornithine.
  • D-Alanine, D-Arginine, D-Asparagine, D-Aspartic acid D-
  • Cysteine D-Glutamic acid, D-Glutamine, D-Histidine, D-Isoleucine, D-Leucine, D- Lysine, D-Methionine, D-Phenylalanine, D-Proline, D-Serine, D-Threonine, D- Tryptophan, D-Tyrosine, D-Valine and D-Ornithine.
  • the amino acid comprises arginine, lysine, histidine, or a combination thereof.
  • the amino acid is L-lysine hydrochloride.
  • the amino acid or a salt thereof in the oral liquid unit dosage form is present in an amount of 0.4 to 6.0 % w/V, specifically 1.0 to 4.0 % w/V, more specifically 0.4 to 2.0 % w/V and most specifically 1.0 % w/V.
  • the amino acid or a salt thereof in the oral liquid unit dosage form is present in an amount of 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8 or 6.0 % w/V.
  • the molar ratio of vancomycin to amino acid is 1 :0.5 to 1:40, specifically 1 :1 to 1:10, more specifically 1: 1 to 1:8, and most specifically 1:1, 1:2, 1:3, 1:4, 1 :5, 1 :6, 1:7, 1:8, 1:9 or 1:10.
  • the oral liquid unit dosage form comprises a polyethylene glycol, such as PEG400.
  • the polyethylene glycol comprises 0.0, 0.1, 0.5 or 1.0 to 15.0 % w/V, specifically 9.0 tol5.0 % w/V, and more specifically 11.3% w/V of the oral liquid unit dosage form.
  • pH is a measurement unit of hydrogen ion activity in a solution at 25°C unless another temperature is specified.
  • the oral liquid unit dosage form has a pH of 3.8 to 4.4, specifically 4.05-4.15, or more specifically 4.1.
  • the oral liquid unit dosage form comprises an optional pH adjusting agent.
  • the pH of the oral liquid formulations can be adjusted by addition of aqueous hydrochloric acid solutions or aqueous sodium hydroxide solutions.
  • Exemplary pH adjusting agents include, but are not limited to, 0.01 M HC1, 0.1 M HC1, 1 M HC1, 2 M HC1, 3 M HC1, 4 M HC1, 5 M HC1, 6 M HC1, 0.01 M NaOH, 0.1 M NaOH, 1 M NaOH, 2 M NaOH, 3 M NaOH, 4 M NaOH, 5 M NaOH and 6 M NaOH.
  • Exemplary pH adjusting agents include, but are not limited to, 0.01-6 M HC1 and 0.01-6 M NaOH.
  • the oral liquid unit dosage form optionally comprises a preservative such as potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride.
  • a preservative such as potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride.
  • said preservative is potassium sorbate.
  • the preservative can be present in an amount of 0.002 to 0.3 %w/V. Exemplary amounts include 0.2 % w/V potassium sorbate, 0.02% w/V sodium benzoate, 0.16% w/V sodium propionate, 0.00725 % w/V benzethonium chloride, and 0.0125 % w/V benzalkonium chloride.
  • the amount is in the range of 0.01 to 0.2 %w/V, specifically 0.05 to 0.2 %w/V and more specifically 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 and 0.2 %w/V.
  • the oral liquid unit dosage form comprises an antioxidant.
  • the antioxidant to choose for an oral product will be well known for the skilled person in the art.
  • the balance of the ready to use oral liquid unit dosage form is water.
  • sweetener includes natural and artificial sweeteners. Artificial sweeteners include sucralose, saccharin, acesulfame, aspartame, and neotame.
  • Sugar sweeteners include monosaccharides, di saccharides and polysaccharides such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch (such as maltitol syrup) or corn syrup solids and sugar alcohols such as sorbitol, xylitol, mannitol, erythritol, isomalt, lactitol, glycerin and the like.
  • monosaccharides such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch (such as maltitol syrup) or corn syrup solids and sugar alcohols such as sorbitol, xylitol, mannitol, erythritol, isomalt, lactitol,
  • flavoring agent means an agent used to improve the taste and palatability of pharmaceutical formulations.
  • Flavoring agents include natural flavors, natural fruit flavors, artificial flavors, artificial fruit flavors, flavor enhancers, and the like.
  • Exemplary flavors include mint (such as peppermint or spearmint), menthol, cinnamon, vanilla, artificial vanilla, chocolate, artificial chocolate, bubblegum, and the like.
  • Fruit flavors include cherry, mixed berry, grape, orange, strawberry, lemon and the like.
  • a preservative selected from potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride, and water, wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
  • Another specific ready to use oral liquid unit dosage form comprises, consists essentially of, or consists of
  • a preservative selected from potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride, and water, wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
  • the molar ratio of vancomycin to L-Lysine hydrochloride to N-acetyl-D-alanine is 1:8:13.
  • Another specific ready to use oral liquid unit dosage form comprises, consists essentially of, or consists of
  • a preservative selected from potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride, and water, wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
  • the molar ratio of vancomycin to L-Lysine hydrochloride to N-acetyl-D-alanine is 1:8:13.
  • Also included herein is a method of improving patient compliance, comprising administering to a patient in need thereof the ready to use oral liquid unit dosage forms described herein.
  • the patient is in need of treatment for enterocolitis caused by Staphylococcus aureus or antibiotic-associated pseudomembranous colitis caused by Clostridium difficile.
  • the patient is a pediatric or geriatric patient.
  • a method of improving palatability of a vancomycin oral liquid dosage form the absence of added sweeteners and flavoring agents comprises combining N-acetyl-D-alanine with the vancomycin, wherein the ratio of vancomycin to N-acetyl-D-alanine is 1 :2 to 1 :44.
  • the vancomycin is present at 1.5 to7.5 % % w/V, specifically 3.0 to 6.0 % w/V, and most specifically 5.0% w/V.
  • the N-acetyl-D-alanine is present in an amount of 1.4 to 6.0 % w/V, specifically 3.0-6.0 % w/V, more specifically 3.0 to 5.0 %w/V and most specifically about 4.52 % w/V.
  • the oral liquid formulation is in the form of a ready to use oral liquid dosage form.
  • a method of improving palatability of a vancomycin oral liquid dosage form the absence of added sweeteners and flavoring agents comprises combining an amino acid and polyethylene glycol with the vancomycin, wherein the molar ratio of vancomycin to amino acid is 1:0.5 to 1 :40, and wherein the polyethylene glycol is in an amount of 0.0, 0.1, 0.5 or 1.0 to 15.0% w/V.
  • the vancomycin is present at 1.5-7.5 % w/V, specifically 3.0 to 6.0 % w/V, and most specifically 5.0% w/V.
  • the amino acid is present in an amount of 0.4 to 6.0 % w/V, specifically 0.4 to 2.0 % w/V and most specifically 1.0 % w/V
  • the polyethylene glycol is present in an amount of 0.0, 0.1, 0.5 or 1.0 to 15 % w/V, specifically 9.0-15.0 % w/V, and more specifically 11.3% w/V.
  • the taste perception of the oral liquid formulations and oral liquid unit dosage forms may be assessed by electronic taste sensing based on ChemFET liquid sensors and conductivity measurements such as by the Astree® electronic tongue (e-tongue).
  • the e-tongue measures and maps the relative repartition and proximity of the taste between an oral liquid formulation according to the present disclosure and various controls.
  • Controls can include an undiluted reconstituted injection formulation (that is, vancomycin in water which is a formulation with no taste- masking additives), a reconstituted injection formulation containing a flavoring agent such as a SyrSpend® SF PH4 cherry, and a flavoring agent such as a SyrSpend® SF PH4 cherry with no active agent (also referred to as a “blank” control).
  • a flavoring agent such as a SyrSpend® SF PH4 cherry
  • a flavoring agent such as a SyrSpend® SF PH4 cherry with no active agent
  • the e-tongue measurements are analyzed by principal component analysis (PCA). It is assumed that the control containing a flavoring agent represents the ideal “target” taste profile, since the unpleasant tasting active component is not present or is taste masked. Therefore, taste proximity is quantified using the Euclidean distance between the active, e.g.
  • the discrimination index takes into account the difference between the center of gravity of the sensors output for each pair of formulations as well as the dispersion within the sensors output for the formulations. The higher the value of discrimination index (closer to 100%), the less similarity between the formulations flavors and less taste masking occurred.
  • the oral liquid unit dosage form has a discrimination index of at least 50%, 60%, 70%, 80% or 90% compared to a control containing only vancomycin and water.
  • Vancomycin liquid formulation 1 Vancomycin liquid formulation 1 :
  • Formulation 1 was made by adding vancomycin into water and then adding N-acetyl-D-alanine into the solution and mix until fully dissolved. L-Lysine and polyethylene glycol were added. Solution was mixed until L-Lysine and polyethylene glycol were fully dissolved. pH was adjusted using NaOH and the volume was filled up with water to reach the targeted concentrations.
  • the assays were realized on an Astree® e-tongue system equipped with an Alpha MOS sensor set #2 composed of 7 specific sensors (ZZ, AB, GA, BB, CA, DA, JE) on a 16-position autosampler using 100 ml-beakers. Acquisition times were fixed at 120s for sample tests and 20s for the cleaning solutions. The data processing was carried out with the software Alphasoft VI 2.4.
  • This indicator takes into account the average difference between the pairs to compare, as well as the dispersion of each sample. The closer the index to 100%, the higher the distance between the centers of gravity and the smaller the dispersion within groups. The DI will help then to assess the significance of difference between the groups.
  • the assays were realized on an Astree® e-tongue system equipped with an Alpha MOS sensor set #2 composed of 7 specific sensors (ZZ, AB, GA, BB, CA, DA, JE) on a 16-positions autosampler using 100 ml-beakers. Acquisition times were fixed at 120s for sample tests and 20s for the cleaning solutions. The data processing was carried out with the software Alphasoft VI 2.4.
  • the second principal component depicts clear separation between mainly two groups of samples, which are also clearly separated from sample l l : group 1: sample Ol and sample_07 (Vanco/NADA/lysine/PEG and Vanco/NADA); group 2: sample_08 and sample_14 (Vanco/lysine/PEG and Blank solution SyrSpend®). Samples in these two groups could be also distinguished by the e-tongue , but they were found the most similar. [0079] The Euclidian distances between control (sample l l : Vanco reference) and formulations (sample Ol, sample_07, sample_08) were calculated to assess taste proximity between samples: the lower the distance, the closer the taste.
  • DI in % a Discrimination Index (DI in %) was determined for each formulation. This indicator takes into account the average difference between the pairs to compare, as well as the dispersion of each sample. The closer the index to 100%, the higher the distance between the centers of gravity and the smaller the dispersion within groups. The DI will help then to assess the significance of difference between the groups.
  • the differences between the different formulations and sample l l (Vanco reference- reconstituted (50 mg/mL) w/o further dilution) are significant (DI>94%) ( Figure 4).
  • the biggest distance against sample l 1 was found for sample_14 (Blank solution of SyrSpend® SF PH4 cherry flavored syrup), which is in a good agreement with Example 1.
  • the smallest distance against sample l 1 was found for sample_01 (Vanco/NADA/lysine/PEG), which followed by sample_08
  • % w/V as used herein is defined as the number of grams of an ingredient, referred to percentage by volume of solute in 100ml of solution.
  • “About” or “approximately” as used herein is inclusive of the stated value and means within an acceptable range of deviation for the particular value as determined by one of ordinary skill in the art, considering the measurement in question and the error associated with measurement of the particular quantity (i.e., the limitations of the measurement system). For example, “about” can mean within one or more standard deviations, or within ⁇ 10% or 5% of the stated value. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Described herein are ready to use oral liquid unit dosage forms including vancomycin or a salt thereof, N-acetyl-D-alanine, and/or an amino acid and a polyethylene glycol, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to N-acetyl-D-alanine is 1 :2 to 1 : 44, wherein the molar ratio of vancomycin to amino acid is 1 :0.5 to 1 :26, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4 and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent. Also included are method of improving patient compliance and methods of taste masking vancomycin oral liquid formulations.

Description

ORAL LIQUID VANCOMYCIN FORMULATIONS
FIELD OF THE DISCLOSURE
[0001] The present disclosure is related to taste masked oral liquid vancomycin formulations.
BACKGROUND
[0002] Vancomycin is a tricyclic glycopeptide antibiotic derived from Amycolatopsis orientalis (formerly Nocardia orientalis) . Vancomycin hydrochloride is indicated for the treatment of serious or severe infections caused by susceptible strains of methicillin-resistant (beta-lactam-resistant) staphylococci. Vancomycin oral solutions are indicated for use to treat enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) and antibiotic- associated pseudomembranous colitis caused by Clostridium difficile. [0003] As evidenced by U.S. Patent No. 6,806,256, antibiotics typically have an unpleasant and/or bitter taste which is usually masked by sweeteners such as sugar sweeteners and sucralose and flavoring agents such as fruit flavors, mint flavors and bubblegum flavors. The commercially available FIRVANQ® oral vancomycin product, for example, includes vancomycin powder in one bottle and a grape- flavored diluent in a second bottle. The vancomycin powder must be reconstituted in the grape-flavored diluent prior to administration.
[0004] Another issue with oral liquid vancomycin products, for example, is that vancomycin hydrochloride is known to have limited stability in aqueous solution.
As disclosed in U.S. Patent No. 10,039,804, amino acid derivatives such as N- acetyl-glycine and N-acetyl-D-alanine stabilize glycopeptide antibiotics such as vancomycin at low concentrations in aqueous solutions for injection.
[0005] What is needed are improved ready to use oral liquid vancomycin products.
SUMMARY OF INVENTION [0006] In an aspect, a ready to use oral liquid dosage form, comprising
1.5 to 7.5% w/V vancomycin or a salt thereof,
0.4 to 6.0 % w/V of at least either N-acetyl-D-alanine or an amino acid, optionally 0.0, 0.1, 0.5 or 1.0 to 15 % w/V of a polyethylene glycol, optionally a pH adjusting agent, optionally a preservative, and water, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
[0007] In an aspect, a ready to use oral liquid unit dosage form comprises, consists essentially of, or consists of: 1.5 to 7.5 % w/V vancomycin or a salt thereof,
1.4 to 6.0 % w/V N-acetyl-D-alanine,
0.4 to 6.0 % w/V of an amino acid or a salt thereof,
0.0, 0.1, 0.5 or 1.0 to - 15.0 % w/V of a polyethylene glycol, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to N-acetyl-D-alanine is 1:2 to 1: 44, wherein the molar ratio of vancomycin to amino acid is 1 :0.5 to 1:40, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
[0008] In another aspect, a ready to use oral liquid unit dosage form comprises, consists of, or consists essentially of:
1.5 to 7.5 % w/V vancomycin or a salt thereof, 1.4 to 6.0 % w/V N-acetyl-D-alanine, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to N-acetyl-D-alanine is 1 :2 to 1 : 44, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent. [0009] In a further aspect, a ready to use oral liquid unit dosage form comprises, consists essentially of, or consists of
1.5 to 7.5 % w/V vancomycin or a salt thereof,
0.4 to 6.0 % w/V of an amino acid or a salt thereof,
0.0, 0.1, 0.5 or 1.0 to 15.0 % w/V of a polyethylene glycol, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to amino acid is 1:0.5 to 1:40, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
[0010] In one aspect, the ready to use oral liquid unit dosage form is in a single-use container.
[0011] In a further aspect, a method of improving patient compliance comprises administering to a patient in need thereof the ready to use oral liquid unit dosage forms described herein.
[0012] In a still further aspect, a method of improving palatability of a vancomycin oral liquid dosage form in the absence of added sweeteners and flavoring agents comprises combining N-acetyl-D-alanine with the vancomycin, wherein the molar ratio of vancomycin to N-acetyl-D-alanine is 1:2 to 1:44.
[0013] In another aspect, a method of improving palatability of a vancomycin oral liquid dosage form in the absence of added sweeteners and flavoring agents comprises combining an amino acid and polyethylene glycol with the vancomycin, wherein the molar ratio of vancomycin to amino acid is 1 :0.5 to 1:40, and wherein the polyethylene glycol is in an amount of 0.0, 0.1, 0.5 or 1.0 to 15% w/V.
[0014] In another aspect, the oral liquid unit dosage forms described herein for use as a medicament improving compliance in patient in need of vancomycin administration.
[0015] In another aspect, the oral liquid unit dosage forms described herein for use as a medicament in treatment of antimicrobial infection. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 shows a taste map based on principal component analysis (PC A) of samples for EXAMPLE 1.
[0017] Figure 2 shows the distance between formulations for EXAMPLE 1.
[0018] Figure 3 shows a taste map based on principal component analysis (PC A) of samples for EXAMPLE 2.
[0019] Figure 4 shows the distance between formulations for EXAMPLE 2.
[0020] The above-described and other features will be appreciated and understood by those skilled in the art from the following detailed description, drawings, and appended claims.
DETAILED DESCRIPTION
[0021] Taste is a crucial factor that determines both the palatability of oral dosage forms and patient compliance. Pediatric and geriatric populations are the most sensitive to the bad taste of medicaments. Taste-masking is defined as a perceived reduction of an unpleasant taste that would otherwise exist in a formulation. As is known in the art, vancomycin has an unpleasant taste which is typically masked by strong flavoring agents. It would be advantageous to provide stable, oral liquid vancomycin formulations, particularly ready to use oral liquid unit dosage forms, that do not require added sweeteners or flavoring agents.
[0022] The inventors have unexpectedly found that the addition of N-acetyl-D- alanine and/or an amino acid and optionally polyethylene glycol to a vancomycin oral liquid formulation effectively masks the unpleasant taste of vancomycin. This result is particularly surprising as Schiffmann et al. (“Taste of Acetylated Amino Acids”, Chemical Senses and Flavor 1, pp. 387-401, 1975) concluded that, when compared to their amino acid counterparts, the N-acetylated amino acids have different taste properties. Of particular relevance, while alanine has a sweet taste, both the D- and L- acetylated forms of alanine were disclosed to have a sour taste. Thus, one would not expect N-acetyl-D-alanine, for example, to effectively mask the unpleasant taste of vancomycin.
[0023] In an aspect, a ready to use oral liquid unit dosage form comprises, consists of, or consists essentially of: 1.5 to 7.5 % w/V vancomycin or a salt thereof,
1.4 to 6.0 % w/V N-acetyl-D-alanine,
0.4 to 6.0 % w/V of an amino acid or a salt thereof,
0.0, 0.1, 0.5 or 1.0 to 15.0 % w/V of a polyethylene glycol, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to N-acetyl-D-alanine is 1:2 to 1: 44, wherein the molar ratio of vancomycin to amino acid is 1 :0.5 to 1:40, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
[0024] In further experiments as described herein, in addition to the combination of N- acetyl-D-alanine, an amino acid and polyethylene glycol, either N-acetyl-D-alanine or an amino acid and polyethylene glycol also taste-masked vancomycin compared to a control containing only vancomycin and water.
[0025] In another aspect, a ready to use oral liquid unit dosage form comprises, consists of, or consists essentially of:
1.5 to 7.5 % w/V vancomycin or a salt thereof,
1.4 to 6.0 % w/V N-acetyl-D-alanine, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to N-acetyl-D-alanine is 1 :2 to 1 : 44, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
[0026] In a further aspect, a ready to use oral liquid unit dosage form comprises, consist essentially of, or consists of
1.5 to 7.5 % w/V vancomycin or a salt thereof,
0.4 to 6.0 % w/V of an amino acid or a salt thereof,
0.1, 0.5 or 1.0 to 15.0 % w/V of a polyethylene glycol, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to amino acid is 1 :0.5 to 1:40, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
[0027] As used herein, a ready to use oral liquid unit dosage form is a single unit dose in the form marketed for use, that is, an oral liquid dosage form meant for oral administration without dilution or the addition of any component not found in the oral liquid unit dosage form. A ready to use oral liquid unit dosage form is to be administered completely at one time, not divided up into multiple administrations. A ready to use oral liquid unit dosage form may be in a single use container, specifically a non-reusable container. An exemplary non-reusable container is a sealed plastic cup, wherein removal of the seal allows a patient to consume the entire contents of the cup. Other containers include plastic blow fill sealed pouches, sealed ampoules, or any other non-reusable container known in the art.
[0028] Vancomycin is a tricyclic glycopeptide antibiotic. Its structure is represented in Formula 1. Its purity in the formulation can be assessed by the content of Vancomycin B.
Figure imgf000007_0001
Formula 1. [0029] “Vancomycin” as used herein means the compound represented in Formula 1 and also pharmaceutically acceptable salts thereof, for example vancomycin hydrochloride.
[0030] In an aspect, the vancomycin or a salt thereof in the oral liquid unit dosage form is present in an amount of 1.5 to 7.5 % w/V, specifically 3.0 to 6.0 % w/V, and most specifically 5.0% w/V.
[0031] “N-acetyl-D-Alanine” or NAD A is a compound represented by the following structure:
Figure imgf000008_0001
or the compound as indicated by the CAS registry number: 19436-52-3. It can exist as an acid or in deprotonated form. The term “N-acetyl-D-Alanine” is also meant to cover any salt thereof, especially pharmaceutically acceptable salts.
[0032] When present, the N-acetyl-D-Alanine in the oral liquid unit dosage form is present in an amount of 1.4 to 6.0 % w/V, specifically 3.0-6.0 % w/V, more specifically 3.0 to 5.0 %w/V and most specifically about 4.5 % w/V. When present, the N-acetyl-D-Alanine in the oral liquid unit dosage form is present in an amount of 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 or 6.0 %w/V.
[0033] In an aspect, the molar ratio of vancomycin to N-acetyl-D-alanine is 1:2 to 1:44, specifically 1:4 to 1:20, more specifically 1: 10 to 1:15, and most specifically 1:10. In an aspect, the molar ratio of vancomycin to N-acetyl-D-alanine is 1 :4, 1 :5,
1:6, 1:7, 1 :8, 1 :9, 1:10, 1:11, 1 :12, 1:13, 1 :14, 1:15, 1:16, 1 :17, 1:18, 1: 19 or 1:20. [0034] The term “amino acid” means any amino acid, including, but not limited to the 20 amino acids naturally occurring in peptides in both D and L-form and is also meant to cover any salt thereof, especially pharmaceutically acceptable salts. For example, the term “amino acid” includes alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine and ornithine, and any conformations thereof. [0035] Thus the term “amino acid” includes L-alanine, L-arginine, L-asparagine, L- aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-Phenylalanine, L-Proline, L-Serine, L- Threonine, L-Tryptophan, L-Tyrosine, L-Valine and L-Ornithine. [0036] Thus included is D-Alanine, D-Arginine, D-Asparagine, D-Aspartic acid, D-
Cysteine, D-Glutamic acid, D-Glutamine, D-Histidine, D-Isoleucine, D-Leucine, D- Lysine, D-Methionine, D-Phenylalanine, D-Proline, D-Serine, D-Threonine, D- Tryptophan, D-Tyrosine, D-Valine and D-Ornithine.
[0037] In an aspect, the amino acid comprises arginine, lysine, histidine, or a combination thereof.
[0038] In a specific aspect, the amino acid is L-lysine hydrochloride.
[0039] When present, the amino acid or a salt thereof in the oral liquid unit dosage form is present in an amount of 0.4 to 6.0 % w/V, specifically 1.0 to 4.0 % w/V, more specifically 0.4 to 2.0 % w/V and most specifically 1.0 % w/V. When present, the amino acid or a salt thereof in the oral liquid unit dosage form is present in an amount of 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8 or 6.0 % w/V.
[0040] In an aspect, the molar ratio of vancomycin to amino acid is 1 :0.5 to 1:40, specifically 1 :1 to 1:10, more specifically 1: 1 to 1:8, and most specifically 1:1, 1:2, 1:3, 1:4, 1 :5, 1 :6, 1:7, 1:8, 1:9 or 1:10.
[0041] In an aspect, the oral liquid unit dosage form comprises a polyethylene glycol, such as PEG400. When present, the polyethylene glycol comprises 0.0, 0.1, 0.5 or 1.0 to 15.0 % w/V, specifically 9.0 tol5.0 % w/V, and more specifically 11.3% w/V of the oral liquid unit dosage form. [0042] “pH” is a measurement unit of hydrogen ion activity in a solution at 25°C unless another temperature is specified. In an aspect, the oral liquid unit dosage form has a pH of 3.8 to 4.4, specifically 4.05-4.15, or more specifically 4.1.
[0043] In an aspect, the oral liquid unit dosage form comprises an optional pH adjusting agent. The pH of the oral liquid formulations can be adjusted by addition of aqueous hydrochloric acid solutions or aqueous sodium hydroxide solutions.
Such solutions can be diluted or concentrated. Exemplary pH adjusting agents include, but are not limited to, 0.01 M HC1, 0.1 M HC1, 1 M HC1, 2 M HC1, 3 M HC1, 4 M HC1, 5 M HC1, 6 M HC1, 0.01 M NaOH, 0.1 M NaOH, 1 M NaOH, 2 M NaOH, 3 M NaOH, 4 M NaOH, 5 M NaOH and 6 M NaOH. Exemplary pH adjusting agents include, but are not limited to, 0.01-6 M HC1 and 0.01-6 M NaOH. [0044] In an aspect, the oral liquid unit dosage form optionally comprises a preservative such as potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride. In one aspect, said preservative is potassium sorbate. When present, the preservative can be present in an amount of 0.002 to 0.3 %w/V. Exemplary amounts include 0.2 % w/V potassium sorbate, 0.02% w/V sodium benzoate, 0.16% w/V sodium propionate, 0.00725 % w/V benzethonium chloride, and 0.0125 % w/V benzalkonium chloride. When present and the chosen preservative is potassium sorbate, the amount is in the range of 0.01 to 0.2 %w/V, specifically 0.05 to 0.2 %w/V and more specifically 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 and 0.2 %w/V.
[0045] In an aspect, the oral liquid unit dosage form comprises an antioxidant. The antioxidant to choose for an oral product will be well known for the skilled person in the art.
[0046] The balance of the ready to use oral liquid unit dosage form is water.
[0047] The oral liquid unit dosage forms described herein include no added sweetener or flavoring agent. [0048] As used herein, the term “sweetener” includes natural and artificial sweeteners. Artificial sweeteners include sucralose, saccharin, acesulfame, aspartame, and neotame. Sugar sweeteners include monosaccharides, di saccharides and polysaccharides such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch (such as maltitol syrup) or corn syrup solids and sugar alcohols such as sorbitol, xylitol, mannitol, erythritol, isomalt, lactitol, glycerin and the like.
[0049] As used herein, the term “flavoring agent” means an agent used to improve the taste and palatability of pharmaceutical formulations. Flavoring agents include natural flavors, natural fruit flavors, artificial flavors, artificial fruit flavors, flavor enhancers, and the like. Exemplary flavors include mint (such as peppermint or spearmint), menthol, cinnamon, vanilla, artificial vanilla, chocolate, artificial chocolate, bubblegum, and the like. Fruit flavors include cherry, mixed berry, grape, orange, strawberry, lemon and the like. [0050] A specific ready to use oral liquid unit dosage form comprises, consists essentially of, or consists of
5.0 % w/V vancomycin or a salt thereof,
4.52 % w/V N-acetyl-D-alanine,
I.0% w/V L-Lysine or salts thereof
I I.3 % w/V polyethylene glycol, wherein the pH adjusting agent is NaOH to adjust the pH to 4.05-4.15,
0.002 to 0.3 % w/V of a preservative selected from potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride, and water, wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
[0051] Another specific ready to use oral liquid unit dosage form comprises, consists essentially of, or consists of
5.0 %w/V vancomycin or a salt thereof,
5.88 %w/V N-acetyl-D-alanine,
4.05 %w/V L-Lysine or salts thereof 0.16 %w/V polyethylene glycol, wherein the pH adjusting agent is NaOH to adjust the pH to 4.05-4.15,
0.002 to 0.3 % w/V of a preservative selected from potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride, and water, wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
[0052] In the foregoing embodiment, the molar ratio of vancomycin to L-Lysine hydrochloride to N-acetyl-D-alanine is 1:8:13.
[0053] Another specific ready to use oral liquid unit dosage form comprises, consists essentially of, or consists of
5.0 %w/V vancomycin or a salt thereof,
5.88 %w/V N-acetyl-D-alanine,
4.05 %w/V L-Lysine or salts thereof 0.26 %w/V polyethylene glycol, wherein the pH adjusting agent is NaOH to adjust the pH to 4.05-4.15,
0.0025 to 0.3 % w/V of a preservative selected from potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride, and water, wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
[0054] In the foregoing embodiment, the molar ratio of vancomycin to L-Lysine hydrochloride to N-acetyl-D-alanine is 1:8:13.
[0055] Also included herein is a method of improving patient compliance, comprising administering to a patient in need thereof the ready to use oral liquid unit dosage forms described herein. In an aspect, the patient is in need of treatment for enterocolitis caused by Staphylococcus aureus or antibiotic-associated pseudomembranous colitis caused by Clostridium difficile. In another aspect, the patient is a pediatric or geriatric patient.
[0056] In yet another aspect, a method of improving palatability of a vancomycin oral liquid dosage form the absence of added sweeteners and flavoring agents comprises combining N-acetyl-D-alanine with the vancomycin, wherein the ratio of vancomycin to N-acetyl-D-alanine is 1 :2 to 1 :44. In an aspect, the vancomycin is present at 1.5 to7.5 % % w/V, specifically 3.0 to 6.0 % w/V, and most specifically 5.0% w/V. In another aspect, the N-acetyl-D-alanine is present in an amount of 1.4 to 6.0 % w/V, specifically 3.0-6.0 % w/V, more specifically 3.0 to 5.0 %w/V and most specifically about 4.52 % w/V. In an aspect, the oral liquid formulation is in the form of a ready to use oral liquid dosage form.
[0057] In another aspect, a method of improving palatability of a vancomycin oral liquid dosage form the absence of added sweeteners and flavoring agents comprises combining an amino acid and polyethylene glycol with the vancomycin, wherein the molar ratio of vancomycin to amino acid is 1:0.5 to 1 :40, and wherein the polyethylene glycol is in an amount of 0.0, 0.1, 0.5 or 1.0 to 15.0% w/V. In an aspect, the vancomycin is present at 1.5-7.5 % w/V, specifically 3.0 to 6.0 % w/V, and most specifically 5.0% w/V. In another aspect, the amino acid is present in an amount of 0.4 to 6.0 % w/V, specifically 0.4 to 2.0 % w/V and most specifically 1.0 % w/V, and the polyethylene glycol is present in an amount of 0.0, 0.1, 0.5 or 1.0 to 15 % w/V, specifically 9.0-15.0 % w/V, and more specifically 11.3% w/V.
[0058] Also included is a method of manufacturing an oral liquid formulation. The order in which the vancomycin, N-acetyl-D-alanine, polyethylene glycol and amino acid, for example, are mixed is not critical.
[0059] The taste perception of the oral liquid formulations and oral liquid unit dosage forms may be assessed by electronic taste sensing based on ChemFET liquid sensors and conductivity measurements such as by the Astree® electronic tongue (e-tongue). The e-tongue measures and maps the relative repartition and proximity of the taste between an oral liquid formulation according to the present disclosure and various controls. Controls can include an undiluted reconstituted injection formulation (that is, vancomycin in water which is a formulation with no taste- masking additives), a reconstituted injection formulation containing a flavoring agent such as a SyrSpend® SF PH4 cherry, and a flavoring agent such as a SyrSpend® SF PH4 cherry with no active agent (also referred to as a “blank” control). The e-tongue measurements are analyzed by principal component analysis (PCA). It is assumed that the control containing a flavoring agent represents the ideal “target” taste profile, since the unpleasant tasting active component is not present or is taste masked. Therefore, taste proximity is quantified using the Euclidean distance between the active, e.g. oral liquid formulation according to the present disclosure, and control formulations on the PCA map, with a smaller distance indicating a more similar taste or flavor. The discrimination index (D1 in %) takes into account the difference between the center of gravity of the sensors output for each pair of formulations as well as the dispersion within the sensors output for the formulations. The higher the value of discrimination index (closer to 100%), the less similarity between the formulations flavors and less taste masking occurred.
[0060] In an aspect, based on electronic taste sensing based on ChemFET liquid sensors and conductivity measurements and a principal component analysis, the oral liquid unit dosage form has a discrimination index of at least 50%, 60%, 70%, 80% or 90% compared to a control containing only vancomycin and water.
[0061] The invention is further illustrated by the following non-limiting examples. EXAMPLES
EXAMPLE 1: Taste-masking of vancomycin formulations [0062] Samples were prepared according to Table 1: TABLE 1: Samples for e-tongue testing
Figure imgf000014_0001
[0063] Vancomycin liquid formulation 1 :
5.0% w/V vancomycin
4.52 % w/V N-acetyl-D-alanine,
I.26 % w/V L-Lysine hydrochloride (wherein calculation is based on L- Lysine hydrochloride)
I I.3 % w/V polyethylene glycol pH 4.1 [0064] Formulation 1 was made by adding vancomycin into water and then adding N-acetyl-D-alanine into the solution and mix until fully dissolved. L-Lysine and polyethylene glycol were added. Solution was mixed until L-Lysine and polyethylene glycol were fully dissolved. pH was adjusted using NaOH and the volume was filled up with water to reach the targeted concentrations.
[0065] The assays were realized on an Astree® e-tongue system equipped with an Alpha MOS sensor set #2 composed of 7 specific sensors (ZZ, AB, GA, BB, CA, DA, JE) on a 16-position autosampler using 100 ml-beakers. Acquisition times were fixed at 120s for sample tests and 20s for the cleaning solutions. The data processing was carried out with the software Alphasoft VI 2.4.
[0066] The signal of each sensor on each assay was integrated in a matrix of data that could be computed by multidimensional statistic tools. A taste map based on Principal Component Analysis (PCA) can be generated using all sensors (Figure 1). It shows the relative repartition and proximity of taste of each formulation. Formulations are discriminated on PCI axis (more than 90.54 % of the information).
[0067] The Euclidian distances between target reference and formulations were calculated to assess taste proximity between samples: the lower the distance, the closer the taste. [0068] Also, a Discrimination Index (DI in %) was determined for each formulation.
This indicator takes into account the average difference between the pairs to compare, as well as the dispersion of each sample. The closer the index to 100%, the higher the distance between the centers of gravity and the smaller the dispersion within groups. The DI will help then to assess the significance of difference between the groups.
[0069] The differences between the different formulations and undiluted Reference formulation (RLD U) are significant (DI>94%) (Figure 2). The biggest distance against undiluted Reference formulation (RLD U) was found for blank solution of SyrSpend® SF PH4 cherry flavored syrup (SFC W). The lowest distance against undiluted Reference formulation (RLD U) was found for samples RLD diluted with 30 mL of water (RLD-W) and Reference formulation with 30 mL of SyrSpend® SF PH4 cherry flavored syrup (RLD-S). [0070] The repeatability of the measurements on Astree® e-tongue was determined for each sample on 3 replicates. The results are comparable.
[0071] Based on the results of Astree® e-tongue , which expresses much higher sensitivity than those of the human taste sensation, there is a clear difference between each tested formulation.
[0072] Blank solution of SyrSpend® SF PH4 cherry flavored syrup (SFC-W) was found the most different from the undiluted Reference formulation (RLD U). This difference assumes they express different taste. The lowest distances from undiluted Reference formulation (RLD U) in increasing order were the following: · Reference formulation (RLD-U) diluted with 30 mL of water
• Reference formulation (RLD-U) diluted with 30 mL of SyrSpend® SF
PH4 cherry flavored syrup
• Formulation 1 diluted with 30 mL of water (XLV-W) [0073] The highest distances from undiluted Reference formulation (RLD-U) in decreasing order were the following:
• Blank solution of SyrSpend® SF PH4 cherry flavored syrup (SFC-W)
• Undiluted Formulation 1 (XLV-U)
• Undiluted SyrSpend® SF PH4 cherry flavored syrup (SFC-U) [0074] The results suggest Formulation 1 (XLV-U) has a more similar palatability to Undiluted SyrSpend® SF PH4 cherry flavored syrup (SFC-U) than to Reference formulation (Fresenius Kabi (RLD)- lyophilized injection; RLD-U) based on the results of electronic tongue. The addition of 30ml cherry flavored syrup slightly modified the taste of Formulation 1 (XLV-S) which remained still more similar to Undiluted SyrSpend® SF PH4 cherry flavored syrup (SFC-U) than the one diluted with water. The addition of water to Formulation 1 to form a diluted solution (XLV- W) is significantly different from the Reference formulation (Fresenius Kabi (RLD)- lyophilized injection; RLD-U). EXAMPLE 2: Role of NADA and/or Lysine/PEG on taste masking
[0075] In a second set of experiments, the following samples were tested
Figure imgf000016_0001
Figure imgf000017_0001
[0076] The assays were realized on an Astree® e-tongue system equipped with an Alpha MOS sensor set #2 composed of 7 specific sensors (ZZ, AB, GA, BB, CA, DA, JE) on a 16-positions autosampler using 100 ml-beakers. Acquisition times were fixed at 120s for sample tests and 20s for the cleaning solutions. The data processing was carried out with the software Alphasoft VI 2.4.
[0077] The solutions were poured directly into the beakers. They were analyzed by the Astree® e-tongue with the following analytical conditions: Sample volume: 100 ml; Acquisition time: 120 s; Time per analysis: 150 s. The e-tongue signal in each sample was measured at the equilibrium on 7 sensors (average between 100 and 120s). Three replicates were taken into account for the analysis.
[0078] The signal of each sensor on each assay was integrated in a matrix of data that could be computed by multidimensional statistic tools. A taste map based on Principal Component Analysis (PCA) can be generated using all sensors (Figure 3). It shows the relative repartition and proximity of taste of each formulation. Sample l l (Reference vancomycin reconstituted (50 mg/mL) w/o further dilution) presented the best separation from the other four tested samples based on the first principal component (PCI) describing more than 82.34 % of the information. The second principal component (PC2, showing 16.155% of the information) depicts clear separation between mainly two groups of samples, which are also clearly separated from sample l l : group 1: sample Ol and sample_07 (Vanco/NADA/lysine/PEG and Vanco/NADA); group 2: sample_08 and sample_14 (Vanco/lysine/PEG and Blank solution SyrSpend®). Samples in these two groups could be also distinguished by the e-tongue , but they were found the most similar. [0079] The Euclidian distances between control (sample l l : Vanco reference) and formulations (sample Ol, sample_07, sample_08) were calculated to assess taste proximity between samples: the lower the distance, the closer the taste. Also, a Discrimination Index (DI in %) was determined for each formulation. This indicator takes into account the average difference between the pairs to compare, as well as the dispersion of each sample. The closer the index to 100%, the higher the distance between the centers of gravity and the smaller the dispersion within groups. The DI will help then to assess the significance of difference between the groups. The differences between the different formulations and sample l l (Vanco reference- reconstituted (50 mg/mL) w/o further dilution) are significant (DI>94%) (Figure 4). The biggest distance against sample l 1 was found for sample_14 (Blank solution of SyrSpend® SF PH4 cherry flavored syrup), which is in a good agreement with Example 1. The smallest distance against sample l 1 was found for sample_01 (Vanco/NADA/lysine/PEG), which followed by sample_08
(Vanco/lysine/PEG) with a bit bigger distance and finally followed by sample_07 (Vanco/NADA).
[0080] The repeatability of the measurements on Astree® e-tongue was determined for each sample on 3 replicates. The results are comparable. [0081] Based on the results of Astree® e-tongue , which express much higher sensitivity than those of the human taste sensation, there is a clear difference between each of the tested five formulations.
[0082] All of the numbers used herein are modified by the term “about.” This means that each number includes minor variations as defined ±10% of the numerical value or range in question.
[0083] All numbers for amounts of vancomycin and salts thereof and amino acids and salts thereof are based on the atomic masses of vancomycin and amino acids, and not the atomic masses of the salts of vancomycin or salts of amino acids unless otherwise is specified. [0084] The term % w/V as used herein is defined as the number of grams of an ingredient, referred to percentage by volume of solute in 100ml of solution.
[0085] The use of the terms “a” and “an” and “the” and similar referents (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms first, second etc. as used herein are not meant to denote any particular ordering, but simply for convenience to denote a plurality of, for example, layers. The terms “comprising”, “having”, “including”, and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”) unless otherwise noted. “About” or “approximately” as used herein is inclusive of the stated value and means within an acceptable range of deviation for the particular value as determined by one of ordinary skill in the art, considering the measurement in question and the error associated with measurement of the particular quantity (i.e., the limitations of the measurement system). For example, “about” can mean within one or more standard deviations, or within ± 10% or 5% of the stated value. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein.
[0086] While the invention has been described with reference to an exemplary embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not to be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

1. A ready to use oral liquid dosage form, comprising
1.5 to 7.5% w/V vancomycin or a salt thereof,
0.4 to 6.0 % w/V of at least either N-acetyl-D-alanine or an amino acid, optionally 0.0, 0.1, 0.5 or 1.0 to 15 % w/V of a polyethylene glycol, optionally a pH adjusting agent, optionally a preservative, and water, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
2. A ready to use oral liquid unit dosage form of claim 1, comprising
1.5 to 7.5 % w/V vancomycin or a salt thereof,
1.4 to 6.0 % w/V N-acetyl-D-alanine,
0.4 to 6.0 % w/V of an amino acid or a salt thereof,
0.0, 0.1, 0.5 or 1.0 to 15 % w/V of a polyethylene glycol, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to N-acetyl-D-alanine is 1:2 to 1: 44, wherein the molar ratio of vancomycin to amino acid is 1 :0.5 to 1:40, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
3. A ready to use oral liquid unit dosage form, consisting of
1.5 to7.5 % w/V vancomycin or a salt thereof,
1.4 to 6.0 % w/V N-acetyl-D-alanine,
0.4 to 6.0% w/V of an amino acid or a salt thereof,
0.1, 0.5, or 1.0 to 15.0 % w/V of a polyethylene glycol, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to N-acetyl-D-alanine is 1 :2 to 1 :44, wherein the molar ratio of vancomycin to amino acid is 1:0.5 to 1:40 to, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
4. The ready to use oral liquid unit dosage form of claim 2 or claim 3, wherein ready to use oral liquid unit dosage form is in a single-use container.
5. The ready to use oral liquid unit dosage form of claim 2 or claim 3, wherein the amino acid comprises arginine, lysine, histidine, or a combination thereof.
6. The ready to use oral liquid unit dosage form of claim 2 or claim 3, wherein the amino acid comprises lysine hydrochloride.
7. The ready to use oral liquid unit dosage form claim 2 or 3, wherein the polyethylene glycol is polyethylene glycol 400.
8. The ready to use oral liquid unit dosage form of claim 2 or 3, wherein the oral liquid unit dosage form has a pH of 4.1.
9. The ready to use oral liquid unit dosage form of claim 2 or 3, wherein the vancomycin is present at 5.0% w/V.
10. The ready to use oral liquid unit dosage form of claim 2 or 3, wherein the preservative is potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride.
11. The ready to use oral liquid unit dosage form of claim 10, wherein the preservative is potassium sorbate.
12. The ready to use oral liquid unit dosage form of claim 2, comprising
5.0 % w/V vancomycin or a salt thereof,
4.52 % w/V N-acetyl-D-alanine,
I.0 % w/V L-Lysine or salts thereof
I I.3 % w/V polyethylene glycol, wherein the pH adjusting agent sodium hydroxide and/or hydrochloric acid is used to adjust the pH to 4.05-4.15, and
0.002 to 0.3% w/V of a preservative selected from potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride, or
5.0 %w/V vancomycin or a salt thereof,
5.88 %w/V N-acetyl-D-alanine,
4.05 %w/V L-Lysine or salts thereof 0.16 %w/V polyethylene glycol, wherein the pH adjusting agent sodium hydroxide and/or hydrochloric acid is used to adjust the pH to 4.05-4.15, and
0.002 to 0.3% wV of a preservative selected from potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride, water, wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent, or
5.0 %w/V vancomycin or a salt thereof, 5.88 %w/V N-acetyl-D-alanine,
4.05 %w/V L-Lysine or salts thereof 0.26 %w/V polyethylene glycol, wherein the pH adjusting agent sodium hydroxide and/or hydrochloric acid is used to adjust the pH to 4.05-4.15, and 0.002 to 0.3% wV of a preservative selected from potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride, water, wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
13. A ready to use oral liquid unit dosage form of claim 1, comprising
1.5 to 7.5 % w/V vancomycin or a salt thereof,
1.4 to 6.0 % w/V N-acetyl-D-alanine, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to N-acetyl-D-alanine is 1 :2 to 1 : 44, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
14. A ready to use oral liquid unit dosage form of claim 1, consisting of
1.5 to 7.5 % w/V vancomycin or a salt thereof,
1.4 to 6.0 % w/V N-acetyl-D-alanine, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to N-acetyl-D-alanine is 1 :2 to 1 :44, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
15. The ready to use oral liquid unit dosage form of claim 13 or claim 14, wherein ready to use oral liquid unit dosage form is in a single-use container.
16. The ready to use oral liquid unit dosage form of claim 13 or claim 14, wherein the oral liquid unit dosage form has a pH of 4.1.
17. The ready to use oral liquid unit dosage form of claim 13 or claim 14, wherein the vancomycin is present at 5.0% w/V.
18. The ready to use oral liquid unit dosage form of claim 13 or claim 14, wherein the preservative is potassium sorbate, sodium benzoate, sodium propionate, benzethonium chloride, or benzalkonium chloride.
19. A ready to use oral liquid unit dosage form of claim 1, comprising 1.5 to 7.5 % w/V vancomycin or a salt thereof,
0.4 to 6.0 % w/V of an amino acid or a salt thereof,
0.0, 0.1, 0.5 or 1.0 to 15.0 % w/V of a polyethylene glycol, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to amino acid is 1 :0.5 to 1 :40, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
20. A ready to use oral liquid unit dosage form of claim 1, consisting of 1.5 to 7.5 % w/V vancomycin or a salt thereof, 0.4 to 6.0 % w/V of an amino acid or a salt thereof,
0.1, 0.5 or 1.0 to 15.0 % w/V of a polyethylene glycol, optionally a pH adjusting agent, optionally a preservative, and water, wherein the molar ratio of vancomycin to amino acid is 1 :0.5 to 1 :40 to, wherein the oral liquid unit dosage form has a pH of 3.8 to 4.4, and wherein the oral liquid unit dosage form includes no added sweetener and no added flavoring agent.
21. The ready to use oral liquid unit dosage form of claim 19 or claim 20, wherein ready to use oral liquid unit dosage form is in a single-use container.
22. The ready to use oral liquid unit dosage form of claim 19 or claim 20, wherein the oral liquid unit dosage form has a pH of 4.1.
23. The ready to use oral liquid unit dosage form of claim 19 or claim 20, wherein the amino acid comprises arginine, lysine, histidine, or a combination thereof.
24. The ready to use oral liquid unit dosage form of claim 19 or claim 20, wherein the amino acid comprises lysine hydrochloride.
25. The ready to use oral liquid unit dosage form of claim 19 or claim 20, wherein the polyethylene glycol is polyethylene glycol 400.
26. The ready to use oral liquid unit dosage form of claim 1 to 3, wherein, based on electronic taste sensing based on ChemFET liquid sensors and conductivity measurements and a principal component analysis, the oral liquid unit dosage form has a discrimination index of at least 50%, 60%, 70%, 80% or 90% compared to a control containing only vancomycin and water.
27. A method of improving patient compliance, comprising administering to a patient in need thereof the ready to use oral liquid unit dosage form of any of claims 1 to 12 and 26.
28. The method of claim 27, wherein the patient is in need of treatment for enterocolitis caused by Staphylococcus aureus or antibiotic-associated pseudomembranous colitis caused by Clostridium difficile.
29. The method of claim 27, wherein the patient is a pediatric or geriatric patient.
30. A method of treating enterocolitis caused by Staphylococcus aureus or antibiotic- associated pseudomembranous colitis caused by Clostridium difficile in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the ready to use oral liquid unit dosage form of any of claims 1 to 12 and 26.
31. A method of improving palatability of a vancomycin oral liquid dosage form in the absence of added sweeteners and flavoring agents, comprising combining N-acetyl- D-alanine with the vancomycin, wherein the ratio of vancomycin to N-acetyl-D-alanine is 1:2 to 1:44.
32. The method of claim 31, wherein the vancomycin is present at 1.5 to 7.5 % w/V.
33. The method of claim 31, wherein the N-acetyl-D-alanine is present at 0.4 to 6.0 % w/V.
34. The method of claim 31, wherein the oral liquid formulation is in the form of a ready to use oral liquid dosage form.
35. A method of improving palatability of a vancomycin oral liquid dosage form in the absence of added sweeteners and flavoring agents, comprising combining an amino acid and polyethylene glycol with the vancomycin, wherein the ratio of vancomycin to amino acid is 1 :0.5 to 1 :40, and wherein the polyethylene glycol is in an amount of 0.0, 0.1, 0.5 or 1.0 to 15.0% w/V.
36. The method of claim 35, wherein the amino acid comprises arginine, lysine, histidine, or a combination thereof.
37. The method of claim 35, wherein the amino acid comprises lysine hydrochloride.
38. The method of claim 35, wherein the vancomycin is present at 1.5-7.5 % w/V.
39. The method of claim 35, wherein the amino acid or a salt thereof is present at 0.4 to 6.0 % w/V.
40. The method of claim 35, wherein the oral liquid formulation is in the form of a ready to use oral liquid dosage form.
PCT/EP2022/062191 2021-05-07 2022-05-05 Oral liquid vancomycin formulations WO2022234036A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163185774P 2021-05-07 2021-05-07
US63/185,774 2021-05-07

Publications (1)

Publication Number Publication Date
WO2022234036A1 true WO2022234036A1 (en) 2022-11-10

Family

ID=81941041

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2022/062191 WO2022234036A1 (en) 2021-05-07 2022-05-05 Oral liquid vancomycin formulations

Country Status (1)

Country Link
WO (1) WO2022234036A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6806256B2 (en) 2001-03-05 2004-10-19 Ortho -Mcneil Pharmaceutical, Inc. Taste masked liquid pharmaceutical compositions
WO2016071495A1 (en) * 2014-11-06 2016-05-12 Xellia Pharmaceuticals Aps Glycopeptide compositions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6806256B2 (en) 2001-03-05 2004-10-19 Ortho -Mcneil Pharmaceutical, Inc. Taste masked liquid pharmaceutical compositions
WO2016071495A1 (en) * 2014-11-06 2016-05-12 Xellia Pharmaceuticals Aps Glycopeptide compositions
US10039804B2 (en) 2014-11-06 2018-08-07 Xellia Pharmaceuticals Aps Glycopeptide compositions

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CAS, no. 19436-52-3
MARY ENSOM ET AL: "Stability of Vancomycin 25 mg/mL in Ora-Sweet and Water in Unit-Dose Cups and Plastic Bottles at 4°C and 25°C", CANADIAN SOCIETY OF HOSPITAL PHARMACY, vol. 63, no. 5, 1 September 2010 (2010-09-01), pages 366 - 369, XP055358217, ISSN: 0008-4123, DOI: 10.4212/cjhp.v63i5.948 *
SCHIFFMANN ET AL.: "Taste of Acetylated Amino Acids", CHEMICAL SENSES AND FLAVOR, vol. 1, 1975, pages 387 - 401

Similar Documents

Publication Publication Date Title
EP3215173B1 (en) Glycopeptide compositions
US10729708B2 (en) Stabilized glycopeptide antibiotic formulations
US11179434B2 (en) Lisinopril formulations
US11896570B2 (en) Compositions for therapy and health containing amino acids with bitter taste
RU2352333C2 (en) Pregabalin composition
US11766441B2 (en) Oral liquid compositions including chlorpromazine
WO2022234036A1 (en) Oral liquid vancomycin formulations
ES2507500T3 (en) Compositions comprising cyclohexylamines and aminoadamantans
US20240173253A1 (en) Liquid preparation of l-serine or pharmaceutically acceptable salt thereof and method for preparing same
US5698562A (en) Palatable trimethoprim oral solution
WO2024023367A1 (en) Lisdexamfetamine containing oral solution
CN115645357A (en) Lacosamide oral solution prescription and preparation process thereof
US20240189229A1 (en) Liquid pharmaceutical compositions of baclofen for oral administration
TR201510144A2 (en) NEW ORAL SOLUTION FORMULATION

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22728122

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22728122

Country of ref document: EP

Kind code of ref document: A1