Acetaminophen liquid suspension

Abstract

The present invention relates to liquid suspensions of acetaminophen. The present invention relates to pharmaceutical liquid suspensions suitable for oral administration. More specifically, the present invention relates to pharmaceutical liquid suspensions containing acetaminophen, wherein the suspension is formulated with acetaminophen particles having a d50 less than or equal to 10 µm and a d90 less than or equal to 35 µm, such that browning discoloration is reduced over the course of long term storage.

Description

[0001] This application is a divisional application of the invention patent application filed on August 22, 2019, with application number 201980070808.8 and invention title "acetaminophen liquid suspension". Invention Field

[0002] This invention relates to pharmaceutical liquid suspensions suitable for oral administration. More specifically, this invention relates to pharmaceutical liquid suspensions containing N-acetyl-p-aminophenol (known by the common names acetaminophen, paracetamol, and APAP, hereinafter referred to as acetaminophen). Specifically, this invention relates to acetaminophen liquid suspensions formulated with acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 35 µm, thereby reducing browning and discoloration during long-term storage compared to acetaminophen liquid suspensions formulated with acetaminophen particles having a larger average particle size. Background of the Invention Acetaminophen is a commonly used analgesic and antipyretic that has been used in many countries for over 40 years. Extensive experience has clearly established it as the standard antipyretic and analgesic for mild to moderate pain conditions. Acetaminophen is available in many countries in over-the-counter forms for routine oral administration, including solid forms (e.g., capsules, small capsules, gel caps, or tablets) and liquid forms (e.g., solutions), such as syrups and elixirs, emulsions, or suspensions.

[0003] Medications administered in solid form are generally intended to be swallowed whole. However, even though tablets or capsules are very small, children and some adults (including disabled or incapacitated patients) may find solid dosage forms difficult to swallow. Chewing tablets is also an option, but this is unacceptable if the active pharmaceutical ingredient (API) has an unpleasant taste. For many patients, including pediatricians and the elderly, liquid oral dosage forms are preferred over chewable forms because they are easier to swallow without chewing. Liquid dosage forms can be syrups or suspensions.

[0004] A liquid suspension is a two-phase system having solid, poorly water-soluble API particles dispersed throughout a liquid medium. In a suspension, the API does not dissolve or dissolves to a limited extent in the liquid medium and thus remains intact as small particles. Suspensions do not include emulsions, which are intended to describe liquids suspended within a liquid carrier. Suspensions also do not include syrup formulations containing completely dissolved API.

[0005] The preparation of such suspensions is often underestimated and involves more than just mixing solids in a liquid. To produce products with target quality properties, knowledge of particle behavior in liquids, as well as of wetting agents, suspending agents, polymers, preservatives, colorants, and flavoring agents is required (David B. Troy, Paul Beringer, The Science and Practice of Pharmacy, pp. 767-768, Lippincott Williams & Wilkins, 2006).

[0006] One challenge associated with liquid suspensions is sedimentation, the tendency of particles in a suspension to settle out of the fluid. Of all the components of a suspension, the suspended phase (i.e., containing API particles, in this case, acetaminophen particles) is one of the most critical components because it tends to settle over time and under specific conditions. Various factors influence the sedimentation rate of particles in a suspension. Stokes' law is often used to describe sedimentation rates: Where dS / dt is the settling velocity, d is the particle diameter, and ρ is the settling velocity. P It is the density of the particles, ρ M Let ρ be the density of the medium, g be the gravitational constant, and η be the viscosity of the medium. According to Stokes' law, the settling rate of a suspension decreases as the particle diameter decreases, the difference between the particle density and the medium density decreases, and the viscosity of the medium increases.

[0007] U.S. Patent Nos. 5,272,137 and 5,409,907 teach the use of suspending agents such as xanthan gum and microcrystalline cellulose to minimize sedimentation. U.S. Patent No. 5,658,919 discloses the use of a mixture of xanthan gum, microcrystalline cellulose, and sodium carboxymethyl cellulose, and a suspending agent selected from salts of hydroxyethyl cellulose and carboxymethyl cellulose, to minimize sedimentation of acetaminophen suspensions.

[0008] Color changes in pharmaceutical products (which typically occur during product storage) are considered an important quality attribute and are frequently monitored as an indicator of inappropriate manufacturing or formulation instability. Therefore, color is monitored during drug product development. Color changes in pharmaceutical products can occur under specific conditions. The color of liquid formulations containing acetaminophen can change more easily than that of solid formulations containing acetaminophen because color changes can be caused by several reactions, such as acetaminophen degradation via hydrolysis or oxidation; and other chemical reactions of the active ingredient and other additives, such as the Maillard reaction.

[0009] Color changes in acetaminophen suspensions typically occur due to a change from white to off-white or brown. For this reason, the terms discoloration or browning are often used to describe these color changes. Dyes are frequently added to drug suspensions to improve appearance and patient acceptability, and to mask discoloration. However, it has been found that some patients develop or have allergic reactions to dyed suspensions, or are sensitive to dyed suspensions, or such suspensions can stain clothes, furniture, carpets, etc., upon spillage. Therefore, dye-free suspensions are highly desirable. Colorants are frequently added to liquid pharmaceutical products to create pharmaceutically acceptable characteristics, provide identification factors, and ensure consistency between batches of the product. Often, the color of the excipients used in the production of the product can cause discoloration. This color often depends on the batch of the excipient, and they can change during storage without adversely affecting the product. However, consumers may perceive color changes as adversely affecting the product's efficacy, potentially leading to product rejection.

[0010] EP 2 229 937 B1 relates to a dye-free acetaminophen liquid suspension, wherein each 100 mL of the suspension comprises: 1-15 g of APAP having an average particle size between 10-100 micrometers; 0.1-0.25 g of xanthan gum; 0.4-1 g of microcrystalline cellulose; 20-65 g of sorbitol solution; 1-20 g of glycerol; 0.01-1 g of flavoring agent; 20-50 g of water; 0.001-0.10 g of an antimicrobial preservative selected from butylparaben, methylparaben, propylparaben, and combinations thereof; 0.003-0.20 g of citric acid; and 0.1-0.5 g of propylene glycol; wherein the dye-free APAP suspension has a pH of 5-6 and is substantially free of reducing sugars. The formulation contains sucrose. According to EP 2 229 937 B1, the unique combination of APAP with sorbitol and sucrose at a pH of about 5.1-5.9 produces an APAP suspension that is advantageously stable in storage and uniformly dispersed.

[0011] U.S. Patent No. 7,300,670 teaches a suspension comprising: a particulate drug having a density of about 0.9 to about 1.6 g / ml and an average particle size (X50) of less than about 20 micrometers; a polymer exhibiting plastic flow selected from, but not limited to, xanthan gum, carbomer, microcrystalline cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, and combinations thereof; and wherein the suspension has a final plastic strain value of less than about 15 Pa to ensure that the product can be poured without shaking, and that it does not clump during storage and can maintain its homogeneity without shaking after long-term storage. Examples in the '670 patent teach a 0.02-15% by weight paracetamol liquid suspension containing invert sugar, sucrose, and a colorant or dye.

[0012] Despite the challenges associated with formulating suspensions, numerous attempts have been made to formulate acetaminophen as a liquid suspension. In fact, many products are currently available on the market, including Panadol® Children's 1-6 Years (sold by GlaxoSmithKline Consumer Healthcare), Children's Tylenol Pain and Fever Reliever (sold by Johnson & Johnson Consumer Inc.), and Panodil Jr. suspension.

[0013] The present invention is an improvement on these commercially available products and relates to the discovery of a dye-free, optionally sugar-free, storage-stable acetaminophen liquid suspension that provides a pleasant taste, low sedimentation, and surprisingly advantageous reduction in browning over extended periods of time. Invention Overview The present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 35 µm, said composition being substantially dye-free.

[0014] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 30 µm, said composition being substantially dye-free.

[0015] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 25 µm, said composition being substantially dye-free.

[0016] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 20 µm, said composition being substantially dye-free.

[0017] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 16 µm, said composition being substantially dye-free.

[0018] In yet another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 35 µm, said composition being substantially dye-free.

[0019] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 30 µm, said composition being substantially dye-free.

[0020] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 25 µm, said composition being substantially dye-free.

[0021] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 20 µm, said composition being substantially dye-free.

[0022] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 16 µm, said composition being substantially dye-free.

[0023] In one embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 35 µm, said composition being substantially dye-free and substantially free of invert sugar.

[0024] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 30 µm, said composition being substantially dye-free and substantially free of invert sugar.

[0025] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 25 µm, said composition being substantially dye-free and substantially free of invert sugar.

[0026] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 20 µm, said composition being substantially dye-free and substantially free of invert sugar.

[0027] In yet another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 16 µm, said composition being substantially dye-free and substantially free of invert sugar.

[0028] In one embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 35 µm, said composition being substantially dye-free and substantially free of invert sugar.

[0029] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 30 µm, said composition being substantially dye-free and substantially free of invert sugar.

[0030] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 25 µm, said composition being substantially dye-free and substantially free of invert sugar.

[0031] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 20 µm, said composition being substantially dye-free and substantially free of invert sugar.

[0032] In yet another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 16 µm, said composition being substantially dye-free and substantially free of invert sugar.

[0033] In one embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 35 µm, said composition being substantially dye-free and substantially free of reducing sugars.

[0034] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 30 µm, said composition being substantially dye-free and substantially free of reducing sugars.

[0035] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 25 µm, said composition being substantially dye-free and substantially free of reducing sugars.

[0036] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 20 µm, said composition being substantially dye-free and substantially free of reducing sugars.

[0037] In yet another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 16 µm, said composition being substantially dye-free and substantially free of reducing sugars.

[0038] In one embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 35 µm, said composition being substantially dye-free and substantially free of reducing sugars.

[0039] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 30 µm, said composition being substantially dye-free and substantially free of reducing sugars.

[0040] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 25 µm, said composition being substantially dye-free and substantially free of reducing sugars.

[0041] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 20 µm, said composition being substantially dye-free and substantially free of reducing sugars.

[0042] In yet another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 16 µm, said composition being substantially dye-free and substantially free of reducing sugars.

[0043] In one embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 35 µm, said composition being substantially dye-free and substantially free of reducing sugars and substantially free of invert sugars.

[0044] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 30 µm, said composition being substantially dye-free and substantially free of reducing sugars and substantially free of invert sugars.

[0045] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 25 µm, said composition being substantially dye-free and substantially free of reducing sugars and substantially free of invert sugars.

[0046] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 20 µm, said composition being substantially dye-free and substantially free of reducing sugars and substantially free of invert sugars.

[0047] In yet another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 16 µm, said composition being substantially dye-free and substantially free of reducing sugars and substantially free of invert sugars.

[0048] In one embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 35 µm, said composition being substantially dye-free and substantially free of reducing sugars and substantially free of invert sugars.

[0049] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 30 µm, said composition being substantially dye-free and substantially free of reducing sugars and substantially free of invert sugars.

[0050] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 25 µm, said composition being substantially dye-free and substantially free of reducing sugars and substantially free of invert sugars.

[0051] In another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 20 µm, said composition being substantially dye-free and substantially free of reducing sugars and substantially free of invert sugars.

[0052] In yet another embodiment, the present invention relates to a pharmaceutical composition comprising acetaminophen particles having a d50 of less than or equal to 8 µm and a d90 of less than or equal to 16 µm, said composition being substantially dye-free and substantially free of reducing sugars and substantially free of invert sugars.

[0053] In one embodiment, the composition according to the invention is substantially free of non-reducing sugars, such as sucrose. Invention Details definition As used herein, the term "invert sugar" refers to a mixture of glucose and fructose obtained through the hydrolysis of sucrose. In sucrose, the enzyme invertase produces "invert sugar" (so named because hydrolysis causes a reversal of the rotation of plane-polarized light), a 50:50 mixture of fructose and glucose (its two component monosaccharides). It should be understood that the term "substantially free of an invert sugar" or "substantially free of invert sugars" means that invert sugar is not added as a separate component to the formulation described herein at any point during its preparation process, and therefore is not a separate component of the final product liquid suspension. It should be understood that trace amounts of invert sugar can be found in one or more excipients used in the formulation, such as in polyols like maltitol and sorbitol.

[0054] The term "particle" as used in this article can refer to crystals, granules, agglomerates, or any undissolved solid material.

[0055] As used herein, the term "extended period of time" refers to a time range greater than about 12 months. In one embodiment, the extended period of time is up to and includes about 18 months. In another embodiment, the extended period of time is up to and includes about 24 months. In yet another embodiment, the extended period of time is up to and includes about 36 months.

[0056] The term "reducing sugar" as used in this article refers to any sugar that can act as a reducing agent (and therefore can be oxidized) because it has a free aldehyde or free ketone group. All monosaccharides are reducing sugars, as are some disaccharides, oligosaccharides, and polysaccharides. Monosaccharides can be divided into two categories: aldoses, which have an aldehyde group, and ketoses, which have a ketone group. Ketosaccharides must first tautomerize to form aldoses before they can act as reducing sugars. Common dietary monosaccharides—galactose, glucose, and fructose—are reducing sugars. It should be understood that sucrose consists of two monosaccharides: glucose and fructose. Because the reducing groups (i.e., free aldehyde / ketone groups) of glucose and fructose participate in glycosidic bond formation and are unavailable, sucrose is a non-reducing sugar.

[0057] The term “substantially dye-free” as used herein means that no dye was added as a separate component to the formulation described herein at any point in its manufacturing process, and therefore it is not a separate component of the final product, the pharmaceutical liquid suspension.

[0058] It should be understood that the term "substantially free of a reducing sugar" or "substantially free of reducing sugars" means that reducing sugars are not added as a separate component to the formulation described herein at any point during its manufacturing process, and are therefore not a separate component of the final product, the pharmaceutical liquid suspension. Further understanding is needed, trace amounts of reducing sugars may be found in one or more excipients used in the formulation, for example, in maltitol syrup or sorbitol solution. Based on an analytical certificate for maltitol syrup, less than 0.10% reducing sugar is present on a dry weight basis (commercially available from Roquette Freres, France). Based on an analytical certificate for 70% sorbitol solution, for example, 0.08% reducing sugar is present on a dry weight basis; the maximum is 0.14% (commercially available from Roquette Freres, France).

[0059] It should be understood that the term "substantially free of non-reducing sugars for sucrose" means that sucrose is not added as a separate component to the formulation described herein at any point in its manufacturing process, and is therefore not a separate component of the final product, the pharmaceutical liquid suspension.

[0060] The active agent or ingredient is present in a therapeutically effective amount in an aqueous suspension per unit dose volume, which is the amount that produces the desired therapeutic response after oral administration and can be readily determined by those skilled in the art. In determining such an amount, as is known in the art, the active agent being administered, the bioavailability characteristics of the active agent, the dosage regimen, the patient's age and weight, and other factors must be considered. The "unit dose volume" of an aqueous suspension used herein is a convenient volume for administering the product to a patient. Dosage instructions will instruct the patient to ingest an amount that is a multiple of the unit dose volume, depending on, for example, the patient's age or weight. Typically, a unit dose volume of a suspension will contain a therapeutically effective amount of the active agent for the minimum patient. For example, a suitable unit dose volume may include one teaspoon (about 5 mL), one tablespoon (about 15 mL), one drop, or one milliliter. Brief description of the attached figures Figure 1The degradation products of acetaminophen in solution were described. Koshy KT, Lach JL (1961). Stability of aqueous solutions of N-acetyl-paminophenol. J Pharm Sci50:113-18. Imaizumi H, Nagai K (1978). Stability of non-pyrine antipyreticanalgesic. J.Pract.Pharm. 29:1161-6.

[0061] Figure 2 The CIELAB color space diagram is depicted (CIE L*a*b* (CIELAB is a color space designated by the International Commission on Illumination (the French International Commission on Illumination, hence its abbreviation CIE). It describes all colors visible to the human eye and is created as a device-independent model for use as a reference).

[0062] Figure 3 It is a graphical depiction of the color change contrast defined by the ΔE* values ​​of the analyzed samples (including formulations A, B, and C).

[0063] Figure 4A This is a graphical depiction of the total color difference ΔE* between formulation A and formulation B at a paracetamol concentration of 48 mg / mL. A freshly manufactured sample of formulation A is used as a reference.

[0064] Figure 4B This is a graphical depiction of the total color difference ΔE* for formulations A, B, and C at a paracetamol concentration of 24 mg / ml. A freshly manufactured sample of formulation A is used as a reference.

[0065] Figure 5 The effects of acetaminophen particle size and storage temperature on color measurements (in terms of luminance L*) were described for samples collected over 9 months.

[0066] Figure 6 This is a graphical depiction of the total color difference ΔE* between formulation A and formulation B at a paracetamol concentration of 48 mg / ml. A freshly manufactured sample of formulation A is used as a reference.

[0067] Figure 7 This is a graphical depiction of the total color difference ΔE* between formulations A, B, and C at a paracetamol concentration of 24 mg / ml. A freshly manufactured sample of formulation A is used as a reference.

[0068] Acetaminophen can be affected by a variety of degradation reactions. This is of particular concern when acetaminophen is formulated into a drug liquid suspension. Figure 1 The degradation products of acetaminophen in solution are shown. Figure 1 The reaction mechanism involves the hydrolysis of acetaminophen in aqueous solution to form p-aminophenol, which is then further oxidized to form pink quinineimide. The effect of oxygen on the discoloration of acetaminophen solution is a consequence of oxygen in the container's headspace and dissolved oxygen in the liquid. Recommendations given to limit discoloration are: (a) controlling the amount of oxygen in the container by controlling the fill volume and headspace; (b) ensuring appropriate packaging choices to minimize oxygen transfer through the packaging; (c) using degassing methods under reduced pressure or replacing oxygen with an inert gas (e.g., nitrogen) during manufacturing and / or filling; (d) considering the use of antioxidants in the formulation to minimize oxidation; and (e) removing or replacing excipients or major packaging components that may promote oxidation, such as trace metal ions, hydroperoxides, or initiators remaining in the polymer. (Mochizuchi, K et al.) Prediction of color changes in acetaminophen solution using the time- temperature superposition principle Drug Development and Industrial Pharmacy, Vol. 42, No. 7, pp. 1050-1057, (2015)).

[0069] The literature does not recognize that reducing the particle size of acetaminophen particles may be a limiting factor for discoloration in liquid suspensions containing acetaminophen. Furthermore, it is not recognized that acetaminophen liquid suspensions formulated with acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 35 µm would significantly limit discoloration, allowing the formulation to be substantially dye-free and still provide a commercially acceptable product.

[0070] It has also been found that temperature has a significant effect on the hydrolysis rate of acetaminophen and therefore on browning, because increased temperature translates into an increase in the solubility of acetaminophen (i.e., its concentration in solution) (Koshy KT et al., (1961), Stability of aqueous solutions of N-acetyl-paminophenol). J Pharm Sci 50:113-18 and Imaizumi H et al., (1978). Stability of non-pyrine antipyreticanalgesic, J Pract. Pharm , 29:1161-6).

[0071] Sedimentation is also a challenge when preparing liquid suspensions. It is known that the viscosity of a suspension affects sedimentation. Generally, as viscosity increases, the sedimentation rate decreases.

[0072] It is generally believed that the particle size of APIs affects the sedimentation rate of suspensions. Larger particle sizes are generally expected to result in a higher sedimentation rate. As particle size decreases, a lower sedimentation rate is expected. However, as particle size decreases, the color of the suspension is also expected to be negatively affected, i.e., increased browning is expected, because the particles have a larger surface area and are therefore exposed to more degradation reactions.

[0073] Surprisingly, the inventors have found the opposite in this paper. The present invention relates to a liquid suspension of acetaminophen, wherein the particle size distribution (d50 and d90) and particle size span are significantly smaller than those found in commercially available products. Despite the smaller particle size distribution, the present invention provides a storage-stable suspension that does not brown over extended periods, and therefore eliminates the need for dyes to mask discoloration or browning.

[0074] One of the most widely used methods for describing particle size distribution is the percentile, or "d" value. The d10, d50, and d90 values ​​are particle size values ​​corresponding to the cumulative distribution of 10%, 50%, and 90%, respectively. Based on mass distribution, the d-value can be thought of as a "mass-dividing diameter." This diameter divides the sample mass into a specified percentage when all particles in a sample are arranged in ascending order of mass. The percentage of mass below the target diameter is represented by the number following the "d". For example, the d10 diameter is the diameter when 10% of the sample mass contains smaller particles, and the d50 diameter is the diameter when 50% of the sample mass contains smaller particles. The d50 is also called the "mass median diameter" because it divides the sample equally by mass.

[0075] The median is defined as a value in which half of a population of particles of a specified size lies above the median and half lies below the median. For particle size distributions, the median is called d50 (or x50 when following certain International Organization for Standardization guidelines). d50 is a dimension in micrometers that separates the particle population distribution, with half above and half below a given diameter. For example, according to the present invention, a d50 for acetaminophen is defined as 10 µm, meaning that 50% of the acetaminophen particles are smaller than 10 µm and 50% are larger than 10 µm. For further details, see page 4 of https: / / www.horiba.com / fileadmin / uploads / Scientific / eMag / PSA / Guidebook / pdf / PSA_Guidebook.pdf.

[0076] As defined in this article, the span or width of the particle size distribution is defined as follows: It should be understood that a lower span corresponds to a narrower particle size distribution. Suitablely, the acetaminophen particles used in this invention have a span of less than 4.5 (e.g., from about 0.1 to about 4 or from about 0.5 to about 3.5). In one embodiment, the span is from about 1 to about 3. In another embodiment, the span is from about 2 to about 3. In this invention, assuming the d10 value is much smaller than d90, a sufficient approximation of the above span equation is the d90 / d50 value. Clearly, the d50 value is so low and d10 (by definition) even lower, that the d10 parameter will not substantially affect the span. Suitablely, in one aspect of the invention, the acetaminophen particles have a d10 value of less than about 5 µm (e.g., less than about 4 µm or less than about 3 µm). In one embodiment, the acetaminophen particles have a d10 value of about 2 µm.

[0077] Typical percentile values ​​of the particle size distribution of acetaminophen used in this paper were measured using a laser diffraction particle size analyzer (Malvern, Mastersizer 2000), and the d-values ​​are based on the volume distribution.

[0078] The present invention relates to the discovery that when the particle size distribution of acetaminophen in a pharmaceutical liquid suspension and the span of the particle size distribution of acetaminophen in a pharmaceutical liquid suspension are specifically defined, browning of the suspension is significantly reduced over a prolonged period of time.

[0079] Suitably, the acetaminophen particles have a d50 of less than or equal to 10 µm. In one embodiment, the acetaminophen particles have a d50 of from 5 µm to 10 µm. In another embodiment, the acetaminophen particles have a d50 of from 8 µm to 10 µm. In yet another embodiment, the acetaminophen particles have a d50 of less than or equal to 8 µm. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars, and substantially free of invert sugars.

[0080] Suitably, the acetaminophen particles have a distribution range in which d50 is less than or equal to 10 µm and d90 is less than or equal to 35 µm. In another embodiment, the acetaminophen particles have a distribution range in which d50 is less than or equal to 10 µm and d90 is less than or equal to 30 µm. In another embodiment, the acetaminophen particles have a distribution range in which d50 is less than or equal to 10 µm and d90 is less than or equal to 25 µm. In another embodiment, the acetaminophen particles have a distribution range in which d50 is less than or equal to 10 µm and d90 is less than or equal to 20 µm. In yet another embodiment, the acetaminophen particles have a distribution range in which d50 is less than or equal to 10 µm and d90 is less than or equal to 16 µm. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitable for any of these embodiments, the formulation is substantially free of dyes, substantially free of reducing sugars and substantially free of invert sugars.

[0081] Suitably, the acetaminophen particles have a distribution range where d50 is from 5 µm to 10 µm and d90 is less than or equal to 35 µm. In one embodiment, the acetaminophen particles have a distribution range where d50 is from 8 µm to 10 µm and d90 is less than or equal to 35 µm. In another embodiment, the acetaminophen particles have a distribution range where d50 is less than or equal to 8 µm and d90 is less than or equal to 35 µm. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars, and substantially free of invert sugars.

[0082] Suitably, the acetaminophen particles have a distribution range where d50 is from 5 µm to 10 µm and d90 is less than or equal to 30 µm. In one embodiment, the acetaminophen particles have a distribution range where d50 is from 8 µm to 10 µm and d90 is less than or equal to 30 µm. In another embodiment, the acetaminophen particles have a distribution range where d50 is less than or equal to 8 µm and d90 is less than or equal to 30 µm. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars, and substantially free of invert sugars.

[0083] Suitably, the acetaminophen particles have a distribution range where d50 is from 5 µm to 10 µm and d90 is less than or equal to 25 µm. In one embodiment, the acetaminophen particles have a distribution range where d50 is from 8 µm to 10 µm and d90 is less than or equal to 25 µm. In another embodiment, the acetaminophen particles have a distribution range where d50 is less than or equal to 8 µm and d90 is less than or equal to 25 µm. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars, and substantially free of invert sugars.

[0084] Suitably, the acetaminophen particles have a distribution range where d50 is from 5 µm to 10 µm and d90 is less than or equal to 20 µm. In one embodiment, the acetaminophen particles have a distribution range where d50 is from 8 µm to 10 µm and d90 is less than or equal to 20 µm. In another embodiment, the acetaminophen particles have a distribution range where d50 is less than or equal to 8 µm and d90 is less than or equal to 20 µm. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars, and substantially free of invert sugars.

[0085] Suitably, the acetaminophen particles have a distribution range where d50 is from 5 µm to 10 µm and d90 is less than or equal to 16 µm. In one embodiment, the acetaminophen particles have a distribution range where d50 is from 8 µm to 10 µm and d90 is less than or equal to 16 µm. In another embodiment, the acetaminophen particles have a distribution range where d50 is less than or equal to 8 µm and d90 is less than or equal to 16 µm. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars, and substantially free of invert sugars.

[0086] Acetaminophen is present in the pharmaceutical liquid suspension of the present invention at a concentration of about 2.0 to about 5.0% by weight / volume (those skilled in the art will understand that 2.0% by weight / volume is equivalent to 2.0 g / 100 mL suspension, which is equivalent to 20 mg / mL suspension). In one embodiment of the present invention, acetaminophen is present at an amount of 2.4 g / 100 mL suspension. In another embodiment of the present invention, acetaminophen is present at an amount of 3.2 g / 100 mL suspension. In yet another embodiment of the present invention, acetaminophen is present at an amount of 4.8 g / 100 mL suspension.

[0087] Water is present in the pharmaceutical liquid suspension according to the invention. Suitably, water is present in an amount of about 30 to about 70% by weight / volume (it will be understood that 70% corresponds to 70 g / 100 mL of suspension). In one embodiment of the invention, water is present in an amount of about 40 to about 60% by weight / volume, such as about 50% (i.e., about 50 g / 100 mL). It should be understood that the amount of water includes added free water and water added together with other substances (such as with sorbitol and / or maltitol solutions).

[0088] The pharmaceutical liquid suspension of the present invention may contain other components known to those skilled in the art, commonly referred to as additives. Additives may include, but are not limited to, known components such as flavoring agents, sweeteners, antioxidants, chelating agents, thickeners, preservatives, pH adjusters, surfactants, defoamers, cosolvents, humectants, and mixtures thereof.

[0089] Water-soluble high-intensity sweeteners can also be used in this invention. Examples of suitable high-intensity sweeteners include, but are not limited to, sucralose, aspartame, saccharin, acetylsupan, cyclohexanesulfonate, and pharmaceutically acceptable salts and combinations thereof. The amount of high-intensity sweetener used in the suspension will vary depending on the desired sweetness level for the particular suspension. Typically, the amount of high-intensity sweetener used in the suspension can vary between about 0 and about 2.0 g / 100 mL of suspension. In embodiments employing high-intensity sweeteners such as sucralose, aspartame, acetylsupan, saccharin, and pharmaceutically acceptable salts thereof, the level of high-intensity sweetener is about 0 to about 1 g / 100 mL of suspension. In one embodiment, the high-intensity sweetener is sucralose. In one embodiment of the invention, the suspension contains about 0 to about 0.5 g / 100 mL of high-intensity sweetener (e.g., about 0.1 to about 0.4 g / 100 mL of suspension).

[0090] Suitablely, the polyols used as sweeteners in this invention include, but are not limited to, sorbitol, mannitol, xylitol, erythritol, maltitol, and combinations thereof. The amount of polyol sweetener used in the suspension will vary depending on the desired sweetness level for a particular suspension. Typically, the amount of polyol sweetener can be in the range of about 0 to about 90 g / 100 mL suspension. In this invention, the suspension contains about 20 to about 70 g / 100 mL of maltitol solution. In one embodiment, the suspension contains about 50 to about 70 g / 100 mL of maltitol solution. In another embodiment, the suspension contains about 50 to about 60 g / 100 mL of maltitol solution. In one embodiment, the suspension contains about 0 to about 20 g / 100 mL of sorbitol solution (as a 70% aqueous solution). In another embodiment, the suspension comprises about 5 to about 15 g / 100 mL of sorbitol solution (as a 70% aqueous solution). In another embodiment, the suspension comprises about 10 to about 15 g / 100 mL of sorbitol solution (as a 70% aqueous solution). In one embodiment, the suspension comprises about 10 to about 20 g / 100 mL of sorbitol solution (as a 70% aqueous solution) and about 50 to about 60 g / 100 mL of maltitol solution. Suitably, the sorbitol solution is a non-crystalline sorbitol solution.

[0091] Suitable flavoring agents include natural and / or artificial flavoring agents such as peppermint (i.e., peppermint, spearmint, etc.), menthol, cinnamon, vanilla, artificial vanilla, chocolate, artificial chocolate, natural and / or artificial fruit flavoring agents (e.g., cherry, grape, orange, strawberry, etc.), and combinations of two or more of these. Flavoring agents are often complex mixtures of chemical compounds dissolved or dispersed in an inert medium (e.g., propylene glycol). These solutions or dispersions are typically provided as a minor component of the suspension in an amount that effectively imparts a palatable flavor to the suspension. In one embodiment, the flavoring agent is present in the suspension in an amount ranging from 0.01 to 1 g / 100 mL of suspension. In another embodiment, the flavoring agent is present in the suspension in an amount ranging from 0.05 to 0.15 g / 100 mL of suspension.

[0092] The pH of the suspension should be optimized to minimize solubility and maximize the chemical stability of APAP, an active agent with an unpleasant taste and hydrolysis sensitivity. In this invention, the pH of the suspension is suitably in the range of 4.5-6 or 5.5-6.5. In one embodiment of the invention, the pH of the suspension is 4.7-5.5. In one embodiment, the pH of the suspension is about 6.0. Suitably, in one embodiment, the target pH of the suspension according to the invention is about 5.0.

[0093] A pH adjuster can be used to buffer the suspension to maintain its pH within a desired pH range. A suitable pH adjuster can be present in the suspension in an amount sufficient to provide the desired level of pH buffering. pH adjusters are typically used in the range of about 0 to about 1 g / 100 mL of dye-free drug suspension. The pH adjuster can be selected from weak organic acids, such as citric acid, malic acid, sodium citrate (dihydrate), glutamic acid, etc., which have acceptable taste characteristics for use in oral suspensions that mask taste. In this invention, citric acid is present at 0.003-0.20 g / 100 mL of suspension. Citric acid is added to the suspension to stabilize its pH between 4.5 and 6, for example, about 4.7 to about 5.5. Antimicrobial preservatives are selected based on their activity within this pH range.

[0094] Optionally, an antimicrobial preservative is present in the dye-free suspension of the present invention. Suitable preservatives include, but are not limited to, methylparaben, propylparaben, sodium methylparaben, sodium ethylparaben, sodium propylparaben, and combinations thereof. Combinations of sodium methylparaben, sodium ethylparaben, and sodium propylparaben can be used, which are commercially available from Clariant in the form of Niasept sodium. Suitably, the preservative is present in a weight / volume percentage of about 0.00-0.25 g / 100 mL suspension. In one embodiment, methylparaben is present in an amount of 0.2 g / 100 mL suspension. In one embodiment, propylparaben is present in an amount of 0.045 g / 100 mL suspension. In another embodiment of the invention, methylparaben is present in an amount of 0.2 g / 100 mL suspension and propylparaben is present in an amount of 0.045 g / 100 mL suspension.

[0095] Suitable chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), including its salts, such as disodium salt and calcium disodium salt. Properly, the chelating agent is used in a weight / volume percentage of about 0.005-0.015 g / 100 mL suspension.

[0096] The dye-free pharmaceutical liquid suspension of the present invention is substantially free of coloring agents, such as dyes, lakes, etc. However, the dye-free pharmaceutical liquid suspension of the present invention may optionally incorporate certain pigments (e.g., titanium dioxide, etc.) as opacifiers.

[0097] The suspension of the present invention can employ a suspension system known in the art, which includes, but is not limited to, at least one thickening component. In one embodiment of the invention, the thickening component is present in the drug liquid suspension at an amount of about 0.05 to about 1.5 g / 100 mL of suspension (e.g., about 0.05 to about 0.70 g / 100 mL of suspension). In another embodiment of the invention, the thickening component is xanthan gum. In yet another embodiment of the invention, xanthan gum is present in the drug liquid suspension at an amount of about 0.65 g / 100 mL of suspension.

[0098] Another optional component of the pharmaceutical liquid suspension of the present invention is a humectant. Humectants suitable for use in the present invention include glycerin, sorbitol, polyethylene glycol, propylene glycol, and other edible polyols. Typically, the amount of humectant can be in the range of about 10 to about 20 grams per 100 mL suspension. In one embodiment of the invention, the humectant is glycerin. In another embodiment of the invention, the humectant is glycerin in the amount of about 10 to about 20 grams (such as about 15 grams) per 100 mL suspension.

[0099] An exemplary composition according to the present invention is a pharmaceutical liquid suspension comprising, on a basis of g / 100 mL suspension: (a) A therapeutically effective amount of acetaminophen in the form of microparticles, wherein the acetaminophen particles have a D50 of less than or equal to 10 µm and a D90 of less than or equal to 20 µm. (b) Approximately 0.20 to approximately 0.30 grams of a high-intensity sweetener such as sucralose; (c) A combination of approximately 40 to approximately 80 grams of polyol sweeteners such as maltitol and sorbitol; (d) A combination of preservatives such as methylparaben and propylparaben, in amounts of about 0.1 to about 0.3 grams; (e) Approximately 0.2 to approximately 0.4 grams of buffer; (f) Thickeners such as xanthan gum, in amounts of about 0.5 to about 1 gram; (g) Approximately 10 to 20 grams of a moisturizer such as glycerin; (h) Approximately 0.05 to approximately 0.1 grams of flavoring agent; (i) Approximately 40-60 grams of water; The pH of the composition is approximately 5.5 to approximately 6.5.

[0100] A suitable method for preparing the suspension composition described herein is a standard method as understood by those skilled in the art, and includes the following steps: a) Transfer the polyol sweetener into the master mixing container and add purified water, and mix continuously to produce a homogeneous mixture; b) If a preservative is present in the liquid suspension, the preservative is dissolved in pure water in a small premixing container with continuous stirring, and then transferred to the main mixing container with continuous stirring. c) Dissolve the water-soluble components in a small premixing container and transfer them to the main mixing container with continuous stirring; d) Add the thickener to the main mixing container and mix continuously until a homogeneous suspension is obtained; e) Add acetaminophen to the main mixing container and stir until a homogeneous suspension is obtained; f) Add the flavoring agent to the main mixing vessel under continuous stirring; and g) Add and mix enough water to the mixture from step (f) to produce a 100% desired volume of the drug suspension according to the invention, thereafter transferring the suspension to a storage tank for filling, labeling and packaging. Example

[0101] The invention will now be illustrated by examples. These examples are not intended to limit the scope of the invention, but are read in conjunction with the foregoing detailed and general description to provide a further understanding of the invention and an overview of preferred compositions thereof. Examples are provided using three acetaminophen drug liquid suspensions having the compositions shown in Table 1 below. It should be understood that the following units are expressed as weight / volume percentages, which are grams per 100 mL of solution.

[0102] Table 1 Element Formulation A Formulation B Formulation C Acetaminophen, European Pharmacopoeia (*) 2.0-5.0%wt / v (2.0-5.0mg / 100mL; 20mg / mL to 50mg / mL) 2.0-5.0%wt / v (2.0-5.0mg / 100mL; 20mg / mL to 50mg / mL) 2.0-5.0%wt / v (2.0-5.0mg / 100mL; 20mg / mL to 50mg / mL) Carbomer, European Pharmacopoeia 0.20-0.70 - Xanthan gum, European Pharmacopoeia 0.50-1.00 0.01-0.08 0.50-1.00 Nipasept sodium - 0.10-0.20 - Methylparaben 0.01-0.20 - - propylparaben 0.01-0.065 - - Sodium p-hydroxybenzoate - - 0.01-0.15 Sodium ethylparaben - - 0.01-0.03 Sodium p-hydroxybenzoate - - 0.01-0.03 glycerin 10-20 - - EDTA, European Pharmacopoeia 0.005-0.015 0.005-0.015 - Non-crystalline sorbitol (70% solution), European Pharmacopoeia 10-20 10-20 10-20 Sorbitol - - 2.0-2.5 Maltitol solution, European Pharmacopoeia 50-60 50-60 65-75 Malic acid, European Pharmacopoeia - 0.05-0.15 0.01-0.07 Anhydrous citric acid 0.020-0.030 - 0.02 Sodium citrate (dihydrate) 0.20-.030 - - Sodium hydroxide, European Pharmacopoeia - 0.10-0.20 - Sucralose, European Pharmacopoeia 0.20-0.30 0.05-.0.10 - Acetaminosulfamate potassium, European Pharmacopoeia - 0.01-0.05 - strawberry flavoring 0.05-0.10 0.010-0.015 0.05-0.15 Orange flavoring 0.05-0.15 0.05-0.15 - purified water Volume adjusted to 100 Volume adjusted to 100 Volume adjusted to 100 pH 6.0 6.0 5.0

[0103] Fine-grained acetaminophen (commercially available from Granules India, Ltd. or Farmson Ltd.) was used in formulation A. Coarser-grained acetaminophen (commercially available from Granules India, Ltd. or Farmson Ltd.) was used in formulations B and C. Therefore, formulation A falls within the scope of this invention. Formulations B and C fall outside the scope of this invention. The particle size distribution of the formulations is shown in Table 2 below. Particle size was measured using a Malvern Mastersizer 2000 by laser diffraction.

[0104] Table 2 : Formulation A Formulation B / C d10 (µm) 1.764 3.039 d50 (µm) 5.578 16.690 d90 (µm) 15.190 89.081 span 2.41 5.16 Importantly, it is noted that not only are the d50 and d90 of formulation A significantly smaller than those of formulations B and C, but the span between d50 and d90 of formulation A (i.e., d50 5.578µm and d90 15.190µm) and the span between d50 and d90 of formulations B and C (i.e., d50 16.690µm and d90 89.081µm) are also significantly smaller.

[0105] Example 1 Color was quantitatively measured using a spectrophotometer, and CIELAB color parameters were used. a *, b *, L * and Δ E * indicates a color change. L * indicates the brightness from white (100) to black (0). a * is green (-) a * to red (+) a *),and b * is blue (-) b * to yellow (+) b *). Figure 2 This represents a simplified 3D diagram of the CIELAB color space. The total color difference parameter Δ is calculated from the initial conditions before heat treatment.E * represents the Euclidean distance between two points in the three-dimensional CIELAB color space: .

[0106] ΔE* ≈ 2.3 (approximately 2.3) corresponds to the minimum perceptible difference (JND), which is defined as the amount of color that must be changed to make a color difference perceptible. (Sharma, Gaurav (2003), Digital Color Imaging Handbook (1.7.2 ed.), CRC Press. ISBN 0-8493-0900-X.)

[0107] Use the following measurement method: - Device: Colorflex-EZ available from HunterLab; - Mode: Reflection ability.

[0108] For each recorded measurement, two readings are obtained.

[0109] - The scale used is L*a*b*, set at D65 / 10.

[0110] Prior to characterization, the samples were stored in 60 mL amber glass vials under the following conditions: - The temperature represents a reference condition of 5°C (at which very limited color change is expected); - Temperature 25℃; - Temperature 40℃ represents accelerated test conditions.

[0111] Each bottle has the same top space to minimize differences caused by oxidation.

[0112] In Example 1, Reference Formulation A contained 48 mg / 100 mL of acetaminophen suspension and 0.0% wt. / v of methylparaben or propylparaben preservative. Figure 3 The results shown depict color trends over a maximum storage period of 6 months. According to... Figure 3 ΔE* increases with storage temperature and time. The dashed line represents the threshold for visible difference, i.e., when a visible color change or JND can be detected. At temperatures of 0 and 5°C, no visible color change was observed in the 48 mg / 100 mL acetaminophen suspension of reference formulation A. Figure 3 As shown, under accelerated stability conditions at 40°C, reference formulation A showed no visible color change after 1 or 2 months. Conversely, under... Figure 3In the study, the 48 mg / 100 mL acetaminophen suspension of reference formulation B, maintained at 40°C for 1 month, exhibited a ΔE* of approximately 35. For reference formulation A, only a slight visible color change was observed under accelerated stability conditions at 40°C for 3 months. Furthermore, even under accelerated stability conditions at 6 months and 40°C, the color change ΔE* of reference formulation A remained only approximately 7-8. Figure 3 As shown, under accelerated stability conditions, the perceived color change ΔE* for reference formulation A was significantly lower than that for reference formulations B and C. In terms of color change over time, formulation A is significantly superior and therefore more advantageous than formulations B and C.

[0113] Example 2 Using the same conditions and instruments as in Example 1, additional color measurements were obtained. In Example 2, Formulation A contained 4.8 g / 100 mL suspension (48 mg / mL) of acetaminophen, 0.2 g / 100 mL suspension of methylparaben, and 0.045 g / 100 mL suspension of propylparaben as preservatives. Formulation B contained 4.8 g / 100 mL suspension (48 mg / mL) of acetaminophen.

[0114] The color measurement results for samples of formulation A and formulation B are shown in Table 3 below. The formulation A sample at time 0 will be used as a reference for the calculation of ΔE*.

[0115] Table 3 : preparation L* a* b* ΔL* Δa* Δb* ΔE* Formulation A 48 mg / ml, at time 0 82.68 -0.52 2.8 0.00 0.00 0.00 0 Formulation A 48 mg / ml, at 3M 25℃ 81.9 -0.18 4.33 -0.78 0.34 1.53 1.75 Formulation A 48 mg / ml, at 3M 40℃ 75.97 1.46 7.96 -6.71 1.98 5.16 8.69 Formulation B, 48 mg / ml, at time 0 67.14 -0.59 -2.49 -15.54 -0.07 -5.29 16.42 Formulation B 48 mg / ml at 3M 40℃ 51.18 1.94 10.89 -31.5 2.46 8.09 32.62

[0116] The color measurement results of samples of formulations A, B, and C, each with a paracetamol concentration of 24 mg / ml, are shown in Table 4 below. The sample of formulation A at time 0 is used as a reference for the calculation of ΔE*.

[0117] Table 4 : preparation L* a* b* ΔL* Δa* Δb* ΔE* Formulation A 24 mg / ml, at time 0 70.55 -1.07 2.2 0 0 0 0.00 Formulation A 24 mg / ml at 3M, 25℃ 63.03 -0.54 2.74 -7.52 0.53 0.54 7.56 Formulation A 24 mg / ml at 3M, 40℃ 48.01 1.34 6.11 -22.54 2.41 3.91 23.00 Formulation C 3M, at 40℃ 40.94 2.2 6.3 -29.61 3.27 4.1 30.07 Formulation B 3M, at 40℃ 38.32 2.3 10.85 -32.23 3.37 8.65 33.54

[0118] Based on the values ​​shown in Tables 3 and 4, for a given acetaminophen concentration and under the same storage conditions, formulation A exhibited less color change than formulations B and C. At a concentration of 48 mg / mL, under accelerated stability conditions maintained at 40°C for 3 months, formulation A had a ΔE* of 8.69, which is above the JND threshold (ΔE* ≈ 2.3), and significantly lower than the ΔE* of formulation B at the same accelerated stability conditions of 32.62. These accelerated stability conditions at 40°C for 3 months represent a shelf life greater than approximately 36 months.

[0119] Comparing the ΔE* values ​​in Table 3, it can be seen that at the highest acetaminophen concentration of 48 mg / mL, this result is more pronounced for formulation A, where at time 0, formulation A has a ΔE* of 0, while formulation B has a ΔE* of 16.42. Nevertheless, at lower acetaminophen concentrations of 24 mg / mL, formulation A is still less dark compared to formulations B and C, even though the color difference is not very significant at this concentration. The difference between formulations is higher than the analytical variability (approximately ΔE* = ±1).

[0120] These results are in Figure 4A and Figure 4B It is depicted in graphic form.

[0121] Example 3 In Example 3, reference formulation A contained 48 mg / mL of acetaminophen suspension and 0.0% wt. / v of methylparaben or propylparaben preservative. Formulation A samples were prepared using two different acetaminophen particle size grades: fine (i.e., d10 1.764 µm, d50 5.578 µm, and d90 15.190 µm) and extra-fine (i.e., d10 3.039 µm, d50 16.690 µm, and d90 89.081 µm). Samples were stored under different temperature conditions and measured at different time points (the most recent measurement was taken after 9 months of storage). Bottles containing the samples had the same headspace. Results were analyzed using Design-Expert software (commercially available from Stat-Ease Inc.). Figure 5 The table shows the color measurement results of samples collected at 9 months. Measurement results of samples collected at 6 months showed a similar trend. Based on the above conditions, an experimental plan with three variables and mixed levels was constructed using the parameters in Table 5 below.

[0122] Table 5 : Acetaminophen particle size - d90 (µm) Storage temperature (°C) Minimum level 15 5 intermediate level - 25 maximum level 80 40

[0123] Figure 5The particle size distribution (PSD) along the A-axis, the temperature along the B-axis, and the L* (brightness from white (100) to black (0)) along the Y-axis were plotted. As the L* value increases, more light is visible through the formulation, and it appears whiter. As the L* value decreases, less light is visible through the formulation, and it appears darker and browner. For the extra-dense version of reference formulation A (d90 89.081µm rounded to 90µm) at 5°C, the L* value is approximately 67; at 25°C, the L* value is approximately 59; and at 40°C, the L* value is approximately 51. Therefore, for the extra-dense version of reference formulation A, the L* value decreases with increasing temperature, and the suspension appears darker and browner. For the fine version of reference formulation A (d90 approximately 15µm) at 5°C, the L* value is approximately 83; at 25°C, the L* value is approximately 81; and at 40°C, the L* value is approximately 69. Therefore, for the finer grade version of reference formulation A, the L* value did not change significantly from 5°C to 25°C, and the suspension appeared white. Furthermore, as the temperature increased to 40°C, the L* value of approximately 69 remained high, and thus the suspension appeared whiter compared to the approximately 67 L* value of the extra-fine grade version of formulation A at 5°C. As observed in previous measurements, the change in brightness L* was the primary cause of the overall color difference. For any storage temperature, the finer the acetaminophen particle size, the higher the brightness L* consistently appears, thus indicating a product with less discoloration.

[0124] Example 4 Using the same conditions and instruments as in Example 1, additional color measurements were obtained. In Example 4, Formulation A contained 4.8 g / 100 mL suspension (48 mg / mL) of acetaminophen. Formulation B contained 4.8 g / 100 mL suspension (48 mg / mL) of acetaminophen.

[0125] The color measurement results for samples of formulation A and formulation B are shown in Table 6 below. The formulation A (48 mg / mL) sample at time 0 will be used as a reference for ΔE* calculation.

[0126] Table 6: preparation L* a* b* ΔL* Δa* Δb* ΔE* Formulation A 48 mg / ml, at time 0 82.68 -0.52 2.8 0.00 0.00 0.00 0.00 Formulation A 48 mg / ml, after 3 months at 25°C 81.9 -0.18 4.33 -0.78 0.34 1.53 1.75 Formulation A 48 mg / ml, after 3 months at 40°C 75.97 1.46 7.96 -6.71 1.98 5.16 8.69 Formulation B 48mg / ml, at time 0 67.14 -0.59 -2.49 -15.54 -0.07 -5.29 16.42 Formulation B 48mg / ml, at 25℃ for 3 months. 66.39 -1.01 5.42 -16.29 -0.49 2.62 16.51 Formulation B 48mg / ml, within 3 months, at 40℃ 51.18 1.94 10.89 -31.5 2.46 8.09 32.62

[0127] Based on the results shown in Table 6, under the given storage conditions, the sample of formulation A (48 mg / ml) was confirmed to have lower darkness compared to the sample of formulation B (48 mg / ml). This conclusion was also confirmed after 3 months of storage at 25°C, and was validated by a ΔE* of 1.75 for formulation A, compared to 16.51 for formulation B. These results are in Figure 6 It is depicted in graphic form.

[0128] Example 5 Using the same conditions and instruments as in Example 1, additional color measurements were obtained. The color measurement results for samples of formulations A, B, and C, each with a paracetamol concentration of 24 mg / ml, are shown in Table 7 below. The formulation A (24 mg / ml) sample at time 0 is used as a reference for ΔE* calculation.

[0129] Table 7: preparation L* a* b* ΔL* Δa* Δb* ΔE* Formulation A 24 mg / ml, at time 0 70.55 -1.07 2.2 0 0 0 0 Formulation A 24 mg / ml, after 3 months at 25°C 63.03 -0.54 2.74 -7.52 0.53 0.54 7.56 Formulation A 24 mg / ml, after 3 months at 40°C 48.01 1.34 6.11 -22.54 2.41 3.91 23.00 Formulation B 24 mg / ml, at time 0 48.25 -0.5 -1.51 -22.3 0.57 -3.71 22.61 Formulation B 24mg / ml, within 3 months, at 25℃ 49.03 -0.39 0.02 -21.52 0.68 -2.18 21.64 Formulation B 24 mg / ml, within 3 months, at 40℃ 43.13 0.5 6.38 -27.42 1.57 4.18 27.78 Formulation C 24 mg / ml, at time 0 51.31 -0.78 -1.47 -19.24 0.29 -3.67 19.59 Formulation C 24 mg / ml, within 3 months, at 25°C 51.2 -0.49 -0.62 -19.35 0.58 -2.82 19.56 Formulation C 24 mg / ml, within 3 months, at 40℃ 42.94 1.32 3.92 -27.61 2.39 1.72 27.77

[0130] Based on the results shown in Table 7, for the given storage conditions, it was confirmed that the sample of formulation A (24 mg / ml) had a lower darkness than the samples of formulations B (24 mg / ml) and C (24 mg / ml). This conclusion was confirmed at (a) time 0, (b) after 3 months of storage at 25°C, and (c) after 3 months of storage at 40°C, and it was further confirmed by the lower ΔE* value of formulation A under each given storage condition.

[0131] These results are depicted graphically. Figure 7 middle.

[0132] Example 6 Using the same conditions and instruments as in Example 1, additional color measurements were obtained. In Example 6, formulation A contained 4.8 g / 100 mL suspension (48 mg / mL) of acetaminophen, and the color was tested after (a) storage at 40°C for 3 months and (b) storage at ambient temperature of 15–25°C for 27 months (representing the end of the storage period).

[0133] The color measurement results of the sample of formulation A are shown in Table 8 below. The sample of formulation A (48 mg / mL) at time 0 will be used as a reference for the calculation of ΔE*.

[0134] Table 8: preparation L* a* b* ΔL* Δa* Δb* ΔE* Formulation A 48 mg / ml, at time 0 82.68 -0.52 2.8 0 0 0 0 Formulation A 48 mg / ml, after 3 months at 40°C 75.97 1.46 7.96 -6.71 1.98 5.16 8.69 Formulation A 48 mg / ml is kept at 15-25°C for 27 months. 78.14 0.66 7.65 -4.54 1.18 4.85 6.75

[0135] As shown in Table 8, the results indicate similar ΔE* values ​​for formulation A after 3 months of storage at 40°C and for the same formulation A after 27 months of storage at 15-25°C (representing the end of the storage period). Based on these results, the color measurement results after 3 months of storage at 40°C can be considered an indication of the end of the storage period.

Claims

1. A pharmaceutical composition comprising a liquid suspension of acetaminophen particles having a d50 of less than or equal to 10 µm and a d90 of less than or equal to 35 µm, said composition being substantially dye-free and substantially free of reducing sugars.

2. The pharmaceutical composition according to claim 1, wherein the concentration of acetaminophen is 24 mg / ml.

3. The pharmaceutical composition according to claim 1, wherein the concentration of acetaminophen is 32 mg / ml.

4. The pharmaceutical composition according to claim 1, wherein the concentration of acetaminophen is 48 mg / ml.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the pharmaceutical composition comprises a high-intensity sweetener selected from sucralose, aspartame, saccharin, acetylsupan, cyclohexanesulfonate, and pharmaceutically acceptable salts thereof.

6. The pharmaceutical composition according to claim 5, wherein the high-intensity sweetener is sucralose.

7. The pharmaceutical composition according to any one of claims 1-6, wherein the pharmaceutical composition comprises a polyol sweetener selected from sorbitol, mannitol, xylitol erythritol, maltitol and combinations of at least two or more thereof.

8. The pharmaceutical composition according to claim 7, wherein the polyol sweetener is a combination of sorbitol and maltitol.

9. The pharmaceutical composition according to any one of claims 1-8, wherein the pharmaceutical composition comprises an antimicrobial preservative selected from methylparaben, propylparaben, sodium methylparaben, sodium ethylparaben, sodium propylparaben, and combinations of two or more thereof.

10. The pharmaceutical composition according to claim 9, wherein the antimicrobial preservative is a combination of methylparaben and propylparaben.

11. The pharmaceutical composition according to any one of claims 1-10, wherein the pharmaceutical composition comprises a thickener being xanthan gum.

12. The pharmaceutical composition according to any one of claims 1-11, wherein the pharmaceutical composition comprises a moisturizer selected from glycerin, sorbitol, polyethylene glycol, propylene glycol, and combinations of two or more thereof.

13. The pharmaceutical composition according to claim 12, wherein the humectant is glycerin.

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