Compositions of Vitamin A Palmitate, Methods for Their Preparation, Uses and Methods Involving Them

Abstract

The present invention relates to pharmaceutical compositions containing a therapeutically effective dose of vitamin A palmitate, processes for their preparation, and therapeutic uses and methods containing them. The compositions provided by the present invention can be used in the treatment and / or prevention of conditions and diseases caused by vitamin A deficiency.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of vitamin A palmitate; processes for their preparation; and uses and methods of treatment involving them. The compositions provided by the present invention can be used to treat and / or prevent conditions and diseases caused by vitamin A deficiency. [Background technology]

[0002] Vitamin A deficiency can result from inadequate intake, fat malabsorption, or liver disease. Premature separation from normal umbilical cord nutrition at preterm birth also results in significant deficiencies of a wide range of nutrients and metabolites, including vitamin A. Deficiency impairs immunity and hematopoiesis, causes rashes, and induces eye abnormalities such as xerophthalmia and night blindness. Treatment consists of oral administration of vitamin A, or parenteral administration if symptoms are severe or due to malabsorption.

[0003] Primary vitamin A deficiency is usually caused by long-term dietary restriction. It is endemic to regions of South and East Asia, where rice, lacking beta-carotene, is the staple food. Secondary vitamin A deficiency can result from reduced bioavailability of provitamin A carotenoids or from impaired absorption, storage, or transport of vitamin A. Impaired absorption or storage is more likely in celiac disease, cystic fibrosis, pancreatic insufficiency, duodenal bypass, chronic diarrhea, bile duct obstruction, giardiasis, and liver cirrhosis.

[0004] Impaired eye dark adaptation is an early symptom of vitamin A deficiency and can lead to night blindness. Xerophthalmia, which is almost pathognomonic, results from keratinization of the eye. It is accompanied by drying (xerosis) and thickening of the conjunctiva and cornea. Superficial, foamy patches (Bitot's spots) composed of epithelial debris and secretions develop on the exposed bulbar conjunctiva. In advanced deficiency, the cornea may become blurred and eroded, leading to corneal destruction (keratomalacia).

[0005] The younger the patient, the more severe the effects of vitamin A deficiency. Growth retardation and infections are common in children. Mortality can exceed 50% in children with severe vitamin A deficiency.

[0006] Other conditions associated with vitamin A deficiency include neonatal sepsis, hospital-acquired sepsis, sepsis due to premature rupture of membranes, measles, meningitis, pneumonia, necrotizing enterocolitis, and other viral or bacterial infections.

[0007] Despite technological advances, preterm birth and its associated complications remain a major public health problem. Each year, 10,000 to 15,000 infants develop chronic lung disease of prematurity (CLD), also known as bronchopulmonary dysplasia (BPD) (see, e.g., Non-Patent Documents 1 and 2). Many affected infants require long-term mechanical ventilation or supplemental oxygen, are repeatedly hospitalized for respiratory infections, and suffer from persistent airway obstruction and distal lung growth retardation (see, e.g., Non-Patent Document 3). Contrary to the conventional belief that BPD corrects with age due to compensatory lung growth (see, e.g., Non-Patent Document 4), evidence suggests that even mild BPD cases continue to exhibit pulmonary dysfunction throughout childhood and beyond (see, e.g., Non-Patent Document 5). In fact, pulmonary dysfunction in infants with BPD persists into adulthood, contributing to adult chronic respiratory disease, raising concerns that individuals who develop BPD in infancy may never achieve normal lung function (see, e.g., Non-Patent Documents 1 and 6). Furthermore, infants with BPD also exhibit physical growth retardation, neurocognitive delay, and cardiac dysfunction, including pulmonary hypertension (see, e.g., Non-Patent Documents 7 and 8). Despite recent advances in understanding the pathophysiology of BPD, no treatment options other than vitamin A administration have been consistently shown to be effective in clinical trials and meta-analyses. However, current forms of vitamin A therapy have not achieved widespread clinical acceptance.

[0008] For example, currently approved formulations of vitamin A for parenteral administration contain chlorobutanol as a preservative (e.g., AQUASOL A™; see prescribing information). It has been suggested that chlorobutanol should not be used as a preservative in injectable preparations for neonates and children (see, e.g., Non-Patent Document 9). Chlorobutanol has been implicated in causing somnolence in patients receiving high-dose salicylamide or morphine infusions containing chlorobutanol as a preservative (see, e.g., Non-Patent Documents 10 and 11). Delayed-type cellular hypersensitivity has also been reported when chlorobutanol is injected subcutaneously to preserve heparin (see, e.g., Non-Patent Document 12).

[0009] Therefore, improving vitamin A therapy for widespread clinical use is an important step in preventing BPD, with associated clinical, financial, and societal implications. In preterm infants, vitamin A plays an important role in lung maturation and development. Vitamin A deficiency (VAD) has been implicated in the development of BPD in this vulnerable population, particularly given that human fetuses accumulate vitamin A primarily during the third trimester of pregnancy. The mechanism of vitamin A transport across the placenta, its regulation, and fetal reserves have been the subject of research over the past 40 years. Premature infants have reduced hepatic retinyl ester stores (see, e.g., Non-Patent Document 13). In plasma, vitamin A binds to a specific carrier protein, retinol-binding protein (RBP), and the resulting complex is further complexed with transthyretin (see, e.g., Non-Patent Document 13). Premature infants have lower plasma RBP concentrations than term infants, and most premature infants have low plasma vitamin A concentrations and low plasma retinol / RBP molar ratios, indicating vitamin A deficiency (see, e.g., Non-Patent Document 14). Preterm infants with vitamin A concentrations below 200 μg / L (0.70 μmol / L) are considered deficient, and concentrations below 100 μg / L are severely deficient, indicating depletion of liver stores (see, e.g., Non-Patent Document 15 and Non-Patent Document 14). The plasma RBP response and relative increase in plasma retinol concentration after intramuscular (IM) vitamin A administration have been described as useful tests to assess functional vitamin A status (Non-Patent Document 16).

[0010] Vitamin A has been shown to play an important role in lung development, and it has been hypothesized that VAD predisposes to or contributes to BPD / CLD in these low-birth-weight infants (see, e.g., Non-Patent Documents 17-20). Indeed, two previous studies have reported that very low-birth-weight infants who developed CLD have lower vitamin A concentrations than similar infants who did not develop CLD (see, e.g., Non-Patent Documents 19 and 20). Preclinical studies further support the contribution of low plasma and tissue concentrations of vitamin A to the development of BPD / CLD in preterm infants. VAD in experimental animals has been shown to result in a series of histopathological changes in the airway epithelium, including necrotizing bronchial clefts and squamous metaplasia (see, e.g., Non-Patent Documents 21 and 22), which can be reversed by restoring adequate vitamin A status (see, e.g., Non-Patent Document 23). Similar changes are also observed in artificially ventilated infants with chronic neonatal lung injury and vitamin A deficiency (see, for example, Non-Patent Document 19).

[0011] Vitamin A supplementation has been shown to promote healing and recovery from lung injury and reduce the incidence of BPD / CLD in preterm infants (see, for example, non-patent literature 24-26). Thus, there is strong evidence supporting the role of vitamin A supplementation in preventing BPD / CLD and treating the underlying disease process, which begins within hours to days after birth. These underlying processes lead to the clinical manifestation that results in a diagnosis of BPD, defined historically or according to the current NIH definition of BPD (requirement of supplemental oxygen at 36 weeks postmenstrual age (non-patent literature 27)), which includes subclassifications of severity based on varying needs for supplemental oxygen or ventilatory support.

[0012] In preterm infants, particularly very low birth weight infants, oral administration of vitamin A has proven insufficient because most initially tolerate enteral nutrition and vitamin A absorption from the immature intestine is generally poor (see, e.g., Non-Patent Document 28). Preterm infants unable to tolerate oral intake typically require nutritional support via total parenteral nutrition (TPN). Despite the addition of a multivitamin containing retinol (or equivalent) to TPN, a significant decrease in delivered vitamin A occurs, hypothesized to be due to photolysis of vitamin A and / or adsorption to the intravenous tubing.

[0013] Intramuscular vitamin A monotherapy has been extensively evaluated in a series of studies specifically focusing on vitamin A administration for the prevention and treatment of BPD / CLD as well as as a supplement for VAD in preterm infants (see, for example, non-patent literature 29-32). [Prior art documents] [Non-patent literature]

[0014] [Non-Patent Document 1] Bronchopulmonary Dysplasia, National Heart, Lung and Blood Institute (NHLBI) [Internet] https: / / www.nhlbi.nih.gov / health-topics / bronchopulmonary-dysplasia [Non-patent document 2] Strueby, L., Thebaud, B., Advances in bronchopulmonary dysplasia, Expert Rev Respir Med, June 2014, 8(3);327-38 [Non-patent document 3] Baker, CD, Alvira, CM, Disrupted lung development and bronchopulmonary dysplasia: opportunities for lung repair and regeneration, Curr Opin Pediatr., June 2014, 26(3):306-14 [Non-patent document 4] O'Reilly, M., Sozo, F., Harding, R., Impact of preterm birth and bronchopulmonary dysplasia on the developing lung: long-term consequences for respiratory health, Clin Exp Pharmacol Physiol., November 2013, 40(11), 765-73 [Non-Patent Document 5] Grenough, A. et al., Lung volumes in infants who had mild to moderate bronchopulmonary dysplasia, Eur J Pediatr, September 2005, 164(9);583-6 [Non-patent document 6] Wong PM, Lees AN, Louw J, et al., Emphysema in young adult survivors of moderate-to-severe bronchopulmonary dysplasia. Eur Respir J, 2008;32(2):321-8 [Non-Patent Document 7] Cerny L, Torday JS, Rehan VK., Prevention and treatment of bronchopulmonary dysplasia: contemporary status and future outlook. Lung, 2008;186(2):75-89 [Non-patent document 8] Levy PT, Dioneda B, Holland MR, et al., Right ventricular function in preterm and term neonates: reference values for right ventricle areas and fractional area of change. J Am Soc Echocardiogr, 2015;28(5):559-69 [Non-Patent Document 9] Pharmacy in Practice, May 2004, p.101 [Non-Patent Document 10] Borody, T. et al., Chlorbutanol toxicity and dependence, Med J Aust 1979, 1:288 [Non-Patent Document 11] DeChristoforo, R. et al., High-dose morphine infusion complicated by chlorobutanol-induced somnolence, Annals of Internal Medicine, 1983;98;335-6 [Non-Patent Document 12] Dux, S. et al., Hypersensitivity reaction to chlorbutanol-preserved heparin, Lancet, 1981;1:149 [Non-Patent Document 13] Mactier H, Weaver LT. Vitamin A and preterm infants: what we know, what we don't know, and what we need to know. Archives of Disease in Childhood-Fetal and Neonatal Edition, 2005;90(2):F103-8 [Non-Patent Document 14] Shenai JP, Rush MG, Stahlman MT, Chytil F., Plasma retinol-binding protein response to vitamin A administration in infants susceptible to bronchopulmonary dysplasia. J Pediatr, 1990;116(4):607-14 [Non-Patent Document 15] Greene HL, Phillips BL, Franck L, et al., Persistently low blood retinol levels during and after parenteral feeding of very low birth weight infants: examination of losses into intravenous administration sets and a method of prevention by addition to a lipid emulsion. Pediatrics 1987;79(6):894-900 [Non-Patent Document 16] Zachman RD, Samuels DP, Brand JM, Winston JF, Pi JT. Use of the intramuscular relative-dose-response test to predict bronchopulmonary dysplasia in premature infants. Am J Clin Nutr, 1996;63(1):123-9 [Non-Patent Document 17] Chytil F, The lungs and vitamin A. Am J Physiol, 1992;262(5 Pt 1):L517-527 [Non-Patent Document 18] Shenai JP, Chytil F, Parker RA, Stahlman MT, Vitamin A status and airway infection in mechanically ventilated very-low-birth-weight neonates. Pediatr Pulmonol 1995;19(5):256-61 [Non-Patent Document 19] Hustead VA, Gutcher GR, Anderson SA, Zachman RD. Relationship of vitamin A (retinol) status to lung disease in the preterm infant. J Pediatr 1984;105(4):610-5 [Non-Patent Document 20] Shenai JP, Chytil F, Stahlman MT, Vitamin A status of neonates with bronchopulmonary dysplasia. Pediatr Res 1985;19(2):185-8 [Non-Patent Document 21] Lancillotti F, Darwiche N, Celli G, De Luca LM. Retinoid status and the control of keratin expression and adhesion during the histogenesis of squamous metaplasia of tracheal epithelium. Cancer Res, 1992;52(22):6144-52 [Non-Patent Document 22] Baybutt RC, Hu L, Molteni A, Vitamin A deficiency injures lung and liver parenchyma and impairs function of rat type II pneumocytes. J Nutr 2000;130(5):1159-65 [Non-Patent Document 23] Hind M, Maden M, Retinoic acid induces alveolar regeneration in the adult mouse lung. Eur Respir J, 2004;23(1):20-7 [Non-Patent Document 24] Guimaraes H, Guedes MB, Rocha G, Tomé T, Albino-Teixeira A., Vitamin A in prevention of bronchopulmonary dysplasia. Curr Pharm Des, 2012;18(21):3101-13 [Non-Patent Document 25] Tropea K, Christou H, Current pharmacologic approaches for prevention and treatment of bronchopulmonary dysplasia, Int J Pediatr, 2012;2012:598606 [Non-Patent Document 26] Young TE, Nutritional support and bronchopulmonary dysplasia, Journal of Perinatology, 2007;27:S75-8 [Non-Patent Document 27] PMA Ehrenkranz RA, Walsh MC, Vohr BR, et al., Validation of the National Institutes of Health Consensus Definition of Bronchopulmonary Dysplasia. Pediatrics, 2005;116(6):1353-60 [Non-patent document 28] Rush MG, Shenal JP, Parker RA, Chytil F, Intramuscular versus enteral vitamin A supplementation in very low birth weight neonates, The Journal of Pediatrics, 1994;125(3):458-62 [Non-Patent Document 29] Tyson JE, Wright LL, Oh W, et al., Vitamin A Supplementation for Extremely-Low-Birth-Weight Infants, New England Journal of Medicine, 1999;340(25):1962-8 [Non-Patent Document 30] Darlow BA, Graham PJ, Rojas-Reyes MX, Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants, In: Cochrane Database of Systematic Reviews, John Wiley & Sons, Ltd; 2016, available at: http: / / onlinelibrary.wiley.com / doi / 10.1002 / 14651858.CD000501.pub4 / abstract [Non-Patent Document 31] Kennedy KA, Cotten CM, Watterberg KL, Carlo WA, Prevention and management of bronchopulmonary dysplasia: Lessons learned from the neonatal research network, Seminars in Perinatology, 2016;40(6):348-55 [Non-Patent Document 32] Couroucli XI, Placencia JL, Cates LA, Suresh GK, Should we still use vitamin A to prevent bronchopulmonary dysplasia? J Perinatol, 2016;36(8):581-5 Summary of the Invention [Means for solving the problem]

[0015] The present invention provides pharmaceutical compositions comprising vitamin A palmitate, a surfactant, and water, preferably suitable for oral and / or parenteral administration. The present invention also provides pharmaceutical compositions prepared by processes according to the present invention, as well as such processes. The present invention further provides methods of treatment including the administration of these pharmaceutical compositions, and uses of these pharmaceutical compositions. DETAILED DESCRIPTION OF THE INVENTION

[0016] Vitamin A palmitate is the palmitate ester of retinol, which has the following structure:

[0017] [ka]

[0018] It should be noted that this structure represents the "all-trans" form of retinol, the common form of vitamin A used therapeutically. Various other forms exist that contain one or more cis- or other modifications to the all-trans-bond arrangement, including 13-cis-retinol (also known as isotretinoin), 9-cis-retinol, 9,13-dicis-retinol, and 3,4-didehydroretinol.

[0019] Surfactants for use in accordance with the present invention include, but are not limited to, polysorbate 20 (e.g., Tween® 20), polysorbate 60 (e.g., Tween® 60), polysorbate 80 (e.g., Tween® 80), stearyl alcohol, polyethylene glycol derivatives of hydrogenated castor oil (e.g., Cremophor® RH40), polyethylene glycol derivatives of hydrogenated castor oil (e.g., Cremophor® RH60), sorbitan monolaurate (e.g., For example, Span® 20), sorbitan monopalmitate (e.g., Span® 40), sorbitan monostearate (e.g., Span® 60), polyoxyethylene (20) oleyl ether (e.g., Brij® 020), polyoxyethylene (20) cetyl ether (e.g., Brij® 58), polyoxyethylene (10) cetyl ether (e.g., Brij® C10), polyoxyethylene (10) oleyl ether (e.g., Brij® O10), polyoxyethylene (20) oleyl ether (e.g., Brij® O20), polyoxyethylene (2 ... Ethylene (100) stearyl ether (e.g., Brij® S100), polyoxyethylene (10) stearyl ether (e.g., Brij® S10), polyoxyethylene (20) stearyl ether (e.g., Brij® S20), polyoxyethylene (4) lauryl ether (e.g., Brij® L4), polyoxyethylene (20) cetyl ether (e.g., Brij® 93), polyoxyethylene (2) cetyl ether (e.g., Brij® S2), caprylocapro Examples of suitable glycerides include polyethylene glycol (20) stearate (e.g., Myrj™ 49), polyethylene glycol (40) stearate (e.g., Myrj™ S40), polyethylene glycol (100) stearate (e.g., Myrj™ S100), polyethylene glycol (8) stearate (e.g., Myrj™ S8), and polyoxyl 40 stearate (e.g., Myrj™ 52), and mixtures thereof.

[0020] In one embodiment of the present invention, the surfactant is polysorbate 80. Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) has the following general structure:

[0021] [ka]

[0022] Regarding the fatty acid content of polysorbate 80, the United States Pharmacopoeia, and prescriptions in other countries, indicate that the acceptable standard for the fatty acid oleic acid content is 58% or greater. Other fatty acids may be present, for example, with acceptable standards of up to 5.0% myristic acid, up to 16.0% palmitic acid, up to 6.0% stearic acid, up to 18.0% linoleic acid, and up to 4.0% linolenic acid.

[0023] Polysorbate 80 of USP acceptable purity levels can be used in the compositions of the present invention, as can formulations of higher purity levels of polysorbate 80, such as 85% to 100% oleic acid (e.g., Super-Refined™ Polysorbate available from Croda), and greater than 98% oleic acid (e.g., Polysorbate 80(HX2)™ available from NOF).

[0024] Phase inversion Phase inversion refers to the phenomenon in which a primarily oily mixture turns into an oil-in-water emulsion when sufficient water or aqueous medium is added and stirred. Similarly, a primarily aqueous solution turns into a water-in-oil emulsion when oil is added. During the phase inversion process, fine droplets can form in the continuous phase. This process is strongly influenced by the preparation method, which can result in very different droplet size distributions. Furthermore, droplet size is related to product stability. Various phenomena affect the morphology of a system and ultimately lead to undesirable phase separation, including coalescence (the merging of two droplets into one), collision, creaming, sedimentation, and droplet rearrangement due to flow. For example, it is known that oil-in-water emulsions become unstable due to significant creaming when droplet radii exceed 0.5 μm (see, e.g., Preziosi, V. et al., Chemical Engineering Transactions, Vol. 32, 2013, pp. 1585-1590). The main mechanism responsible for the increase in droplet size is coalescence, which can be suppressed by the use of surfactants. Phase inversion, i.e., the phenomenon by which the dispersed phase becomes the continuous (main) phase (and vice versa), is an effective means of producing emulsions composed of very fine droplets. This can be brought about, for example, by changing the temperature of the system, changing the volume fraction of the phases, imposing specific stirring conditions, and imposing specific mixing conditions.

[0025] The compositions of the present invention, and the process by which they are prepared, are the result of an unexpected combination of preparation conditions that facilitate the formation of stable compositions with desirable properties for pharmaceutical use. Micelle "Micelle" refers to an aggregate of molecules, a class commonly known as surfactants or similar amphiphilic molecules, that possess both hydrophobic and hydrophilic properties. They are formed into spheres or other compact shapes with an outer surface composed of a monolayer of surfactant molecules, with the hydrophilic portion facing outward and the hydrophobic portion facing inward in aqueous solution. The hydrophilic portion of the surfactant interacts with water, facilitating the stable dispersion or dissolution of the micelles in aqueous media. The hydrophobic core of the micelle is useful for interacting with other hydrophobic molecules, providing a hydrophobic environment within the micelle that allows these other hydrophobic molecules to dissolve in fat, such as in the case of water-insoluble vitamin A palmitate. The hydrophilic surface of the micelle facilitates miscibility of these other water-insoluble hydrophobic molecules in aqueous solutions.

[0026] Micelles are generally small and, generally, are capable of remaining in solution indefinitely, given their density in the same range as water, and such permanent miscibility is a preferred feature of the pharmaceutical compositions of the present invention.

[0027] Micelle size can be determined by methods known in the art. Visual inspection can be used to first determine visual transparency. To directly evaluate micelle radius and particle size distribution, for example, quantification of light scattering at 400 nm and dynamic light scattering (DLS) can be used.

[0028] definition By "pharmaceutically acceptable acid" is meant an acid that is not biologically or otherwise undesirable in the pharmaceutical compositions of the present invention. Pharmaceutically acceptable acids can be inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as acetic acid, oleic acid, palmitic acid, stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, lactic acid, tartaric acid, etc.

[0029] By "pharmaceutically acceptable base" is meant a base that is not biologically or otherwise undesirable in the pharmaceutical compositions of the invention. Pharmaceutically acceptable bases include sodium hydroxide, ammonium hydroxide, potassium hydroxide, histidine, arginine, and lysine.

[0030] "Therapeutically effective amount," "therapeutically effective dose," or "pharmacologically effective amount" refers to an amount of vitamin A palmitate as disclosed in the present invention that has a therapeutic effect, i.e., an amount that alleviates or prevents to some extent one or more symptoms of vitamin A deficiency. A therapeutically useful dose of vitamin A palmitate is a therapeutically effective amount. Thus, as used herein, a therapeutically effective amount refers to an amount of vitamin A palmitate that produces a desired therapeutic effect as determined by clinical trial results and / or animal model studies, or that has been proven effective in routine medical practice to benefit patients.

[0031] "Parenteral administration" refers to routes of administration known to those skilled in the art and includes subcutaneous, intraperitoneal, intravenous, intradermal and intramuscular administration. By "suitable for parenteral administration" it is meant that the pharmaceutical compositions of the present invention meet quality standards known to those skilled in the art, such as those found in the United States Pharmacopoeia, the European Pharmacopoeia, and the Japanese Pharmacopoeia. Such standards include, for example, that the compositions are sterile and pyrogen-free, that they are clear or substantially free of visible particles, and that they are free of sub-visible particles as required by these pharmacopoeias, and that they show no evidence of phase separation or aggregate formation.

[0032] The amount and daily dose of vitamin A palmitate can be routinely determined by those skilled in the art, and varies depending on several factors such as patient's height, weight, sex, age and medical history.For preventive treatment, the therapeutically effective amount is the amount that is effective for preventing the pathology caused by vitamin A deficiency.

[0033] As used herein, "treat," "treatment," or "treating" refers to the administration of a pharmaceutical composition for prophylactic and / or therapeutic purposes. The terms "prophylactic treatment" or "prevention" refer to treating a patient who does not have symptoms of one or more conditions caused by vitamin A deficiency, but who is susceptible to or otherwise at risk for such one or more conditions. The term "therapeutic treatment" refers to administering treatment to a patient who already suffers from one or more conditions resulting from vitamin A deficiency. Thus, in a preferred embodiment, treating refers to administering a prophylactically and / or therapeutically effective amount of vitamin A palmitate to a mammal (for therapeutic or prophylactic purposes).

[0034] "Homogeneous intermediate state" refers to a mixture at or near the inversion point of water-in-oil or oil-in-water.

[0035] The term "substantially all" refers to an amount of 95% or more. As used herein, the term "patient" refers to a mammal, preferably a human.

[0036] Pharmaceutical Composition The preparation of the composition of the present invention is generally carried out in a two-step process. The first step is the slow and controlled addition of water or hot water to the premixture of warmed vitamin A palmitate and surfactant or surfactant mixture. The second step is the final addition of water at low temperature, followed by measuring and adjusting the pH as necessary. This is followed by sterilization by filtration and appropriate packaging.

[0037] First, the desired total volume of water is dispensed into a container, followed by bubbling nitrogen through the water to purge dissolved oxygen. It should be noted that vitamin A palmitate is sensitive to both oxygen and light. The procedure is carried out under inert, oxygen-free, atmospheric, and light-limited conditions. Vitamin A palmitate is preheated, weighed out, and added to a container containing the required amount of surfactant or surfactant mixture. This is gently stirred to avoid the formation of air bubbles in the mixture, and a portion of the final amount of water is slowly added to the mixture. After stirring for an appropriate period of time, the material reaches the oil-in-water / water-in-oil inversion point, sometimes referred to as the liquid crystal state.

[0038] The container is cooled and the remaining water (excluding approximately 5% or less of the remaining water that can be reserved to form a solution of an appropriate acid and / or base) is added as a single bolus, with continued stirring, to form a clear, amber liquid. At this point, if desired, the pH is adjusted by adding an appropriate acid or base, or one or more solutions of an appropriate acid or base. The target pH for a typical pharmaceutical product is pH 7.0-7.5.

[0039] The material can then be sterile filtered, for example, through a 0.22 micron (0.22 μm) or 0.10 micron (0.10 μm) filter. Such filters include nitrocellulose or other membranes whose pore size can be reproducibly controlled and which are generally inert so that the membrane material does not alter the chemical content of the filtrate.

[0040] It should be noted that packaging, such as parenteral injection vials, should be prepared so that the headspace above the compositions of the present invention is primarily nitrogen or other oxygen-depleted gas. Therapeutic and / or prophylactic uses The pharmaceutical compositions according to the present invention are intended for use in the treatment and / or prevention of vitamin A deficiency, including, but not limited to, bronchopulmonary dysplasia and retinopathy of prematurity, neonatal sepsis, hospital-acquired sepsis, sepsis due to premature rupture of membranes, measles, meningitis, pneumonia, necrotizing enterocolitis, and other viral or bacterial infections.

[0041] Vitamin A palmitate administration The amount of vitamin A palmitate, the frequency of administration, and the duration of a given course of treatment can be routinely determined by those skilled in the art, and will vary depending on several factors, including the patient's height, weight, sex, age, and medical history.Prophylactic treatment involves the use of medications and administration schedules to prevent the onset of vitamin A deficiency diseases.

[0042] Amounts of vitamin A palmitate can be expressed as USP units, international units, or weight of vitamin A palmitate. One USP unit is equivalent to one international unit, which is equivalent to 0.3 mcg of retinol.

[0043] Dosage examples include 100,000 units per day intramuscularly for 3 days, followed by 50,000 units per day for 2 weeks in adults; 17,500–35,000 units per day for 10 days in children aged 1–8 years; and 7,500–15,000 units per day for 10 days in infants. For BPD prevention in premature infants, 5,000 units per day intramuscularly 3 times a week for 4 weeks is commonly used.

[0044] Thus, in one embodiment of the present invention, there is provided a pharmaceutical composition comprising 0.03% (w / w) to 4.0% (w / w) vitamin A palmitate and a weight of surfactant that is at least 4.0 times the weight of vitamin A palmitate contained in the composition, wherein the remainder of the composition comprises water, and the pH is optionally adjusted to pH 7.0 to pH 7.5 by the addition of a pharmaceutically acceptable acid and / or a pharmaceutically acceptable base, the composition being composed of particles having an outer surface composed of the hydrophilic portions of the surfactant molecules that interact with water, and a hydrophobic interior composed of the hydrophobic portions of the surfactant molecules and substantially all of the vitamin A palmitate incorporated into the composition.

[0045] In another embodiment of the present invention, there is provided a pharmaceutical composition comprising 0.03% (w / w) to 4.0% (w / w) vitamin A palmitate and a surfactant in an amount by weight that is 4.0 to 5.0 times the amount of vitamin A palmitate contained in the composition, wherein the remainder of the composition comprises water, and the pH is optionally adjusted to a pharmaceutically suitable pH by the addition of a pharmaceutically acceptable acid and / or a pharmaceutically acceptable base, wherein the composition is composed of particles having an outer surface composed of the hydrophilic portions of the surfactant molecules that interact with water, and a hydrophobic interior composed of the hydrophobic portions of the surfactant molecules and substantially all of the vitamin A palmitate incorporated into the composition. In further embodiments, the surfactant is polysorbate 20, polysorbate 60, polysorbate 80, stearyl alcohol, polyethylene glycol derivatives of hydrogenated castor oil, polyethylene glycol derivatives of hydrogenated castor oil, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, polyoxyethylene (20) oleyl ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (10) cetyl ether, polyoxyethylene (10) oleyl ether, polyoxyethylene (100) stearyl ether, polyoxyethylene (10) stearyl ether, polyoxyethylene (20) stearyl ether, polyoxyethylene (4) lauryl ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (2) cetyl ether, caprylocaproyl polyoxyl-8 glyceride, polyethylene glycol (20) stearate, polyethylene glycol (40) stearate, polyethylene glycol, polyethylene glycol (8) stearate and polyoxyl 40 stearate, and mixtures thereof.

[0046] In another embodiment of the present invention, a pharmaceutical composition is provided, comprising 0.03% (w / w) to 4.0% (w / w) vitamin A palmitate and 4.0 to 5.0 times the weight of the vitamin A palmitate in the composition, with the remainder of the composition being water, and optionally adjusted to a pharmaceutically suitable pH by the addition of a pharmaceutically acceptable acid and / or a pharmaceutically acceptable base, wherein the composition is composed of particles having an outer surface comprising the hydrophilic portion of the polysorbate 80 molecule that interacts with water, and a hydrophobic inner portion comprising the hydrophobic portion of the polysorbate 80 molecule and substantially all of the vitamin A palmitate incorporated into the composition. In another embodiment of the present invention, the pharmaceutically suitable pH is between 7.0 and 7.5. In a further embodiment, the particles formed by the vitamin A palmitate and polysorbate 80 are in the form of micelles having a diameter of 500 nm or less. In a further embodiment, the micelles have a diameter of 250 nm or less. In a further embodiment, the micelles have a diameter of 100 nm or less. In another embodiment, a pharmaceutical composition comprising 0.3% to 3.0% vitamin A palmitate is provided. In a further embodiment, a pharmaceutical composition comprising 2.5% to 3.0% vitamin A palmitate is provided. In another embodiment, the fatty acid content of polysorbate 80 is 58% to 100% oleic acid. In a further embodiment, the fatty acid content of polysorbate 80 is 85% to 100% oleic acid. In a further embodiment of the present invention, the fatty acid content of polysorbate 80 is 98% or more oleic acid. In another embodiment of the present invention, the pharmaceutically acceptable acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oleic acid, palmitic acid, stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, lactic acid, and tartaric acid. In a further embodiment, the pharmaceutically acceptable base is selected from sodium hydroxide, ammonium hydroxide, potassium hydroxide, histidine, arginine, and lysine.In a further embodiment, the pharmaceutically acceptable acid is citric acid and the pharmaceutically acceptable base is sodium hydroxide. In a further embodiment of the present invention, a pharmaceutical composition suitable for parenteral administration is provided. In another embodiment of the present invention, a method for treating or preventing a vitamin A deficiency in a patient in need thereof is provided, comprising administering a pharmaceutically effective amount of a pharmaceutical composition in accordance with the present invention. In a further embodiment, the vitamin A deficiency is selected from neonatal sepsis, hospital-acquired sepsis, sepsis from premature rupture of membranes, bronchopulmonary dysplasia, retinopathy of prematurity, measles, meningitis, pneumonia, necrotizing enterocolitis, viral infections, and bacterial infections, and combinations of such disorders. In a further embodiment, the method for treating or preventing a vitamin A deficiency comprises oral or parenteral administration of a pharmaceutically effective amount of a pharmaceutical composition suitable for oral or parenteral administration in accordance with the present invention in a patient in need thereof. In a further embodiment, the patient is a human or a newborn born prematurely. In a further embodiment, the vitamin A deficiency disorder is bronchopulmonary dysplasia or retinopathy of prematurity. In a further embodiment, the vitamin A deficiency disorder is bronchopulmonary dysplasia. In a further embodiment of the present invention, the pharmaceutical composition of the present invention is used for treating or preventing vitamin A deficiency in a patient in need thereof. In a further embodiment, the vitamin A disorder is selected from neonatal sepsis, hospital-acquired sepsis, sepsis from premature rupture of membranes, bronchopulmonary dysplasia, retinopathy of prematurity, measles, meningitis, pneumonia, necrotizing enterocolitis, viral infections and bacterial infections, and combinations of such disorders. In a further embodiment, a pharmaceutical composition is provided for use in treating or preventing vitamin A deficiency, wherein the patient is a human or a newborn born prematurely. In a further embodiment, a pharmaceutical composition is provided for use in treating or preventing bronchopulmonary dysplasia or retinopathy of prematurity. In a further embodiment, a pharmaceutical composition is provided for use in treating or preventing bronchopulmonary dysplasia.

[0047] In another embodiment of the present invention, there is provided a pharmaceutical composition prepared by a process comprising the steps of: (1) Preparation of a mixture by combining vitamin A palmitate with a surfactant in an amount 4 to 5 times the weight of vitamin A palmitate; (2) heating the mixture obtained in step (1) to a temperature of 40°C to 70°C and stirring until homogenous; (3) adding water heated to a temperature between 40°C and 70°C in an amount between 20% and 80% of the weight of the mixture of step (1) over a period of 5 minutes to 90 minutes while stirring, until a homogeneous intermediate state is obtained; (4) cooling the mixture of step (3) to a temperature between 15°C and 40°C; (5) adding water in an amount as a bolus to achieve the appropriate final concentration of vitamin A palmitate, or in an amount of about 95% or more of this amount, followed by stirring for 5 minutes to 6 hours to obtain a stable mixture containing the appropriate micelle size; (6) adjusting the pH of the mixture from step (5) to a pharmaceutically acceptable pH by adding a pharmaceutically acceptable acid and / or a pharmaceutically acceptable base, or by adding one or more solutions of an acid and / or a base, and / or by adding water, as needed, to obtain a final appropriate concentration of vitamin A palmitate; and (7) Sterilizing the mixture from step (6) by filtering through a filter having a pore size between 0.1 microns (0.1 μm) and 0.22 microns (0.22 μm).

[0048] In further embodiments, the surfactant is polysorbate 20, polysorbate 60, polysorbate 80, stearyl alcohol, polyethylene glycol derivatives of hydrogenated castor oil, polyethylene glycol derivatives of hydrogenated castor oil, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, polyoxyethylene (20) oleyl ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (10) cetyl ether, polyoxyethylene (10) oleyl ether, polyoxyethylene (100) stearyl ether, polyoxyethylene (10) stearyl ether, polyoxyethylene (20) stearyl ether, polyoxyethylene (4) lauryl ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (2) cetyl ether, caprylocaproyl polyoxyl-8 glyceride, polyethylene glycol (20) stearate, polyethylene glycol (40) stearate, polyethylene glycol, polyethylene glycol (8) stearate and polyoxyl 40 stearate, and mixtures thereof.

[0049] In another embodiment of the present invention, there is provided a pharmaceutical composition prepared by a process comprising the steps of: (1) Preparation of a mixture by combining vitamin A palmitate with 4 to 5 times the weight of vitamin A palmitate and polysorbate 80; (2) heating the mixture obtained in step (1) to a temperature of 40°C to 70°C and stirring until homogenous; (3) adding water heated to a temperature between 40°C and 70°C in an amount between 20% and 80% of the weight of the mixture of step (1) over a period of 5 minutes to 90 minutes while stirring, until a homogeneous intermediate state is obtained; (4) cooling the mixture of step (3) to a temperature between 15°C and 40°C; (5) adding water in an amount as a bolus to achieve the appropriate final concentration of vitamin A palmitate, or in an amount of about 95% or more of this amount, followed by stirring for 5 minutes to 6 hours to obtain a stable mixture containing the appropriate micelle size; (6) adjusting the pH of the mixture from step (5) to a pharmaceutically acceptable pH by adding a pharmaceutically acceptable acid and / or a pharmaceutically acceptable base, or by adding one or more solutions of an acid and / or a base, and / or by adding water, as needed, to obtain a final appropriate concentration of vitamin A palmitate; and (7) Sterilizing the mixture from step (6) by filtering through a filter having a pore size between 0.1 microns (0.1 μm) and 0.22 microns (0.22 μm).

[0050] In a further embodiment, the pharmaceutically acceptable pH is between pH 7.0 and pH 7.5. In a further embodiment, the mixture obtained in step (1) is heated to a temperature between 45°C and 60°C. In a further embodiment, the mixture obtained in step (1) is heated to a temperature between 50°C and 60°C. In a further embodiment, the amount of water added in step (3) is between 35% and 70% of the weight of the mixture from step (1). In a further embodiment, the amount of water added in step (3) is between 50% and 60% of the weight of the mixture from step (1). In a further embodiment, the stirring in step (5) is carried out for 30 minutes to 2 hours. In a further embodiment of the present invention, the cooling in step (4) is to a temperature between 20°C and 30°C. In a further embodiment, the pharmaceutically acceptable acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oleic acid, palmitic acid, stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, lactic acid, and tartaric acid. In a further embodiment, the pharmaceutically acceptable base is selected from sodium hydroxide, ammonium hydroxide, potassium hydroxide, histidine, arginine, and lysine. In a further embodiment of the present invention, the pharmaceutically acceptable acid is citric acid and the pharmaceutically acceptable base is sodium hydroxide. In a further embodiment, the pharmaceutical composition prepared by the process embodiment described above is suitable for oral or parenteral administration. In a further embodiment, a method for treating or preventing vitamin A deficiency in a patient in need thereof is provided, the method comprising administering a pharmaceutically effective amount of the pharmaceutical composition prepared by the process of the present invention. In a further embodiment, a method for treating or preventing vitamin A deficiency comprises parenterally administering to a patient in need thereof a pharmaceutically effective amount of a pharmaceutical composition prepared by a process of the invention suitable for parenteral or oral administration according to the invention.In a further embodiment, the vitamin A disorder is selected from neonatal sepsis, hospital-acquired sepsis, sepsis from premature rupture of membranes, bronchopulmonary dysplasia, retinopathy of prematurity, measles, meningitis, pneumonia, necrotizing enterocolitis, viral and bacterial infections, and combinations of such disorders. In a further embodiment, the patient is a human or newborn born prematurely. In a further embodiment, the vitamin A deficiency disorder is bronchopulmonary dysplasia or retinopathy of prematurity. In a further embodiment, the vitamin A deficiency disorder is bronchopulmonary dysplasia. In a further embodiment of the present invention, the pharmaceutical composition of the present invention is used in the treatment or prevention of vitamin A deficiency in a patient in need thereof. In a further embodiment, the vitamin A disorder is selected from neonatal sepsis, hospital-acquired sepsis, sepsis from premature rupture of membranes, bronchopulmonary dysplasia, retinopathy of prematurity, measles, meningitis, pneumonia, necrotizing enterocolitis, viral and bacterial infections, and combinations of such disorders. In a further embodiment, a pharmaceutical composition prepared by the process of the invention is provided for use in treating vitamin A deficiency, wherein the patient is a prematurely born human or newborn. In a further embodiment, a pharmaceutical composition prepared by the process of the invention is provided for use in treating or preventing bronchopulmonary dysplasia or retinopathy of prematurity. In a further embodiment, a pharmaceutical composition prepared by the process of the invention is provided for use in treating or preventing bronchopulmonary dysplasia.

[0051] In another embodiment of the present invention, there is provided a process for the preparation of the pharmaceutical composition of the present invention, comprising the steps of: (1) Preparation of a mixture by combining vitamin A palmitate with a surfactant in an amount 4 to 5 times the weight of vitamin A palmitate; (2) heating the mixture obtained in step (1) to a temperature of 40°C to 70°C and stirring until homogenous; (3) adding water heated to a temperature between 40°C and 70°C in an amount between 20% and 80% of the weight of the mixture of step (1) over a period of 5 minutes to 90 minutes while stirring, until a homogeneous intermediate state is obtained; (4) cooling the mixture of step (3) to a temperature between 15°C and 40°C; (5) adding water in an amount as a bolus to achieve the appropriate final concentration of vitamin A palmitate, or in an amount of about 95% or more of this amount, followed by stirring for 5 minutes to 6 hours to obtain a stable mixture containing the appropriate micelle size; (6) adjusting the pH of the mixture from step (5) to a pharmaceutically acceptable pH by adding a pharmaceutically acceptable acid and / or a pharmaceutically acceptable base, or by adding one or more solutions of an acid and / or a base, and / or by adding water, as needed, to obtain a final appropriate concentration of vitamin A palmitate; and (7) Sterilizing the material from step (6) by filtering through a filter having a pore size between 0.1 micron (0.1 μm) and 0.22 micron (0.22 μm).

[0052] In another embodiment, the surfactant is polysorbate 20, polysorbate 60, polysorbate 80, stearyl alcohol, polyethylene glycol derivatives of hydrogenated castor oil, polyethylene glycol derivatives of hydrogenated castor oil, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, polyoxyethylene (20) oleyl ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (10) cetyl ether, polyoxyethylene (10) oleyl ether, polyoxyethylene (100) stearyl ether ether, polyoxyethylene (10) stearyl ether, polyoxyethylene (20) stearyl ether, polyoxyethylene (4) lauryl ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (2) cetyl ether, caprylocaproyl polyoxyl-8 glyceride, polyethylene glycol (20) stearate, polyethylene glycol (40) stearate, polyethylene glycol, polyethylene glycol (8) stearate and polyoxyl 40 stearate, and mixtures thereof.

[0053] In another embodiment of the present invention, there is provided a process for the preparation of the pharmaceutical composition of the present invention, comprising the steps of: (1) Preparation of a mixture by combining vitamin A palmitate with 4 to 5 times the weight of vitamin A palmitate and polysorbate 80; (2) heating the mixture obtained in step (1) to a temperature of 40°C to 70°C and stirring until homogenous; (3) adding water heated to a temperature between 40°C and 70°C in an amount between 20% and 80% of the weight of the mixture of step (1) over a period of 5 minutes to 90 minutes while stirring, until a homogeneous intermediate state is obtained; (4) cooling the mixture of step (3) to a temperature between 15°C and 40°C; (5) adding water in an amount as a bolus to achieve the appropriate final concentration of vitamin A palmitate, or in an amount of about 95% or more of this amount, followed by stirring for 5 minutes to 6 hours to obtain a stable mixture containing the appropriate micelle size; (6) adjusting the pH of the mixture from step (5) to a pharmaceutically acceptable pH by adding a pharmaceutically acceptable acid and / or a pharmaceutically acceptable base, or by adding one or more solutions of an acid and / or a base, and / or by adding water, as needed, to obtain a final appropriate concentration of vitamin A palmitate; and (7) Sterilizing the material from step (6) by filtering through a filter having a pore size between 0.1 micron (0.1 μm) and 0.22 micron (0.22 μm).

[0054] In a further embodiment, the pharmaceutically acceptable pH is between pH 7.0 and pH 7.5. In a further embodiment, the mixture obtained in step (1) is heated to a temperature between 45°C and 60°C. In a further embodiment, the mixture obtained in step (1) is heated to a temperature between 50°C and 60°C. In a further embodiment, the amount of water added in step (3) is between 35% and 70% of the weight of the mixture from step (1). In a further embodiment, the amount of water added in step (3) is between 50% and 60% of the weight of the mixture from step (1). In a further embodiment, the stirring in step (5) is carried out for 30 minutes to 2 hours. In a further embodiment, the cooling in step (4) is to a temperature between 20°C and 30°C. In a further embodiment, the pharmaceutically acceptable acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oleic acid, palmitic acid, stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, lactic acid, and tartaric acid. In a further embodiment, the pharmaceutically acceptable base is selected from sodium hydroxide, ammonium hydroxide, potassium hydroxide, histidine, arginine, and lysine. In a further embodiment of the invention, the pharmaceutically acceptable acid in step (6) is citric acid and the pharmaceutically acceptable base is sodium hydroxide. [Example]

[0055] The following examples serve not only to more fully describe the manner of using the above-described invention, but also to set forth the best mode contemplated for carrying out various aspects of the invention. Examples in accordance with the invention are within the scope of the claims appended hereto.

[0056] Example 1 Dispense 4.8 g of polysorbate 80 (PanReac AppliChem Tween® 80, USP-NF, pure, pharmaceutical grade) into a clean container. Then, add 1.1 g of vitamin A palmitate (DSM 1.7 MIU / g) preheated to 48°C. Stir the mixture in a 48°C water bath under a nitrogen atmosphere for 5 minutes. Next, add 3.2 g of water dropwise into the mixture over 44 minutes, noting that a uniform dispersion is achieved before adding the next drop. Stir the mixture for 5 minutes to obtain a material at or near the water-in-oil, water-in-oil inversion point. Cool the mixture to room temperature, and add 31 g of water as a bolus. Stir the mixture for 1 hour to obtain the composition of the present invention as a clear, amber liquid.

[0057] Example 2 Dispense 12.3 g of polysorbate 80 into a clean container. Then, add 2.8 g of vitamin A palmitate, which has been warmed to 60°C. Stir the mixture in a 60°C water bath under a nitrogen atmosphere for 5 minutes. Next, add 8.0 g of water dropwise to the mixture over 9 minutes, noting that each drop is dispersed throughout the mixture before adding the next drop. The mixture is then stirred for 5 minutes to obtain a material at or near the water-in-oil, water-in-oil inversion point. The mixture is cooled to room temperature, and 31 g of water is added as a bolus. The mixture is then stirred for 50 minutes to obtain the composition of the present invention as a clear, amber liquid.

[0058] Example 3 Dispense 23.9 g of polysorbate 80 (NOF Corporation HX2) into a clean container. Add 5.47 g of prewarmed vitamin A palmitate and stir the mixture for 5 minutes at a temperature of 57°C. A nitrogen blanket is used throughout this and further procedures. Next, add 15.9 g of water dropwise over 16 minutes. The mixture becomes viscous and is subjected to gentle mechanical stirring for an additional 5 minutes after this initial water addition. Cool the mixture to 25°C and add 154 g of water as a single bolus, also at 25°C. Stirring is continued for 75 minutes, resulting in a clear, amber liquid. Adjust the pH to 7.3 by adding sodium hydroxide to obtain the composition of the present invention.

[0059] Example 4 Dispense 23.9 g of polysorbate 80 (NOF Corporation HX2) into a clean container. Add 5.47 g of prewarmed vitamin A palmitate, and stir the mixture for 5 minutes at a temperature of 57°C. A nitrogen blanket is used throughout this and further procedures. Next, add 15.9 g of water dropwise over 16 minutes, stirring sufficiently to ensure that each drop of water is fully incorporated during the dropwise addition. Transfer the mixture to a 25°C environment, and add 154 g of water as a single bolus, also at 25°C. Stirring is continued for at least 75 minutes, or until the formulation is uniformly dispersed and a clear, amber liquid is obtained. Adjust the pH to 7.5 by adding sodium hydroxide, yielding the composition of the present invention.

Claims

1. 1. An aqueous pharmaceutical composition comprising vitamin A palmitate and a surfactant, wherein 95% or more of the vitamin A palmitate in the aqueous pharmaceutical composition comprises particles formed by the vitamin A palmitate and the surfactant in the form of micelles; the vitamin A palmitate is present in the aqueous pharmaceutical composition at a concentration of 0.3% (w / w) to 3.0% (w / w); the weight of the surfactant present in the aqueous pharmaceutical composition is 4.0 to 5.0 times the weight of the vitamin A palmitate present in the aqueous pharmaceutical composition; If necessary, the pH of the aqueous pharmaceutical composition is adjusted to pH 7.0 to 7.5 by the addition of a pharmaceutically acceptable acid and / or a pharmaceutically acceptable base; each of the micelles has a diameter of 500 nm or less; and The aqueous pharmaceutical composition, wherein the surfactant comprises polysorbate 80.

2. 2. The aqueous pharmaceutical composition of claim 1, wherein each of the micelles has a diameter of 250 nm or less.

3. 3. The aqueous pharmaceutical composition of claim 1 or claim 2, wherein each of the micelles has a diameter of 100 nm or less.

4. 4. The aqueous pharmaceutical composition according to claim 1, wherein the vitamin A palmitate is present in the aqueous pharmaceutical composition at a concentration of 2.5% (w / w) to 3.0% (w / w) of vitamin A palmitate.

5. An aqueous pharmaceutical composition according to any one of claims 1 to 4, wherein the fatty acid content of the polysorbate 80 is 98% or more of oleic acid.

6. 6. The aqueous pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable acid comprises citric acid and the pharmaceutically acceptable base comprises sodium hydroxide.

7. The aqueous pharmaceutical composition according to any one of claims 1 to 6, wherein the aqueous pharmaceutical composition is adapted for parenteral administration.

8. The aqueous pharmaceutical composition according to any one of claims 1 to 6, wherein the aqueous pharmaceutical composition is adapted for oral administration.

9. The aqueous pharmaceutical composition according to any one of claims 1 to 8, wherein the aqueous pharmaceutical composition is transparent.

10. 10. The aqueous pharmaceutical composition according to claim 1, wherein the aqueous pharmaceutical composition has transparency that meets or exceeds the standards set forth in European Pharmacopoeia 7.

0.

11. The aqueous pharmaceutical composition according to any one of claims 1 to 10, wherein the micelles are permanently mixed.

12. 12. The aqueous pharmaceutical composition of any one of claims 1 to 11, wherein the aqueous pharmaceutical composition is adapted for sterile filtration.

13. 13. The aqueous pharmaceutical composition according to any one of claims 1 to 12, for use in treating or preventing vitamin A deficiency in a subject in need thereof.

14. 14. The aqueous pharmaceutical composition of claim 13, wherein the vitamin A deficiency includes neonatal sepsis, hospital-acquired sepsis, sepsis from premature rupture of membranes, bronchopulmonary dysplasia, retinopathy of prematurity, measles, meningitis, pneumonia, necrotizing enterocolitis, viral infection, bacterial infection, or a combination thereof.

15. 1. A process for preparing an aqueous pharmaceutical composition, said process comprising: (1) providing a mixture of vitamin A palmitate and a surfactant, wherein the weight of the surfactant is 4 to 5 times the weight of the vitamin A palmitate; (2) warming the mixture of step (1) to a temperature of 40°C to 70°C and stirring the warmed mixture until homogeneous; (3) adding water over a period of 5 to 90 minutes while stirring to obtain a homogeneous intermediate state, wherein the weight of the water is 20% to 80% of the weight of the mixture of step (1), and optionally the water has a temperature of 40°C to 70°C; (4) cooling the mixture of step (3) to a temperature between 15°C and 40°C; (5) adding water to the mixture of step (4) to achieve a vitamin A palmitate concentration of 0.3% (w / w) to 3.0% (w / w); (6) stirring the mixture of step (5) for 5 minutes to 6 hours to obtain a stable mixture comprising micelles, each of which has a diameter of 500 nm or less, and optionally adjusting the pH of the stable mixture to 7.0 to 7.5 by adding a pharmaceutically acceptable acid and / or a pharmaceutically acceptable base; and (7) filtering the mixture of step (6) through a filter having a pore size between 0.1 microns (0.1 μm) and 0.22 microns (0.22 μm); Including, 1. A process for preparing an aqueous pharmaceutical composition, wherein the surfactant comprises polysorbate 80.

16. 13. Use of the aqueous pharmaceutical composition of any one of claims 1 to 12 in the manufacture of a medicament for the treatment or prevention of vitamin A deficiency in a subject in need thereof.

17. 17. The use of claim 16, wherein the vitamin A deficiency comprises neonatal sepsis, hospital-acquired sepsis, sepsis from premature rupture of membranes, bronchopulmonary dysplasia, retinopathy of prematurity, measles, meningitis, pneumonia, necrotizing enterocolitis, viral infection, bacterial infection, or a combination thereof.

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