US20180049983A1 - Liposomal rehydration salt formulation and associated methods of use - Google Patents
Liposomal rehydration salt formulation and associated methods of use Download PDFInfo
- Publication number
- US20180049983A1 US20180049983A1 US15/797,031 US201715797031A US2018049983A1 US 20180049983 A1 US20180049983 A1 US 20180049983A1 US 201715797031 A US201715797031 A US 201715797031A US 2018049983 A1 US2018049983 A1 US 2018049983A1
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- Prior art keywords
- salts
- formulation
- meq
- concentration
- liposomal
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Definitions
- the present invention relates to the technological field of improved oral rehydration salts.
- it relates to liposomal oral rehydration salts.
- Salt concentration as recommended by the WHO for rehydration salts is the following:
- FIG. 1 shows TEM (Transmission Electron Microscopy) images of a liposome sample of the present invention after the final stage of the preparation process.
- FIG. 2 illustrates the diameter distribution of the liposomes of the present invention formulation, wherein the particle size distribution in a DLS (Dynamic Light Scattering) analysis is shown.
- DLS Dynamic Light Scattering
- FIG. 3 illustrates a calibration curve for turbidity measurement.
- FIG. 4 represents the evolution of body mass in male animals according to Example 9.
- FIG. 5 represents the evolution of body mass in female animals according to Example 9.
- FIG. 6 represents the evolution of hematocrit concentration in male animals according to Example 9.
- FIG. 7 represents the evolution of hematocrit concentration in female animals according to Example 9.
- FIG. 8 represents the evolution of sodium concentration (Natremia) (mmol/L) in male animals according to Example 9.
- FIG. 9 represents the evolution of sodium concentration (Natremia) (mmol/L) in female animals according to Example 9.
- FIG. 10 represents the evolution of potassium concentration (Kalemia) (mmol/L) in male animals according to Example 9.
- FIG. 11 represents the evolution of potassium concentration (Kalemia) (mmol/L) in female animals according to Example 9.
- a liposomal rehydration salt formulation comprises phospholipids at a concentration of about 1.0 g/L to 10.0 g/L, salts, water, and a percentage inclusion ratio of salts (salts retained within total salts/liposomes) of at least 50% and a sodium electrolyte of about 12 mEq/L to 90 mEq/L, wherein the formulation has an actual osmolarity lower than 130 based on the at least 50% encapsulation of the salts and the liposomes comprise a particle diameter ranging from 200 nm to 500 nm.
- the sodium electrolyte may be from about 35 mEq/L to 55 mEq/L.
- the liposomal rehydration salt formulation may further comprise about 15 mEq/L to 25 mEq/L of potassium electrolyte.
- the phospholipids may be selected from the group consisting of phosphatidylcholines (PCs), phosphatidylserines (PSs), phosphatidylethanolamines (PEs), phosphatidylglycerols (PGs), phosphatidylinositols (PIs), phosphatidic acids (PAs), and mixtures thereof.
- the composition may further comprises an antioxidant selected from the group consisting of phytosterol, tocopherol, and mixtures thereof.
- the salts may be selected from the group consisting of sodium chloride at a concentration of 0.7 g/L to 2.8 g/L, potassium citrate at a concentration of 0.8 g/L to 2.5 g/L, sodium citrate at a concentration of 0.5 g/L to 2.9 g/L, and mixtures thereof.
- the formulation may further comprise about 10 g/L to 17 g/L of glucose and about 8.0 g/L to 15 g/L of at least one additional sugar.
- the formulation may further comprise Stevia at a concentration of about 0.1 g/L to 0.25 g/L.
- the formulation may further comprise natural flavours at a concentration of about 1 g/L to 3.5 g/L.
- a method of preventing severe dehydration and maintaining body electrolytes and fluids in a human comprises orally administering a liposomal rehydration salt formulation comprising phospholipids at a concentration of about 1.0 g/L to 10.0 g/L, salts, water, and a percentage inclusion ratio of salts (salts retained within total salts/liposomes) of at least 50% and a sodium electrolyte of about 12 mEq/L to 90 mEq/L, wherein the formulation has an actual osmolarity lower than 130 based on the at least 50% encapsulation of the salts and the liposomes comprise a particle diameter ranging from 200 nm to 500 nm.
- the rehydration salt formulation may be formulated for oral administration for use by humans that are pregnant or breast-feeding or engaged in one or more of sport exercises, outdoor activities, extreme weather activities, climbing and flying.
- the liposomal rehydration salt formulation may also be formulated for oral administration for use by patients having one or more of stomach ailments, skin burns, parenteral or enteral nutrition ailments, celiac disorders, diabetes, SGLT2 inhibitor treatment disorders, intestinal failure, Short Bowel Syndrome, Cycling Vomiting Syndrome, Gastroparesis, Postural Orthostatic Tachycardia Syndrome, Ulcerative Colitis, Colon Cancer, Dysphagia, Sjogren Syndrome, Crohn's disease, Lupus, Alzheimer's disease, Renal complications, HIV, Inflammatory Bowel Disease, an Ostomy, Microvillus Inclusion Disease, and Cystic Fibrosis.
- the sodium electrolyte may be from about 35 mEq/L to 55 mEq/L.
- the liposomal rehydration salt formulation may include a potassium electrolyte and administering about 15 mEq/L to 25 mEq/L of the potassium electrolyte.
- the liposomal rehydration salt formulation may comprise about 10 g/L to 17 g/L of glucose and 8.0 g/L to 15 g/L of at least one additional sugar.
- a method of rehydrating a human suffering from dehydration comprises orally administering a liposomal rehydration salt formulation comprising phospholipids at a concentration of about 1.0 g/L to 10.0 g/L, salts, water, and a percentage inclusion ratio of salts (salts retained within total salts/liposomes) of at least 50% and a sodium electrolyte of about 12 mEq/L to 90 mEq/L, wherein the formulation has an actual osmolarity lower than 130 based on the at least 50% encapsulation of the salts and the liposomes comprise a particle diameter ranging from 200 nm to 500 nm.
- the liposomal rehydration salt formulation of the present invention contains phospholipid liposomes, preferably selected from the group consisting of phosphatidylcholines (PCs), phosphatidylserines (PSs), phosphatidylethanolamines (PEs), phosphatidylglycerols (PGs), phosphatidylinositols (PIs), phosphatidic acids (PAs), and mixtures thereof, at a concentration of less than 6% (W/V); and optionally an antioxidant selected from phytosterol, tocopherol, and mixtures thereof, at a concentration of 0.2 to 0.5% (W/V); water; salts selected from the group consisting of sodium chloride at a concentration of 0.7 to 2.8 g/l, potassium citrate at a concentration of 0.8 to 2.5 g/l, sodium citrate at a concentration of 0.5 to 2.9 g/l, and mixtures thereof; optionally, it may further comprise carbohydrates, among which glucose is preferred.
- PCs
- Intestinal salt absorption mechanisms are enterocyte co-transport systems. These systems involve carrying salts into the body along with other molecules, glucose being the most important among them. This is why rehydration salt formulations targeting hyponatremia, associated both with sports and acute diarrhea, are composed of a mixture of salts and glucose. Salt concentration should be higher than that of the body, so that glucose-mediated transport can be enabled by an osmotic gradient allowing for incorporation of salts through membranes. However, glucose intake is restricted by the calorie intake of this molecule.
- Liposomes are nanoparticles consisting of a phospholipid bilayer, the same as cell membranes of enterocytes. Based on different mechanisms, liposomes (and all the contents carried in them) are highly capable of being absorbed by the small intestine cells, increasing bioavailability of the transported actives. Liposomal rehydration salt formulations aim at providing transport mechanisms of liposomes to the basic mechanisms of salts.
- one of the great advantages of the present invention relies on the use of lower carbohydrate concentrations, ranging from 0 to 6 g/l, which improves mouthfeel and tolerance to the formulation. Furthermore, it would be possible to replace glucose with a mixture of carbohydrates such as fructose, dextrose, high fructose corn syrup and mixtures thereof, and even with artificial sweeteners such as sucralose. Low glucose concentration is very important in sport drinks. It is even possible to accomplish efficient rehydration in the absence of glucose, which would allow the formulation to be consumed by diabetics.
- the formulation of the present invention exhibits reduced osmolality with respect to commercially-available formulations, also lower than 190 mmol/L, which accounts for the possibility of accomplishing efficient rehydration without running the risk of inducing hypernatremia in the patient.
- one of the novel aspects of this invention is the fact that it significantly improves percentage inclusion ratio of salts (salts retained within said liposomes/total salts) with respect to the prior art.
- This ratio is at least 40%, preferably at least 50%, more preferably at least 52%.
- said percentage inclusion ratio is at least 56%.
- Example 4 It has been demonstrated in Example 4 that encapsulation of more than 50% of the salts in the formulation of the present invention causes unpleasant taste inherent to salts to be almost imperceptible. This facilitates consumption by children younger than 12 years, who represent the most affected population in terms of acute dehydration.
- the liposomes of the formulation of the invention are produced such that the particle diameter ranges from 200 to 500 nm; preferably from 225 to 450 nm, as shown in FIG. 2 .
- the liposomal rehydration salt formulation of the present invention is an oral administration infusion for oral replacement of fluids and electrolyte salts in the treatment of dehydration caused by diarrhea and vomiting, prevention of severe dehydration, and maintenance of body electrolytes and liquids.
- the present invention may also be an oral administration infusion for use in sport activities.
- the process for preparing the formulation of the invention comprises the following steps:
- aqueous phase or buffer comprising sodium chloride, potassium citrate, sodium citrate dissolved in distilled water;
- step “c” subjecting the liposomal solution obtained in step “c” to a tangential ultrafiltration (TUF) concentration process, removing the buffer and maintaining the liposomes and their contents, thus reducing the volume at least by 10-fold;
- TUF tangential ultrafiltration
- step “d” subjecting the liposomal solution obtained in step “d” to a tangential ultrafiltration (TUF) concentration process, wherein ethanol is eliminated and the buffer is replaced with saline solution, and maintaining the liposomes and their contents.
- TUF tangential ultrafiltration
- said aqueous phase (AP) or buffer comprises sodium chloride at a concentration of 6 to 20 mmol/l, potassium citrate at a concentration of 1 to 12 mmol/l, sodium citrate at a concentration of 2 to 5 mmol/l, and distilled water.
- said saline solution comprises a sodium concentration of 12 to 50 mmol/l, a potassium concentration of 3 to 36 mmol/l, a chloride concentration of 15 to 40 mmol/l, a citrate concentration of 8 to 17 mmol/l, and it further comprises glucose at a concentration of 17 to 45 mmol/l.
- the AP:EP volume ratio in step “c” is at least 10:1; preferably at least 10:0.5; more preferably at least 10:0.4.
- the process of the present invention comprises a perpendicular flow process, wherein the ethanol phase is added on the aqueous phase by perpendicular coupling to the flow of the former, and with a linear velocity ratio REP/RAP of no more than 1/200.
- FIG. 1 shows liposomes formed with both processes.
- FIG. 2 shows the results of particle size distribution in DLS (Dynamic Light Scattering) analysis.
- Ultrafiltration without recirculation, by tangential flow, is carried out so as to remove the aqueous phase solutes that are not trapped in the liposomes. This process is completed after removing 90% volume of the previous liposomal dispersion.
- Ultrafiltration by tangential flow is carried out to remove ethanol from the liposomal salt solution. While the process is conducted, the solution is fed at a speed equal to the permeation speed with an aqueous solution of Sodium chloride (1.05 mg/ml), Potassium citrate (0.83 mg/ml), Sodium citrate (1.17 mg/ml) and Glucose (6.75 mg/ml).
- the liposomal rehydration salt formulation of the present invention is thereby obtained, said formulation having the following features:
- a solution of 4.5 L distilled water with salts is prepared at the following concentration:
- liposomal ORSs Five (5) liters of liposomal ORSs are subjected to a tangential ultrafiltration concentration process. This process allows for removing the buffer without eliminating the liposomes and their contents. This process is performed until the volume is reduced by 10-fold. At the end of the process, 500 ml of liposomal salts having the following concentration is obtained.
- the buffer is substituted by using the TUF process again.
- the total volume is reduced by 10-fold, and replaced with an aqueous solution with the following salt concentration.
- the so obtained formulation exhibits a salt concentration equal to that of the formulation recommended by the WHO, with an encapsulation efficiency of about 56.05%.
- Other features recommended by the WHO and UNICEF in their joint statement issued in May 2004 and accomplished in this invention are reduced glucose content and lower osmolality.
- the liposomal rehydration salt formulation of the present invention is thereby obtained, said formulation having the following features:
- FE1 Two phosphatidylcholine ethanol solutions are prepared, one of them named “FE1”, which has a concentration of 2% Phosphatidylcholine (the same as the one used in the TLEC formulation of U.S. Patent Publication No. 2005/0008685), and the other named “FE2”, with a concentration of 5% Phosphatidylcholine (the same as the one used in the present invention).
- Two liposomal solutions are then prepared using the ethanol phase injection method, in which 10 ml FE1 and FE2 are separately injected in two fractions of 90 ml AP under magnetic stirring at 300 rpm and 25° C. Consequently, 100 ml of two liposomal formulations are obtained:
- the LIPO-2 formulation was subjected to a tangential ultrafiltration process using a hollow fiber cartridge with a 300 KD cut off, without feedback. Ultrafiltration continued until reducing the volume by 10-fold. This is the process we carry out in our invention in order to obtain higher encapsulation efficiency.
- each formulation (LIPO-1 and LIPO-2) is taken and ultrafiltered by using the same system but feeding back each formulation with 126 mM sucrose aqueous buffer.
- the sulphate ions non-encapsulated into liposomes are eliminated from each solution and substituted with a solution having the same osmolality in order to ensure integrity of the liposomal membranes.
- Soluble sulphates precipitate in the presence of barium chloride in the form of barium sulphate (BaSO4) as a white solid. Measurement of tance reduction as a consequence of the presence of barium sulphate, to a certain wave length in a UV/Vis spectrometer allows for determination of the sulphate ion concentration in aqueous solution.
- a calibration curve was plotted by using 50 ml ammonium sulphate patterns with the following concentrations: 0.1 mM, 0.25 mM, 0.5 mM, 0.75 mM and 1 mM. An excess of 31.23 mg (3 mM) barium chloride was added to each solution. Then, transmittance of each solution was determined in triplicate by using an UV/VIS spectrometer (Jenway 7315). The calibration curve is shown in FIG. 3 .
- Formula A Liposomal rehydration salt formulation of example 3 of the present invention.
- Formula B Liposomal rehydration salts according to example 3 of U.S. Patent Publication No. 2005/0008685 A1.
- Healthy individuals from 21 to 40 years of age were recruited. Those individuals with cardiac or renal diseases, diabetics, individuals who had suffered from diarrhea the month prior to the assay, individuals affected by rhinitis, or individuals under antibiotic or iron treatment were excluded from the assay.
- the screening of the individuals took place in four different shopping malls in the city of Santa Fe, Argentina. After explaining the test to the individuals and having them signed their consent (either by themselves or by their parents or legal guardians in case of underage people), the individuals were randomized. Randomization indicates the order in which the two formulations would be tasted. In order to get familiar with this type of flavors, the individuals took a little sip of the two formulations and then rinsed their mouths with water and a piece of salt-free bread. Thereafter, they tasted the two formulations in the order indicated by randomization, and they were asked to indicate the formulation of their preference. The same test was repeated twice with both formulations, after a new mouth rinse with water and pieces of bread. They were offered each formulation in amounts of less than 20 ml in total, inside red plastic glasses (to avoid color influence on the decision). The formulations were administered at room temperature, without any refrigeration.
- a solution of 4.5 L distilled water is prepared with salts at the following concentration:
- the Five (5) liters of liposomal ORSs are subjected to a tangential ultrafiltration (TUF) concentration process. This process allows for removing the buffer without eliminating the liposomes and their contents. This process is carried out until reducing the volume by 10-fold. At the end of the process, 500 ml liposomal salts having the following concentration are obtained.
- TUF tangential ultrafiltration
- This buffer further contains Stevia (Reb A 97—PureCircle) at a concentration of 0.15 g/L; Sucrose at a concentration of 28.5 g/L; Citric Acid at a concentration of 3.6 g/L; and Natural Flavors at a concentration of 1.5 g/L.
- Stevia Reb A 97—PureCircle
- Sucrose at a concentration of 28.5 g/L
- Citric Acid at a concentration of 3.6 g/L
- Natural Flavors at a concentration of 1.5 g/L.
- a liposomal ORS solution containing 40 g/l phospholipid, with the following salt concentration:
- the formulation of the present example is useful for people in need of hydration due to sun exposure, illness, pregnancy, travel fatigue, hangover, mental stress, strenuous work, or just living an active life. It may be produced with orange, strawberry, apple, pear, blueberry, raspberry flavors, among others.
- a solution of 4.5 L distilled water is prepared with salts at the following concentration:
- Liposomal ORSs are subjected to a tangential ultrafiltration concentration process. This process allows for removing the buffer without eliminating the liposomes and their contents. This process is carried out until the volume is reduced by 10-fold. At the end of the process 500 ml of liposomal salts having the following concentration is obtained.
- This buffer further contains Sucralose at a concentration of 0.12 g/L; high fructose corn syrup (55° Brix) at a concentration of 33.3 g/L; Citric Acid at a concentration of 4.0 g/L; and Natural Flavors at a concentration of 1.7 g/L.
- the formulation of the present example is useful for children suffering from vomiting or diarrhea under the risk of dehydration, and it may be produced with orange, strawberry, apple, pear, blueberry, raspberry flavors, among others.
- a solution of 4.5 L distilled water is prepared with salts at the following concentration:
- Liposomal ORSs The five (5) liters of Liposomal ORSs are subjected to a tangential ultrafiltration concentration process. This process allows for removing the buffer without eliminating the liposomes and their contents. This process is carried out until the volume is reduced by 10-fold. At the end of the process, 500 ml of liposomal salts having the following concentration is obtained.
- This buffer further contains Stevia (Reb A 97—PureCircle) at a concentration of 0.13 g/L; Sucrose at a concentration of 22.2 g/L; Citric Acid at a concentration of 3.4 g/L; and Natural Flavors at a concentration of 1.5 g/L.
- Stevia Reb A 97—PureCircle
- Sucrose at a concentration of 22.2 g/L
- Citric Acid at a concentration of 3.4 g/L
- Natural Flavors at a concentration of 1.5 g/L.
- This formulation may be suitable for consumption by sportspeople.
- a solution of 4.5 L distilled water is prepared with salts at the following concentration:
- This buffer further contains high fructose corn syrup (55° Brix) at a concentration of 3.22 g/L; Vitamin B1 at a concentration of 0.002 g/L; Vitamin B5 at a concentration of 0.011 g/L; Vitamin B6 at a concentration of 0.011 g/L; Citric Acid at a concentration of 3.6 g/L; and Natural Flavors at a concentration of 1.5 g/L.
- high fructose corn syrup 55° Brix
- Vitamin B1 at a concentration of 0.002 g/L
- Vitamin B5 at a concentration of 0.011 g/L
- Vitamin B6 at a concentration of 0.011 g/L
- Citric Acid at a concentration of 3.6 g/L
- Natural Flavors at a concentration of 1.5 g/L.
- This formulation may be suitable for consumption by high-performance sportspeople.
- a batch of pediatric liposomal rehydration salts of Example 6 of the present invention as a finished product is compared to commercial product Pedialyte (Abbott Laboratories) taken as reference substance. Said comparison encompassed the development of an osmotic diarrhea model in rats for efficiency evaluation.
- Body weight, Natremia, Kalemia, and Hematocrit variables were analyzed both during treatment and 12 hours after completion. Young female and male Wistar rats with genetic certification were used. They were divided into subgroups, placed into jails, and identified with a correlative integer number.
- the animals were kept under controlled ambient conditions: temperature between 22 ⁇ 3° C., controlled photoperiod (12 hs light/12 hs darkness) and free access to commercial food and water.
- MicroVENT rack systems provided by Allentown Inc., European Type IIIH (POE GC-065) models, were employed.
- Group 1 (5 male and 5 female animals). It was distributed into 2 subgroups: 1-M; 1-F, each consisting of 5 animals of the same sex. These animals were subjected to osmotic diarrhea induction and treated with the test substances.
- Group 2 (5 male and 5 female animals). It was distributed into 2 subgroups: 2-M; 2-F, each consisting of 5 animals of the same sex. These animals were subjected to osmotic diarrhea induction and treated with the reference substance.
- Group 3 (5 male and 5 female animals). It was distributed into 2 subgroups: 3-M; 3-F, each consisting of 5 animals of the same sex. These animals were subjected to osmotic diarrhea induction and treated with physiological solution.
- Group 4 (5 male and 5 female animals). It was distributed into 2 subgroups: 4-M; 4-F, each consisting of 5 animals of the same sex. These animals did not receive any treatment.
- Groups 1, 2, and 3 were orally administered a total dose of 125 ml/kg/day of the different test substances, distributed in 12 doses at a one-hour-interval between each other.
- the dose was selected taking into account the dosing instructions of Pedialyte according to which doses of 100 to 150 ml/kg are recommended.
- the dosage volume of administration was calculated according to the average weight of the male and female rats obtained on Day 5 during the morning, at the time magnesium citrate solution was removed and treatment was initiated, thereby determining differential doses for male and female rats.
- V ⁇ ( ml animal ) P ⁇ 125 12 ⁇ 1000
- P is the average weight in grams, either of the male or female rats, as applicable.
- a microhematocrit was conducted by using heparinized microtubes. The samples were collected at the following times:
- the collected samples were also subjected to Natremia and Kalemia determination.
- the osmotic diarrhea model was developed as described in the literature, resulting in significant weight reduction and hematocrit increase due to dehydration.
- Hematocrit is the percent of the total volume of whole blood that is composed of red blood cells. Hematocrit loss during dehydration due to fecal excretion is negligible. This implies that the reduction of plasma extracellular fluid makes hematocrit increase.
- Natremia and Kalemia analyses are highly influenced by extracellular fluid recovery. Reduction in sodium concentration in all the experimental groups does not mean there is cation loss, but a reduction in cation concentration. This means the body absorbs sodium and recovers a higher liquid percentage; thus, its concentration diminishes.
- osmolality refers to moles per kilogram and the term “osmolarity” refers to moles per liter. They are different terms, but throughout this description, they could be used interchangeably due to low density values that enhance the low impact on the conversion of osmolality to osmolarity of the liposomal rehydration salt formulation as described.
- the concentrated phase of liposomes has been developed in a ratio of 1:20 and the end product profile has been upgraded, replacing HFCS such as high fructose corn syrup, with glucose and Stevia and other sugars while also using natural flavors and colors.
- HFCS high fructose corn syrup
- composition/formulation specification shows the different specifications for sodium, potassium, chloride, citrate, glucose, carbohydrates and calories.
- This current example is also known as Speedlyte® and is later compared to another non-liposome formulation sold by Abbot as Pedialyte® and compared to WHO (World Health Organization) 2002 recommendations.
- composition/formulation osmolarity should be taken as 125.8 mmol/L based on a current theoretical osmolarity of 188, with 54% of the electrolytes being encapsulated.
- composition/formulation osmolarity should be taken as 125.8 mmol/l based on a current theoretical osmolarity of 188, with 54% of the electrolytes being encapsulated.
- the osmolarity analysis (meq/L) is referred to as milliequivalents of solute per liter of solvent and is the amount of substance that reacts or is equivalent to another amount of substance.
- the equivalent is the amount of a substance needed to react with or supply one or more hydrogen ions in an acid-base reaction or react with or supply one or more of electrons in a redox reaction.
- the amount of a substance and equivalence is a very small magnitude and it is routinely described in terms of milliequivalents (meq) as the measure having been multiplied by 1,000.
- the osmolarity analysis comparing the World Health Organization 2002 standards (WHO 2002) with the formulation manufactured by Abbot as Pedialyte® and an example of the current formulation also referred to as Speedlyte® are illustrated above and compare the example values.
- the Pedialyte® composition is a non-liposomal formulation that includes a number ingredients as an oral fluid and electrolyte replacement. As shown in the table, it is evident that its osmolarity is much higher than the osmolarity of the current formulation.
- the electrolytes and liposomes serve as either a maintaining formula or a rehydration formula.
- the percentage deviation ranges described above are applicable and the current formulation as shown in the tables has 45 mEq/L of sodium and 20 mEq/L of potassium from 2.28 g/L of sodium chloride plus 2.04 g/L of potassium citrate and 0.5 g/L of sodium citrate.
- the more important electrolyte is sodium and that can range from 12 mEq/L to as high as 90 mEq/L.
- the potassium electrolytes can also vary based on the percentages described above and in one example is about 15 mEq/L to 25 mEq/L.
- Phospholipids help create the liposomes and the liposome concentrations and the range identified above is 1 to 60 g/L with other ranges as defined in the examples with 1 to 30, 1 to 40, or 1 to 50 g/L with the specific concentrations of 30, 40 and 50.
- the example formulation as described in the tables above has 2.5 g/L of phospholipids and that value can range from about 1 to 5 g/L, 1 to 10 g/L, in a preferred example, 5 to 10 g/L and up to 30, 40, 50 or 60 g/L.
- the amount and type of carbohydrates may vary and in one example, the carbohydrates are at a concentration of up to 6 g/L and up to 30 g/L.
- the current formulation as described in the tables has as carbohydrates 13.5 g/L of glucose and 11.5 g/L of sugar, and in an example may range from about 8.0 g/L to about 15.0 g/L of at least one additional sugar.
- the level of carbohydrates may be increased to as high as 70 g/L to appeal to a more mainstream product and it may be lowered to almost 0 g/L to appeal to diabetics and the elderly.
- Those ranges of glucose and sugar can vary from their mid-range value at 5%, 10%, 15%, 20%, and 25% differences above and below.
- the size of the liposomes are important for absorption as discussed above and can vary as noted above and is preferred about at 225 to 450 nm, but can range in an example from 200 to 500 nm. Although some available commercial products have smaller sized liposomes as alleged by their manufacturers, such as 100 mm, it has been determined their level of inclusion volume is low. Other oral liposome products, for example, using vitamin C, may have liposome sizes greater than 500 nm.
- natural flavors are concentrated at about 1.5 g/L.
- Natural flavorings and masking flavors may be at a concentration of up to 5 g/L.
- the example formulation shown in the charts above has about 3.12 g/L flavorings and these values could vary from 5%, 10%, 15%, 25%, or 25% above and below those values.
- One example range is about 1.0 g/L to about 3.5 g/L.
- Stevia may be used as a natural sweetener and in example, the Stevia in the examples above is indicated at a concentration of about 0.1 to 0.2 g/L, and in the example shown in the tables, is currently about 0.15 g/L, but it is possible to go as high as 0.22 in one example.
- One example range is about 1.0 g/L to about 3.5 g/L.
- the liposomal rehydration salt formulation not only maintains hydration, but also operates to rehydrate those persons that are dehydrated, in some cases serious. For example, it is possible to rehydrate and avoid the intravenous (IV) fluid delivery necessary in some cases because the formulation may be orally administered to humans suffering from dehydration caused by various factors as indicated below or suffering a moderate to severe dehydration with the need for IV fluids.
- the formulation also will allow fluid maintenance and avoid use of IV fluids by preventing severe dehydration while maintaining body electrolytes and fluids.
- the formulation may be used for rehydration due to stomach bugs in children and adults and hydration to prevent hangover or rehydration while in a hangover episode.
- the liposomal rehydration salt formulation may prevent or avoid the need for parenteral hydration, corresponding to fluids that are injected subcutaneously such as parenteral glucose or saline.
- the liposomal rehydration salt formulation may be used for hydration or rehydration for pregnant or breast-feeding women and for persons that need hydration or rehydration due to exercise (sport), outdoor activities, extreme weather or high-altitude conditions, skin burns, flying, hangover episodes, diarrhea, vomiting, high fever, stomach bugs or other types of gastritis, norovirus, rotavirus, and other types of bacteria and infections. Hikers that are climbing steep hills or cliffs may also find the liposomal rehydration salt formulation advantageous to help in maintaining body electrolytes and in hydration or rehydration.
- the liposomal rehydration salt formulation may also be used for hydration or rehydration to different populations, including patients with parenteral and enteral nutrition, to reduce the volume and consequently the time of intravenous (IV) treatments. It may be used with celiac patients, particularly during an episode such as when a person may inadvertently eat protein to which they may be allergic such as found in wheat, rye, and barley and their body mounts an immune response. The symptoms may include abdominal bloating, pain, gas, diarrhea, pale stools and weight loss.
- the liposomal rehydration salt formulation may also be used with elderly patients, pediatric patients, pregnant and breast-feeding patients, and diabetic patients, particularly those under a SGLT2 inhibitor treatment corresponding to a class of prescription medications that inhibit sodium-glucose transport protein 2 and that react to reduce blood to glucose levels.
- a class of prescription medications that inhibit sodium-glucose transport protein 2 and that react to reduce blood to glucose levels.
- Such class of medications are sometimes referred to as gliflozin drugs that inhibit the reabsorption of glucose in the kidney and therefore lower the blood sugar, sometimes too much.
- the liposomal rehydration salt formulation as described may also be used for those that suffer from intestinal failure, including the Short Bowel Syndrome, also called short gut, as a malabsorption disorder caused by the lack of a functioning small intestine. Diarrhea is a typical symptom that sometimes results in dehydration, malnutrition and weight loss.
- liposomal rehydration salt formulation Other populations that will benefit from the liposomal rehydration salt formulation include those that suffer from Cycling Vomiting Syndrome (CVS) with the sudden, repeated attacks as episodes of severe nausea, vomiting and physical exhaustion that could last a few hours to several days.
- CVS Cycling Vomiting Syndrome
- gastroparesis as, for example, delayed gastric emptying with paresis of the stomach and food often remaining in the stomach for an abnormally long time, which may cause chronic nausea and vomiting in some cases with erratic blood glucose levels.
- POTS Postural Orthostatic Tachycardia Syndrome
- Those suffering from ulcerative colitis and colon cancer could use the liposomal rehydration salt formulation to benefit them since often they become dehydrated.
- those having dysphagia and difficulty swallowing could benefit as well as those with Sjogren's syndrome, corresponding to a systemic autoimmune disease that may include dry eyes and dry mouth and often is accompanied by rheumatoid arthritis and lupus.
- Those with lupus or similar immune disorders may also benefit from the liposomal rehydration salt formulation.
- Especially beneficial would be those suffering from Crohn's Disease and lupus with typical abdominal cramping and pain as part of a chronic Inflammatory Bowel Disease (IBD) and inflammation of the digestive or gastrointestinal (GI) tract.
- IBD Inflammatory Bowel Disease
- GI digestive or gastrointestinal
- Crohn's Disease is usually limited to the end of the small intestine, as compared to ulcerative colitis, which is usually limited to the large intestine such as the colon and rectum.
- the liposomal rehydration salt formulation is beneficial for sufferers of either disorder. Those having kidney disease with dangerous levels of fluid, electrolytes and waste build up
- Those suffering from HIV are especially benefitted since often treatment for HIV and AIDS causes vomiting and diarrhea.
- Diarrhea is a typical side effect that accompanies use of HIV medications used for AIDS treatment. Often this includes nausea and headache with some fever, accompanied by vomiting and diarrhea.
- the liposomal rehydration salt formulation is especially beneficial in this type of treatment not only to help maintain electrolytes, but for rehydration.
- Some antiretroviral drugs for AIDS may increase blood sugar and diabetes and the liposomal rehydration salt formulation is beneficial.
- IBD Inflammatory Bowel Disease
- Crohn's Disease and ulcerative colitis would benefit as well as those with an ostomy, i.e., a stoma as a surgically created opening between the intestines and abdominal wall, and thus typically requiring a bag or pouch.
- This may can cause glucose levels and other electrolyte changes in the body, especially in the blood and intestines.
- Those suffering from microvillus inclusion disease also termed Davidson's Disease also suffer from chronic, intractable diarrhea causing metabolic acidosis and severe dehydration and thus would benefit from use of the liposomal rehydration salt formulation.
- CF cystic fibrosis
- CF is a genetic order affecting the lungs, it may also affect the pancreas, liver, kidneys and intestines causing difficulty in breathing. It can also cause fatty stool.
- the liposomal rehydration salt formulation can be used in many different types of cancer treatment and especially those suffering from HIV symptoms.
- the liposomal rehydration salt formulation has superior taste, higher absorption, less intake and lower sugar than other drinks and formulations both using and not using liposomal technology. Testimonies have stated that individuals feel better hydrated after taking the disclosed liposomal rehydration salt formulation and have fewer headaches and less need for IV fluids. Taken regularly, it especially may provide those suffering from gastroparesis, Crohn's Disease, ulcerative colitis, POTS, SBS, and colorectal cancer to reduce IV hydration and hospital visits, increase energy, reduce palpitations, feel less thirst, experience fewer headaches, eliminate cramps and reduce dizziness.
- the liposomal rehydration salt formulation hydrates in one-third of the time and requires only one-third of the intake as compared to many other hydration drinks.
- the current formulation also uses 46% less sugar than many commercially available hydration drinks.
- the current formulation aids those that live with the risk of dehydration and it is better than water since water is a very poor hydrator for moderate and severe situations and may cause loss of fluid greater than the amount of fluid consumed, thus leading to electrolyte imbalance.
- Even coconut water often may not contain enough electrolytes for maintaining proper hydration in severe and chronic dehydration situations.
- sports drinks do not contain enough electrolytes because they are designed for mild dehydration situations.
- electrolyte powders and tablets that are commonly available present absorption limitations and bad taste.
- Many commercially available oral rehydration solutions (ORS) are also old technology as compared to the current liposomal rehydration salt formulation that uses nano-electrolytes for higher fluid absorption, less intake requirements and better taste.
- the formulation can be diluted with water, juices and other drinks, depending on the electrolyte level required.
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Abstract
A liposomal rehydration salt formulation used for preventing severe dehydration, maintaining body electrolytes and fluids in a human, and rehydrating a human includes phospholipids at a concentration of about 1.0 g/L to 10.0 g/L, salts, water, and a percentage inclusion ratio of salts (salts retained within total salts/liposomes) of at least 50% and a sodium electrolyte of about 12 mEq/L to 90 mEq/L, wherein said formulation has an actual osmolarity lower than 130 based on the at least 50% encapsulation of the salts and said liposomes comprise a particle diameter ranging from 200 nm to 500 nm.
Description
- This is a continuation-in-part application based on U.S. patent application Ser. No. 15/111,485 filed Jul. 14, 2016, which is based upon a U.S. national stage application as international Application No. PCT/ES2015/070003 filed Jan. 7, 2015, which claims priority from Argentina Patent Application No. P20140100123 filed Jan. 14, 2014, the disclosures which are hereby incorporated by reference in their entirety.
- The present invention relates to the technological field of improved oral rehydration salts. In particular, it relates to liposomal oral rehydration salts.
- References to oral rehydration salts in the form of liposomes are not abundant in literature. Several attempts to develop isolated products of this kind have been disclosed, which have not been successful.
- It should be noted that U.S. Patent Publication No. 2005/0008685 (now abandoned) describes the use of liposomes for preparing oral rehydration salts. However, the percentage inclusion ratio of salts (salts retained within said liposomes/total salts) disclosed is 25%, which in spite of improving mouthfeel, still causes rejection by consumers or patients.
- On the other hand, there are several reports on the benefits from administering liposomal rehydration salts, such as in “Absorption of Water and Electrolytes from a Liposomal Oral Rehydration Solution: An in vivo Perfusion Study of Rat Small Intestine” by P. K. Bardhan, A. S. M. Hamidur Rahman, Rifaat, and D. A. Sack—ICDDR,B: Centre for Health and Population Research, GPO Box 128, Dhaka 1000, Bangladesh, published in December 2003. This document makes reference to the improved mouthfeel and improved absorption mechanism of rehydration salts due to the presence of liposomes.
- Salt concentration as recommended by the WHO for rehydration salts is the following:
-
ORS Concentration mmol/L Function Component g/L Glucose Na+ K+ Cl− Cit3− Rehydration Sodium 2.6 44.5 44.5 salts chloride Potassium 1.5 20.1 Chloride Sodium 2.9 29.6 9.9 citrate Sweetener Glucose 13.5 74.9 -
FIG. 1 shows TEM (Transmission Electron Microscopy) images of a liposome sample of the present invention after the final stage of the preparation process. -
FIG. 2 illustrates the diameter distribution of the liposomes of the present invention formulation, wherein the particle size distribution in a DLS (Dynamic Light Scattering) analysis is shown. -
FIG. 3 illustrates a calibration curve for turbidity measurement. -
FIG. 4 represents the evolution of body mass in male animals according to Example 9. -
FIG. 5 represents the evolution of body mass in female animals according to Example 9. -
FIG. 6 represents the evolution of hematocrit concentration in male animals according to Example 9. -
FIG. 7 represents the evolution of hematocrit concentration in female animals according to Example 9. -
FIG. 8 represents the evolution of sodium concentration (Natremia) (mmol/L) in male animals according to Example 9. -
FIG. 9 represents the evolution of sodium concentration (Natremia) (mmol/L) in female animals according to Example 9. -
FIG. 10 represents the evolution of potassium concentration (Kalemia) (mmol/L) in male animals according to Example 9. -
FIG. 11 represents the evolution of potassium concentration (Kalemia) (mmol/L) in female animals according to Example 9. - A liposomal rehydration salt formulation comprises phospholipids at a concentration of about 1.0 g/L to 10.0 g/L, salts, water, and a percentage inclusion ratio of salts (salts retained within total salts/liposomes) of at least 50% and a sodium electrolyte of about 12 mEq/L to 90 mEq/L, wherein the formulation has an actual osmolarity lower than 130 based on the at least 50% encapsulation of the salts and the liposomes comprise a particle diameter ranging from 200 nm to 500 nm. The sodium electrolyte may be from about 35 mEq/L to 55 mEq/L. The liposomal rehydration salt formulation may further comprise about 15 mEq/L to 25 mEq/L of potassium electrolyte. The phospholipids may be selected from the group consisting of phosphatidylcholines (PCs), phosphatidylserines (PSs), phosphatidylethanolamines (PEs), phosphatidylglycerols (PGs), phosphatidylinositols (PIs), phosphatidic acids (PAs), and mixtures thereof. The composition may further comprises an antioxidant selected from the group consisting of phytosterol, tocopherol, and mixtures thereof.
- The salts may be selected from the group consisting of sodium chloride at a concentration of 0.7 g/L to 2.8 g/L, potassium citrate at a concentration of 0.8 g/L to 2.5 g/L, sodium citrate at a concentration of 0.5 g/L to 2.9 g/L, and mixtures thereof. The formulation may further comprise about 10 g/L to 17 g/L of glucose and about 8.0 g/L to 15 g/L of at least one additional sugar. The formulation may further comprise Stevia at a concentration of about 0.1 g/L to 0.25 g/L. The formulation may further comprise natural flavours at a concentration of about 1 g/L to 3.5 g/L.
- A method of preventing severe dehydration and maintaining body electrolytes and fluids in a human comprises orally administering a liposomal rehydration salt formulation comprising phospholipids at a concentration of about 1.0 g/L to 10.0 g/L, salts, water, and a percentage inclusion ratio of salts (salts retained within total salts/liposomes) of at least 50% and a sodium electrolyte of about 12 mEq/L to 90 mEq/L, wherein the formulation has an actual osmolarity lower than 130 based on the at least 50% encapsulation of the salts and the liposomes comprise a particle diameter ranging from 200 nm to 500 nm. The rehydration salt formulation may be formulated for oral administration for use by humans that are pregnant or breast-feeding or engaged in one or more of sport exercises, outdoor activities, extreme weather activities, climbing and flying. The liposomal rehydration salt formulation may also be formulated for oral administration for use by patients having one or more of stomach ailments, skin burns, parenteral or enteral nutrition ailments, celiac disorders, diabetes, SGLT2 inhibitor treatment disorders, intestinal failure, Short Bowel Syndrome, Cycling Vomiting Syndrome, Gastroparesis, Postural Orthostatic Tachycardia Syndrome, Ulcerative Colitis, Colon Cancer, Dysphagia, Sjogren Syndrome, Crohn's disease, Lupus, Alzheimer's disease, Renal complications, HIV, Inflammatory Bowel Disease, an Ostomy, Microvillus Inclusion Disease, and Cystic Fibrosis.
- The sodium electrolyte may be from about 35 mEq/L to 55 mEq/L. The liposomal rehydration salt formulation may include a potassium electrolyte and administering about 15 mEq/L to 25 mEq/L of the potassium electrolyte. The liposomal rehydration salt formulation may comprise about 10 g/L to 17 g/L of glucose and 8.0 g/L to 15 g/L of at least one additional sugar.
- A method of rehydrating a human suffering from dehydration comprises orally administering a liposomal rehydration salt formulation comprising phospholipids at a concentration of about 1.0 g/L to 10.0 g/L, salts, water, and a percentage inclusion ratio of salts (salts retained within total salts/liposomes) of at least 50% and a sodium electrolyte of about 12 mEq/L to 90 mEq/L, wherein the formulation has an actual osmolarity lower than 130 based on the at least 50% encapsulation of the salts and the liposomes comprise a particle diameter ranging from 200 nm to 500 nm.
- The liposomal rehydration salt formulation of the present invention contains phospholipid liposomes, preferably selected from the group consisting of phosphatidylcholines (PCs), phosphatidylserines (PSs), phosphatidylethanolamines (PEs), phosphatidylglycerols (PGs), phosphatidylinositols (PIs), phosphatidic acids (PAs), and mixtures thereof, at a concentration of less than 6% (W/V); and optionally an antioxidant selected from phytosterol, tocopherol, and mixtures thereof, at a concentration of 0.2 to 0.5% (W/V); water; salts selected from the group consisting of sodium chloride at a concentration of 0.7 to 2.8 g/l, potassium citrate at a concentration of 0.8 to 2.5 g/l, sodium citrate at a concentration of 0.5 to 2.9 g/l, and mixtures thereof; optionally, it may further comprise carbohydrates, among which glucose is preferred.
- Intestinal salt absorption mechanisms are enterocyte co-transport systems. These systems involve carrying salts into the body along with other molecules, glucose being the most important among them. This is why rehydration salt formulations targeting hyponatremia, associated both with sports and acute diarrhea, are composed of a mixture of salts and glucose. Salt concentration should be higher than that of the body, so that glucose-mediated transport can be enabled by an osmotic gradient allowing for incorporation of salts through membranes. However, glucose intake is restricted by the calorie intake of this molecule.
- Liposomes are nanoparticles consisting of a phospholipid bilayer, the same as cell membranes of enterocytes. Based on different mechanisms, liposomes (and all the contents carried in them) are highly capable of being absorbed by the small intestine cells, increasing bioavailability of the transported actives. Liposomal rehydration salt formulations aim at providing transport mechanisms of liposomes to the basic mechanisms of salts. In vivo tests have shown that an encapsulated ORS formulation having salt concentrations in accordance with WHO standards causes a 1.39-fold hydration increase in animals under normal conditions, as compared to the WHO recommended formula, and a 1.45-fold hydration increase in animals infected with cholera as compared to the WHO recommended formula (“Absorption of Water From a Liposomal Oral Rehydration Solution: an In Vivo Perfusion Study of Rat Small Intestine Exposed to Cholera Toxin” Gastroenterology—Volume 142,
Issue 5,Supplement 1, Pages S-21, May 2012—Pradip K. Bardhan, Nasirul Islam, Rifat Faruqui). - In view of the above, one of the great advantages of the present invention relies on the use of lower carbohydrate concentrations, ranging from 0 to 6 g/l, which improves mouthfeel and tolerance to the formulation. Furthermore, it would be possible to replace glucose with a mixture of carbohydrates such as fructose, dextrose, high fructose corn syrup and mixtures thereof, and even with artificial sweeteners such as sucralose. Low glucose concentration is very important in sport drinks. It is even possible to accomplish efficient rehydration in the absence of glucose, which would allow the formulation to be consumed by diabetics.
- In addition, and also due to lower glucose concentration, the formulation of the present invention exhibits reduced osmolality with respect to commercially-available formulations, also lower than 190 mmol/L, which accounts for the possibility of accomplishing efficient rehydration without running the risk of inducing hypernatremia in the patient.
- Furthermore, one of the novel aspects of this invention is the fact that it significantly improves percentage inclusion ratio of salts (salts retained within said liposomes/total salts) with respect to the prior art. This ratio is at least 40%, preferably at least 50%, more preferably at least 52%. In a preferred alternative of the present invention, said percentage inclusion ratio is at least 56%. These inclusion ratio values have not been previously disclosed in the prior art, and they allow for the preparation of formulations containing lower salt concentrations with improved rehydration effects, as disclosed in the present invention. This inclusion ratio is achieved by using tangential ultrafiltration method. Although well-known, this method has never been employed to increase the ratio of oral rehydration salts encapsulated within liposomes to the total amount of the salts of the formulation, thereby solving the technical problem of rejection caused by oral rehydration salts due to their unpleasant taste.
- It has been demonstrated in Example 4 that encapsulation of more than 50% of the salts in the formulation of the present invention causes unpleasant taste inherent to salts to be almost imperceptible. This facilitates consumption by children younger than 12 years, who represent the most affected population in terms of acute dehydration.
- Furthermore, the liposomes of the formulation of the invention are produced such that the particle diameter ranges from 200 to 500 nm; preferably from 225 to 450 nm, as shown in
FIG. 2 . - The liposomal rehydration salt formulation of the present invention is an oral administration infusion for oral replacement of fluids and electrolyte salts in the treatment of dehydration caused by diarrhea and vomiting, prevention of severe dehydration, and maintenance of body electrolytes and liquids. The present invention may also be an oral administration infusion for use in sport activities.
- The process for preparing the formulation of the invention comprises the following steps:
- a. preparing an aqueous phase (AP) or buffer comprising sodium chloride, potassium citrate, sodium citrate dissolved in distilled water;
- b. separately preparing an ethanol phase (EP), by dissolving said phospholipid at a concentration of 0.1 to 6% (W/V), and optionally an antioxidant at a concentration of 0.2 to 0.5% (W/V) in alcohol, preferably ethyl alcohol;
- c. inducing formation of liposomes by injecting said EP into said AP at room temperature, while stirring;
- d. subjecting the liposomal solution obtained in step “c” to a tangential ultrafiltration (TUF) concentration process, removing the buffer and maintaining the liposomes and their contents, thus reducing the volume at least by 10-fold;
- e. subjecting the liposomal solution obtained in step “d” to a tangential ultrafiltration (TUF) concentration process, wherein ethanol is eliminated and the buffer is replaced with saline solution, and maintaining the liposomes and their contents.
- In step “a”, said aqueous phase (AP) or buffer comprises sodium chloride at a concentration of 6 to 20 mmol/l, potassium citrate at a concentration of 1 to 12 mmol/l, sodium citrate at a concentration of 2 to 5 mmol/l, and distilled water.
- In step “e” of the process of the present invention, said saline solution comprises a sodium concentration of 12 to 50 mmol/l, a potassium concentration of 3 to 36 mmol/l, a chloride concentration of 15 to 40 mmol/l, a citrate concentration of 8 to 17 mmol/l, and it further comprises glucose at a concentration of 17 to 45 mmol/l.
- Furthermore, the AP:EP volume ratio in step “c” is at least 10:1; preferably at least 10:0.5; more preferably at least 10:0.4.
- The process of the present invention comprises a perpendicular flow process, wherein the ethanol phase is added on the aqueous phase by perpendicular coupling to the flow of the former, and with a linear velocity ratio REP/RAP of no more than 1/200.
- Preparation of the Liposomal Rehydration Salt Formulation of the Invention
- 25 g of purified soybean phosphatidylcholine and 0.5 L of ethanol are added, heated to 65° C., and stirred until completely dissolved. A total amount of 2.5 g of mixed tocopherols (ascorbyl palmitate and D-Alpha-Tocopherol) is added as antioxidant. The solution is left to rest until it reaches room temperature.
- 4.33 g Sodium chloride, 3.42 g Potassium citrate, and 4.83 g Sodium citrate are dissolved in 4.5 L water and stirred at room temperature until completely dissolved.
- 0.5 L of Ethanol phase is slowly added on 4.5 L of Aqueous phase under continuous circular stirring. This may be also performed by means of a Cross-Flow or Perpendicular Flow process, wherein the Ethanol phase is added on the Aqueous phase by perpendicular coupling to the flow of the former, and with a linear velocity ratio, REP/RAP, of no more than 1/200.
FIG. 1 shows liposomes formed with both processes.FIG. 2 shows the results of particle size distribution in DLS (Dynamic Light Scattering) analysis. - Ultrafiltration without recirculation, by tangential flow, is carried out so as to remove the aqueous phase solutes that are not trapped in the liposomes. This process is completed after removing 90% volume of the previous liposomal dispersion.
- e) Buffer substitution
- Ultrafiltration by tangential flow is carried out to remove ethanol from the liposomal salt solution. While the process is conducted, the solution is fed at a speed equal to the permeation speed with an aqueous solution of Sodium chloride (1.05 mg/ml), Potassium citrate (0.83 mg/ml), Sodium citrate (1.17 mg/ml) and Glucose (6.75 mg/ml).
- The liposomal rehydration salt formulation of the present invention is thereby obtained, said formulation having the following features:
-
- Percentage inclusion ratio of salts (salts retained within liposomes/total salts) of 56.48%
- Chloride concentration: 39.7 mmol/L
- Citrate concentration: 16 mmol/L
- Potassium concentration: 17.9 mmol/L
- Sodium concentration: 69.7 mmol/L
- Glucose concentration: 33.0 mmol/L
- Process for Preparing the Present Invention Formulation with a Percentage Inclusion Ratio of Salts of 56%
- A solution of 4.5 L distilled water with salts is prepared at the following concentration:
-
Concentration (mmol/L) Glucose Na K Cl Cit Sodium chloride 14.82 14.82 Potassium citrate 6.70 2.23 Sodium citrate 11.23 3.74 Glucose — - Separately, a solution of Phosphatidylcholine in 500 ml of 5% ethyl alcohol (W/V) is prepared.
- Stage c
- Formation of liposomes is induced by injecting the ethanol solution into the aqueous phase while stirring. Then 15% of the salts are encapsulated; therefore, internal and external salt concentrations are as follows:
-
Internal External Na 3.91 22.14 K 1.00 5.70 Cl 2.23 12.60 Cit 0.895 5.074 Glucose 0 0 - Five (5) liters of liposomal ORSs are subjected to a tangential ultrafiltration concentration process. This process allows for removing the buffer without eliminating the liposomes and their contents. This process is performed until the volume is reduced by 10-fold. At the end of the process, 500 ml of liposomal salts having the following concentration is obtained.
-
Internal External Na 39.1 22.14 K 10.0 5.70 Cl 22.3 12.60 Cit 8.95 5.074 Glucose 0 0 - At this stage, the buffer is substituted by using the TUF process again. In this case, the total volume is reduced by 10-fold, and replaced with an aqueous solution with the following salt concentration.
-
Concentration (mmol/L) Na 31.57 K 8.13 Cl 17.96 Cit 7.24 Glucose 40.70 - Accordingly, 500 ml of a solution of liposomal ORSs having the following salt concentration is obtained.
-
Internal External TOTAL Na 39.1 30.64 69.74 K 10.0 7.88 17.88 Cl 22.3 17.45 39.75 Cit 8.95 7.02 15.97 Glucose 0 33.03 33.03 - The so obtained formulation exhibits a salt concentration equal to that of the formulation recommended by the WHO, with an encapsulation efficiency of about 56.05%. Other features recommended by the WHO and UNICEF in their joint statement issued in May 2004 and accomplished in this invention are reduced glucose content and lower osmolality.
- The liposomal rehydration salt formulation of the present invention is thereby obtained, said formulation having the following features:
-
- Percentage inclusion ratio of salts (salts retained within liposomes/total salts) of 56.05%
- Chloride Concentration: 39.75 mmol/l
- Citrate Concentration: 15.97 mmol/l
- Potassium Concentration: 17.88 mmol/l
- Sodium Concentration: 69.74 mmol/l
- Glucose Concentration: 33.03 mmol/l
- Encapsulation Efficiency Using the Barium Sulphate Turbidity Method
- Two phosphatidylcholine ethanol solutions are prepared, one of them named “FE1”, which has a concentration of 2% Phosphatidylcholine (the same as the one used in the TLEC formulation of U.S. Patent Publication No. 2005/0008685), and the other named “FE2”, with a concentration of 5% Phosphatidylcholine (the same as the one used in the present invention).
- Separately, an aqueous solution (AP) of 56.23 mM ammonium sulphate is prepared (this concentration reproduces the ionic strength of the WHO rehydration salts).
- Two liposomal solutions are then prepared using the ethanol phase injection method, in which 10 ml FE1 and FE2 are separately injected in two fractions of 90 ml AP under magnetic stirring at 300 rpm and 25° C. Consequently, 100 ml of two liposomal formulations are obtained:
-
- *1:10 (v/v) FE1:AP (LIPO-1)
- *1:10 (v/v) FE2:AP (LIPO-2)
- The LIPO-2 formulation was subjected to a tangential ultrafiltration process using a hollow fiber cartridge with a 300 KD cut off, without feedback. Ultrafiltration continued until reducing the volume by 10-fold. This is the process we carry out in our invention in order to obtain higher encapsulation efficiency.
- Samples are taken from both final solutions.
- Then, 10 ml of each formulation (LIPO-1 and LIPO-2) is taken and ultrafiltered by using the same system but feeding back each formulation with 126 mM sucrose aqueous buffer. Thus, the sulphate ions non-encapsulated into liposomes are eliminated from each solution and substituted with a solution having the same osmolality in order to ensure integrity of the liposomal membranes.
- Then 5 ml of each formulation is taken before and after the ultrafiltration process, and 10% surfactant Triton X-100 is added to each of them, in order to break the lipid membranes. This solution is kept under stirring at 25° C. for 1 hour.
- Soluble sulphates precipitate in the presence of barium chloride in the form of barium sulphate (BaSO4) as a white solid. Measurement of tance reduction as a consequence of the presence of barium sulphate, to a certain wave length in a UV/Vis spectrometer allows for determination of the sulphate ion concentration in aqueous solution.
- For experimental determination, a calibration curve was plotted by using 50 ml ammonium sulphate patterns with the following concentrations: 0.1 mM, 0.25 mM, 0.5 mM, 0.75 mM and 1 mM. An excess of 31.23 mg (3 mM) barium chloride was added to each solution. Then, transmittance of each solution was determined in triplicate by using an UV/VIS spectrometer (Jenway 7315). The calibration curve is shown in
FIG. 3 . - Then, 0.1 ml of the unknown LIPO-1 solution before ultrafiltration and 1 ml of the solution after ultrafiltration were taken, both already treated with surfactant, and the same excess of barium chloride was added (3 mM). Transmittance of the sample before ultrafiltration was 49.22%±0.17%, corresponding to [Sulphate]=0.5273 mM. Taking dilutions into account, the total sulphate concentration before ultrafiltration is 52.73 mM. Transmittance of the sample after ultrafiltration was 48.25%±0.32%, corresponding to [Sulphate]=0.5091 mM. Taking dilutions into account, the salt concentration after ultrafiltration is 5.091 mM. This indicates that the ratio of sulphate encapsulated in the formulation produced with the concentration of Phosphatidylcholine of U.S. Patent Publication No. 2005/0008685 was 10.59%.
- Likewise, 0.1 ml of the unknown LIPO-2 solution before ultrafiltration, and 0.1 ml of the solution after ultrafiltration were taken, both already treated with surfactant, and the same excess of barium chloride was added (3 mM). Transmittance of the sample before ultrafiltration was 73.19%±0.19%, corresponding to [Sulphate]=0.9818 mM. Taking dilutions into account, the total sulphate concentration before ultrafiltration is 98.18 mM. Transmittance of the sample after ultrafiltration was 50.66%±0.24%, corresponding to [Sulphate]=0.5545 mM. Taking dilutions into account, the salt concentration after ultrafiltration is 55.45 mM. This indicates that the ratio of sulphate encapsulated in the formulation of the present invention was 56.48%.
- Note: The results are directly proportional to the encapsulated rehydration salts, since all the salts have similar and increased water solubility. Therefore, the encapsulation level by the method of liposome formation by ethanol phase injection is statistical, and it will be similar in compounds with similar water solubility.
- Multicenter, Randomized and Single-Blind Mouthfeel Assay
- Formula A: Liposomal rehydration salt formulation of example 3 of the present invention.
- Formula B: Liposomal rehydration salts according to example 3 of U.S. Patent Publication No. 2005/0008685 A1.
- Healthy individuals from 21 to 40 years of age were recruited. Those individuals with cardiac or renal diseases, diabetics, individuals who had suffered from diarrhea the month prior to the assay, individuals affected by rhinitis, or individuals under antibiotic or iron treatment were excluded from the assay.
- The screening of the individuals took place in four different shopping malls in the city of Santa Fe, Argentina. After explaining the test to the individuals and having them signed their consent (either by themselves or by their parents or legal guardians in case of underage people), the individuals were randomized. Randomization indicates the order in which the two formulations would be tasted. In order to get familiar with this type of flavors, the individuals took a little sip of the two formulations and then rinsed their mouths with water and a piece of salt-free bread. Thereafter, they tasted the two formulations in the order indicated by randomization, and they were asked to indicate the formulation of their preference. The same test was repeated twice with both formulations, after a new mouth rinse with water and pieces of bread. They were offered each formulation in amounts of less than 20 ml in total, inside red plastic glasses (to avoid color influence on the decision). The formulations were administered at room temperature, without any refrigeration.
- Each individual tasted both formulations repeatedly (twice the first tasting and twice the second tasting); to corroborate consistency both times each tasting took place, kappa(k) statistic was used (URL: www.graphpad.com/quickcalcs/kappa2.cfm) as well as a 95% CI.
- 120 individual were studied, out of which 4 individuals did not meet the inclusion criteria (out of age), so the final test cohort consisted of 116 individuals with an average of 30-32 years old. The distribution of the individuals per shopping mall was similar: between 27 and 30 per each shopping mall. 59 individuals were female (50.9%).
- Regarding the results obtained, we found very high consistency between the scores of the 2 tests with the same formulations, both in the first tasting (k=0.91; 95% CI: 0.85-0.98), and the second tasting (k=0.87; 95% CI: 0.80-0.94). Therefore, in the statistical analysis, it was decided to use the results corresponding to the second time each of the two tastings was scored.
- Out of the 116 individuals, 97 individuals preferred the taste of formula A, 2 preferred the taste of formula B. 17 individuals were not certain as to which they preferred, so they were not counted.
- Process for Preparing the Formulation of the Present Invention with a Percentage Inclusion Ratio of Salts of 56% (for Sport Activities)
- A solution of 4.5 L distilled water is prepared with salts at the following concentration:
-
Concentration (mmol/L) Glucose Na K Cl Cit Sodium chloride 6.01 6.01 Potassium citrate 3.86 1.29 Sodium citrate 6.02 2.01 Glucose — - On the other hand, a solution of phosphatidylethanolamine in 500 ml of 4% Ethyl Alcohol (W/V) is prepared.
- Liposome formation is induced by injecting the ethanol solution into the aqueous phase while stirring. Here, 15% of the salts are encapsulated. Therefore, the internal and external salt concentrations are the following:
-
Internal External Na 1.57 10.46 K 0.50 3.36 Cl 0.78 5.23 Cit 0.49 2.81 Glucose 0 0 - The Five (5) liters of liposomal ORSs are subjected to a tangential ultrafiltration (TUF) concentration process. This process allows for removing the buffer without eliminating the liposomes and their contents. This process is carried out until reducing the volume by 10-fold. At the end of the process, 500 ml liposomal salts having the following concentration are obtained.
-
Internal External Na 15.7 10.56 K 5.04 3.46 Cl 7.84 5.23 Cit 4.90 2.81 Glucose 0 0 - At this stage, buffer substitution is performed, again with the TUF process. In this case, the total volume is reduced by 10-fold and replaced with an aqueous solution having the following salt concentration:
-
Concentration (mmol/L) Na 12.56 K 3.65 Cl 5.65 Cit 3.04 Glucose 17.80 - This buffer further contains Stevia (Reb A 97—PureCircle) at a concentration of 0.15 g/L; Sucrose at a concentration of 28.5 g/L; Citric Acid at a concentration of 3.6 g/L; and Natural Flavors at a concentration of 1.5 g/L.
- Accordingly, 500 ml of a liposomal ORS solution is obtained, containing 40 g/l phospholipid, with the following salt concentration:
-
Internal External TOTAL Na 15.7 12.35 28.05 K 5.04 3.62 8.66 Cl 7.84 5.61 13.45 Cit 4.90 3.02 7.92 Glucose 0 16.02 16.02 - The formulation of the present example is useful for people in need of hydration due to sun exposure, illness, pregnancy, travel fatigue, hangover, mental stress, strenuous work, or just living an active life. It may be produced with orange, strawberry, apple, pear, blueberry, raspberry flavors, among others.
- Process for Preparing the Formulation of the Present Invention with a Percentage Inclusion Ratio of Salts of 56%
- A solution of 4.5 L distilled water is prepared with salts at the following concentration:
-
Concentration (mmol/L) Glucose Na K Cl Cit Sodium chloride 14.82 14.82 Potassium citrate 6.70 2.23 Sodium citrate 11.23 3.74 Glucose — - On the other hand, a solution of phosphatidylserine in 500 ml of 3% Ethyl alcohol (W/V) is prepared.
- Liposome formation is induced by injecting the ethanol solution into the aqueous phase while stirring. Here, 15% of the salts are encapsulated. Therefore, the internal and external salt concentrations are the following:
-
Internal External Na 3.91 22.14 K 1.00 5.70 Cl 2.23 12.60 Cit 0.895 5.074 Glucose 0 0 - The Five (5) liters of Liposomal ORSs are subjected to a tangential ultrafiltration concentration process. This process allows for removing the buffer without eliminating the liposomes and their contents. This process is carried out until the volume is reduced by 10-fold. At the end of the
process 500 ml of liposomal salts having the following concentration is obtained. -
Internal External Na 39.1 22.14 K 10.0 5.70 Cl 22.3 12.60 Cit 8.95 5.074 Glucose 0 0 - At this stage, buffer substitution is carried out, again with the TUF process. In this case, the total volume is reduced by 10-fold and replaced with an aqueous solution having the following salt concentration:
-
Concentration (mmol/L) Na 31.57 K 8.13 Cl 17.96 Cit 7.24 Glucose 40.70 - This buffer further contains Sucralose at a concentration of 0.12 g/L; high fructose corn syrup (55° Brix) at a concentration of 33.3 g/L; Citric Acid at a concentration of 4.0 g/L; and Natural Flavors at a concentration of 1.7 g/L.
- Accordingly, 500 ml of a liposomal ORS solution with 30 g/l phosphatidylserine and the following salt concentration is obtained:
-
Internal External TOTAL Na 39.1 30.64 69.74 K 10.0 7.88 17.88 Cl 22.3 17.45 39.75 Cit 8.95 7.02 15.97 Glucose 0 33.03 33.03 - The formulation of the present example is useful for children suffering from vomiting or diarrhea under the risk of dehydration, and it may be produced with orange, strawberry, apple, pear, blueberry, raspberry flavors, among others.
- Process for Preparing the Formulation of the Present Invention with a Percentage Inclusion Ratio of Salts of 56%
- A solution of 4.5 L distilled water is prepared with salts at the following concentration:
-
Concentration (mmol/L) Glucose Na K Cl Cit Sodium chloride 6.01 6.01 Potassium citrate 3.86 1.29 Sodium citrate 6.02 2.01 Glucose — - On the other hand, a solution of Phosphatidylcholine in 500 ml of 5% Ethyl alcohol (W/V) is prepared.
- Liposome formation is induced by injecting the ethanol solution into the aqueous phase while stirring. Here, 15% of the salts are encapsulated. Therefore, the internal and external salt concentrations are the following:
-
Internal External Na 1.57 10.46 K 0.50 3.36 Cl 0.78 5.23 Cit 0.49 2.81 Glucose 0 0 - The five (5) liters of Liposomal ORSs are subjected to a tangential ultrafiltration concentration process. This process allows for removing the buffer without eliminating the liposomes and their contents. This process is carried out until the volume is reduced by 10-fold. At the end of the process, 500 ml of liposomal salts having the following concentration is obtained.
-
Internal External Na 15.7 10.46 K 5.04 3.46 Cl 7.84 5.23 Cit 4.90 2.81 Glucose 0 0 - At this stage, buffer substitution is carried out, again with the TUF process. In this case, the total volume is reduced by 10-fold and replaced with an aqueous solution having the following salt concentration:
-
Concentration (mmol/L) Na 12.56 K 3.65 Cl 5.65 Cit 3.04 Glucose 17.80 - This buffer further contains Stevia (Reb A 97—PureCircle) at a concentration of 0.13 g/L; Sucrose at a concentration of 22.2 g/L; Citric Acid at a concentration of 3.4 g/L; and Natural Flavors at a concentration of 1.5 g/L.
- Accordingly, 500 ml of a liposomal ORS solution is obtained having the following salt concentration:
-
TOTAL Internal External (mmol/L) Na 15.7 12.35 28.05 K 5.04 3.62 8.66 Cl 7.84 5.61 13.45 Cit 4.90 3.02 7.92 Glucose 0 16.02 16.02 - This formulation may be suitable for consumption by sportspeople.
- Process for Preparing the Formulation of the Present Invention with a Percentage Inclusion Ratio of Salts of 56% for High-Performance Sportspeople
- A solution of 4.5 L distilled water is prepared with salts at the following concentration:
-
Concentration (mmol/L) Glucose Na K Cl Cit Sodium chloride 6.01 6.01 Potassium citrate 3.86 1.29 Sodium citrate 6.02 2.01 Glucose — - On the other hand, a solution of phosphatidylinositol in 500 ml of 5% Ethyl alcohol (W/V) is prepared.
- Liposome formation is induced by injecting the ethanol solution into the aqueous phase while stirring. Here, 15% of the salts are encapsulated. Therefore, the internal and external salt concentrations are the following:
-
Internal External Na 1.57 10.46 K 0.50 3.36 Cl 0.78 5.23 Cit 0.49 2.81 Glucose 0 0 - The 5 Liters of Liposomal ORSs are subjected to a (TUF) tangential ultrafiltration concentration process. This process allows for removing the buffer without eliminating the liposomes and their contents. This process is carried out until the volume is reduced by 10-fold. At the end of the process, 500 ml of liposomal salts having the following concentration is obtained.
-
Internal External Na 15.7 10.46 K 5.04 3.46 Cl 7.84 5.23 Cit 4.90 2.81 Glucose 0 0 - At this stage, buffer substitution is carried out, again with the TUF process. In this case, the total volume is reduced by 10-fold and replaced with an aqueous solution having the following salt concentration:
-
Concentration (mmol/L) Na 12.56 K 3.65 Cl 5.65 Cit 3.04 Glucose 0 - This buffer further contains high fructose corn syrup (55° Brix) at a concentration of 3.22 g/L; Vitamin B1 at a concentration of 0.002 g/L; Vitamin B5 at a concentration of 0.011 g/L; Vitamin B6 at a concentration of 0.011 g/L; Citric Acid at a concentration of 3.6 g/L; and Natural Flavors at a concentration of 1.5 g/L.
- Accordingly, 500 ml of a liposomal ORS solution with 50 g/l phosphatidylinositol and the following salt concentration is obtained:
-
Internal External TOTAL Na 15.7 12.35 28.05 K 5.04 3.62 8.66 Cl 7.84 5.61 13.45 Cit 4.90 3.02 7.92 Glucose 0 16.02 16.02 - This formulation may be suitable for consumption by high-performance sportspeople.
- Preclinical Assay of the Rehydration Salt Formulation of the Present Invention
- A batch of pediatric liposomal rehydration salts of Example 6 of the present invention as a finished product is compared to commercial product Pedialyte (Abbott Laboratories) taken as reference substance. Said comparison encompassed the development of an osmotic diarrhea model in rats for efficiency evaluation.
- An osmotic diarrhea experimental model was developed as described in Wapnir et al., 1988,1991 (Am.J.Clin. Nutr. 1988; 4784-90; J. Pediatr. 1991; 118:S53-61). Four experimental animal groups were used, each consisting of 10 animals (5 male and 5 female animals).
Groups Group 1 was treated with the test substance;Group 2 was treated with the reference substance; Group 3 received physiological solution; while Group 4 was not treated at all. Body weight, Natremia, Kalemia, and Hematocrit variables were analyzed both during treatment and 12 hours after completion. Young female and male Wistar rats with genetic certification were used. They were divided into subgroups, placed into jails, and identified with a correlative integer number. - The animals were kept under controlled ambient conditions: temperature between 22±3° C., controlled photoperiod (12 hs light/12 hs darkness) and free access to commercial food and water. MicroVENT rack systems provided by Allentown Inc., European Type IIIH (POE GC-065) models, were employed.
- Forty (40) animals divided into four experimental groups (each group comprising 5 male and 5 female animals) were used.
- Group 1: (5 male and 5 female animals). It was distributed into 2 subgroups: 1-M; 1-F, each consisting of 5 animals of the same sex. These animals were subjected to osmotic diarrhea induction and treated with the test substances.
- Group 2: (5 male and 5 female animals). It was distributed into 2 subgroups: 2-M; 2-F, each consisting of 5 animals of the same sex. These animals were subjected to osmotic diarrhea induction and treated with the reference substance.
- Group 3: (5 male and 5 female animals). It was distributed into 2 subgroups: 3-M; 3-F, each consisting of 5 animals of the same sex. These animals were subjected to osmotic diarrhea induction and treated with physiological solution.
- Group 4: (5 male and 5 female animals). It was distributed into 2 subgroups: 4-M; 4-F, each consisting of 5 animals of the same sex. These animals did not receive any treatment.
- In
groups - Liposomal Rehydration Salts—Pediatric Formulation of Example 6 of the present invention.
- Rehydration Salts Pedialyte—Pediatric Formulation manufactured by Abbott Laboratories.
-
Groups Day 5 during the morning, at the time magnesium citrate solution was removed and treatment was initiated, thereby determining differential doses for male and female rats. - The volume corresponding to each dosage was calculated according to the following formula:
-
- Wherein P is the average weight in grams, either of the male or female rats, as applicable.
- Dose administration took place every hour beginning at 9 A.M. on
Day 5. - Upon the extraction of one drop of blood, a microhematocrit was conducted by using heparinized microtubes. The samples were collected at the following times:
-
- Day 5: 08:00 hs, 12:00 hs, 16:00 hs and 20:00 hs.
- The collected samples were also subjected to Natremia and Kalemia determination.
- Data Analysis: A comparative analysis of the different formulations was performed through descriptive statistics and two-way analysis of variance (ANOVA), followed by Tukey's multiple comparison test to identify differences between different times. These operations were performed with GraphPad Prism 6.0 software.
-
-
Media SEM Media SEM Media SEM Media SEM 1 M 2 M 3 M 4 M Day 0 137.2 3.44093 137.8 2.332381 134.2 2.2 138.4 1.805547 Day 1 133.8 2.61534 134 2.387467 130.6 2.357965 143.4 2.014944 Day 2 128.2 2.374868 128 1.760682 123.8 3.168596 143.8 1.714643 Day 3 122.8 2.596151 124.4 3.091925 120.6 3.37046 146.2 2.853069 Day 4 112.8 4.465423 113.8 2.477902 110.6 3.17175 149.6 2.088061 Day 5 (8 hours) 108.6 3.613863 105 2.258318 103.4 2.158703 153.4 3.249615 Day 5 (12 hours) 115.8 4.140048 110.4 1.939072 109 2.50998 153.4 2.501999 Day 5 (16 hours) 124.8 4.476605 115.6 1.122497 114 2.097618 155.8 2.557342 Day 5 (20 hours) 133.4 4.905099 121.4 0.6 119.6 2.249444 156.6 2.61916 Day 6 137.1 5.416641 125.4 1.939072 124.4 3.043025 157.8 2.416609 1 H 2 H 3 H 4 H Day 0 118.4 0.9273618 120.4 1.50333 120 0.9486833 119.4 2.521904 Day 1 112.6 1.536229 114.6 1.469694 115 1.264911 121.2 2.709244 Day 2 105.6 1.28841 109.6 1.28841 107.8 2.034699 123.8 2.61534 Day 3 98.8 1.714643 102 1.30384 102.8 1.907878 124.4 2.785677 Day 4 93.4 1.249 93.6 1.939072 96 0.8944272 126.8 2.2 Day 5 (8 hours) 92.8 1.939072 89.8 1.827567 93.2 2.437212 128.6 2.135416 Day 5 (12 hours) 106.4 1.6 103 2.213594 107.8 0.9695359 127 1.949359 Day 5 (16 hours) 112.6 1.4 101.6 1.860107 108.6 1.886796 126 2.073644 Day 5 (20 hours) 116.6 1.886796 102.6 1.469694 113.2 1.157584 123.4 2.420743 Day 6 118.6 2.420743 102.6 1.16619 110 1.449138 126.8 2.332381 -
-
Media SEM Media SEM Media SEM Media SEM 1 M 2 M 3 M 4 M Day 5 (8 hours) 54.6 1.029563 54 0.83666 52.4 0.4 44.4 0.6 Day 5 (12 hours) 48.6 0.4 50.8 0.374166 50.6 0.6 46.2 0.583095 Day 5 (16 hours) 46.6 0.4 49.2 0.374166 48.4 0.509902 45 0.316228 Day 5 (20 hours) 45 0.547723 48.4 0.678233 45.2 0.860233 43 0.632456 Day 644.4 1.32665 48 1.516575 46.6 2.249444 44 0.948683 1 H 2 H 3 H 4 H Day 5 (8 hours) 55.6 1.32665 54.8 0.734847 53 0.547723 46.6 0.4 Day 5 (12 hours) 47.2 0.2 50.4 0.678233 50.6 0.509902 47.2 0.583095 Day 5 (16 hours) 45.8 0.2 49.6 0.6 47.8 0.2 45.4 0.979796 Day 5 (20 hours) 44.4 0.509902 47.8 0.374166 45.8 1.2 44.8 0.860233 Day 643.2 0.374166 45.4 1.630951 41.4 1.860107 42.2 1.772004 - Natremia (mmol/L):
-
Media SEM Media SEM Media SEM Media SEM 1 M 2 M 3 M 4 M Day 5 (8 hours) 200.8 3.624914 194.6 5.1049 193 4.312772 175 1.341641 Day 5 (12 hours) 178.4 1.32665 191.2 1.655295 192.4 3.893584 169.4 3.059412 Day 5 (16 hours) 175.2 1.655295 190.4 1.363818 192 1.923538 173.4 2.420743 Day 5 (20 hours) 175.6 1.50333 187.2 0.7348469 189.2 1.933908 173.2 1.496663 Day 6175.2 1.593738 185.2 1.714643 187 1.48324 174.4 2.088061 1 H 2 H 3 H 4 H Day 5 (8 hours) 190.2 4.97393 194.8 3.15278 185.6 1.8868 175.2 1.06771 Day 5 (12 hours) 173.6 1.46969 192.4 2.01494 180.2 1.06771 172.6 1.36382 Day 5 (16 hours) 169.8 1.35647 189.4 2.37907 177.2 1.15758 171.2 3.77359 Day 5 (20 hours) 173.2 1.35647 188.4 1.43527 172 1.09545 174.4 2.37907 Day 6171.4 3.58608 185.2 1.88149 171.8 1.98494 174.6 1.20831 - Kalemia (mmol/L):
-
Media SEM Media SEM Media SEM Media SEM 1 M 2 M 3 M 4 M Day 5 (8 hours) 5.06 0.478121 4.87 0.4895406 5.62 0.3527038 8.48 0.2009974 Day 5 (12 hours) 6.76 0.552811 5.75 0.2792848 5.64 0.3187475 8.4 0.2167949 Day 5 (16 hours) 7.94 0.143527 6.56 0.2466778 6.1 0.1294218 8.139 0.1363817 Day 5 (20 hours) 8.16 0.129807 7.33 0.1299999 6.79 0.1372953 8.36 0.1784657 Day 68.23 0.128062 7.5 0.1695582 7.55 0.2720294 8.4 0.0935415 1 H 2 H 3 H 4 H Day 5 (8 hours) 5.06 0.26429 5.75 0.57619 4.9 0.54106 8.34 0.14 Day 5 (12 hours) 6.52 0.69401 6.46 0.52617 5.81 0.12288 8.42 0.08456 Day 5 (16 hours) 8.58 0.09028 7.02 0.157 6.47 0.20224 8.309 0.11662 Day 5 (20 hours) 8.38 0.10794 7.41 0.17986 6.88 0.12806 8.51 0.12787 Day 68.42 0.10794 7.51 0.11225 7.19 0.19261 8.43 0.11023 - The osmotic diarrhea model was developed as described in the literature, resulting in significant weight reduction and hematocrit increase due to dehydration.
- During dehydration process due to fecal excretion, significant loss of extracellular fluid is produced. Sodium concentration in this fluid is about 30 times higher compared to potassium concentration. During the process of fluid loss, significant loss of solutes is also observed, including sodium and potassium ions, responsible for regulating liquid restitution in the body. However, the percentage of potassium loss is higher than that corresponding to sodium. In addition to liquid reduction, this makes the initial dehydration condition show plasma sodium concentration values higher than those belonging to animals that did not experienced dehydration, and plasma potassium concentration values lower than those of non-dehydrated animals.
- The results obtained from the body mass analysis indicated that, as a consequence of diarrhea induction, all the experimental groups by the time treatment was initiated had lost about 20% of their body mass. Thereafter, comparative results showed a significant difference between weight regain in the group treated with the formulation of Example 6 of the present invention and the group treated with Pedialyte®. Both in male and female rats after 24 hours of treatment, the formulation of the present invention induced recovery of average body mass in the experimental group.
- Hematocrit is the percent of the total volume of whole blood that is composed of red blood cells. Hematocrit loss during dehydration due to fecal excretion is negligible. This implies that the reduction of plasma extracellular fluid makes hematocrit increase.
- On the basis of the condition at the time treatment was initiated, it is possible to see that all the induced groups have a hematocrit level higher than 50%, where all normal values always range from 40% to 50%. The treatment results indicate that recovery in the hematocrit level in the group treated with the formulation of the present invention was significantly faster than that achieved by Pedialyte®. In male rats, normal level was achieved after 24 hours of treatment, whereas in female rats the action was much more effective, the normal level being recovered after 8 hours of treatment.
- Natremia and Kalemia analyses are highly influenced by extracellular fluid recovery. Reduction in sodium concentration in all the experimental groups does not mean there is cation loss, but a reduction in cation concentration. This means the body absorbs sodium and recovers a higher liquid percentage; thus, its concentration diminishes. The experimental results revealed that both in male and female rats, the recovery rate of normal sodium and potassium levels was significantly higher for the formulation of the present invention compared to Pedialyte®.
- It should be noted that the term “osmolality” refers to moles per kilogram and the term “osmolarity” refers to moles per liter. They are different terms, but throughout this description, they could be used interchangeably due to low density values that enhance the low impact on the conversion of osmolality to osmolarity of the liposomal rehydration salt formulation as described.
- It is also possible to use a modified manufacturing process than that described above by not creating an ethanol phase, and instead, creating a concentrated phase that already has the liposomes. That concentrated phase is then mixed as an ingredient with the end product. It has also been found that the inclusion level of salts can be increased to as high as 70% in some conditions versus inclusion levels such as 54% or 56%. In an aspect of manufacturing, the concentrated phase of liposomes has been developed in a ratio of 1:20 and the end product profile has been upgraded, replacing HFCS such as high fructose corn syrup, with glucose and Stevia and other sugars while also using natural flavors and colors. A variety of ranges are identified above for the liposomal rehydration salt formulation. A specific composition/formulation specification explained below shows the different specifications for sodium, potassium, chloride, citrate, glucose, carbohydrates and calories. This current example is also known as Speedlyte® and is later compared to another non-liposome formulation sold by Abbot as Pedialyte® and compared to WHO (World Health Organization) 2002 recommendations.
- Example Composition/Formulation Specifications
-
Sodium 1,035 mg/L 45 mEq/L Potassium 782 mg/ L 20 mEq/L Chloride 1,380 mg/L 39 mEq/L Citrate 748 mg/L 8.7 mEq/L Glucose 13.50 g/L 75 mEq/L Total Carbohydrates 25.5 grams Calories 90 - In this example, based on liposome electrolytes, the actual composition/formulation osmolarity should be taken as 125.8 mmol/L based on a current theoretical osmolarity of 188, with 54% of the electrolytes being encapsulated.
- These example values in the table above can vary from 5%, 10%, 15%, 20% and 25% above and below these values, although the greater percentage difference from the listed values is less desirable. Based on the liposome electrolytes, the actual composition/formulation osmolarity should be taken as 125.8 mmol/l based on a current theoretical osmolarity of 188, with 54% of the electrolytes being encapsulated. The osmolarity analysis (meq/L) is referred to as milliequivalents of solute per liter of solvent and is the amount of substance that reacts or is equivalent to another amount of substance. Of course, the equivalent is the amount of a substance needed to react with or supply one or more hydrogen ions in an acid-base reaction or react with or supply one or more of electrons in a redox reaction.
- Osmolarity Analysis (meq/L)
-
Speedlyte ® WHO 2002 Pedialyte ® (conventional/liposomed) Sodium 75 45 45/20.2 Chloride 65 35 39/17.5 Potassium 29 20 20/9 Citrate 10 10 9/4 Glucose 75 139 75/75 Total 245 249 188/125.8 Osmolarity
Values can vary from 5%, 10%, 15%, 20% and 25% for the current formulation. - In the human body, the amount of a substance and equivalence is a very small magnitude and it is routinely described in terms of milliequivalents (meq) as the measure having been multiplied by 1,000. The osmolarity analysis comparing the World Health Organization 2002 standards (WHO 2002) with the formulation manufactured by Abbot as Pedialyte® and an example of the current formulation also referred to as Speedlyte® are illustrated above and compare the example values. The Pedialyte® composition is a non-liposomal formulation that includes a number ingredients as an oral fluid and electrolyte replacement. As shown in the table, it is evident that its osmolarity is much higher than the osmolarity of the current formulation. One differentiating factor in the marketplace and for efficacy is the lower osmolarity of the current formulation and also has beneficial aspects in its higher absorption results. Also, the electrolytes and liposomes serve as either a maintaining formula or a rehydration formula. The percentage deviation ranges described above are applicable and the current formulation as shown in the tables has 45 mEq/L of sodium and 20 mEq/L of potassium from 2.28 g/L of sodium chloride plus 2.04 g/L of potassium citrate and 0.5 g/L of sodium citrate. The more important electrolyte is sodium and that can range from 12 mEq/L to as high as 90 mEq/L. Other intermediate ranges have been found acceptable such as 20 to 70, 30 to 60, 35 to 55, and 40 to 50 mEq/L for the sodium. The potassium electrolytes can also vary based on the percentages described above and in one example is about 15 mEq/L to 25 mEq/L. Phospholipids help create the liposomes and the liposome concentrations and the range identified above is 1 to 60 g/L with other ranges as defined in the examples with 1 to 30, 1 to 40, or 1 to 50 g/L with the specific concentrations of 30, 40 and 50. The example formulation as described in the tables above has 2.5 g/L of phospholipids and that value can range from about 1 to 5 g/L, 1 to 10 g/L, in a preferred example, 5 to 10 g/L and up to 30, 40, 50 or 60 g/L.
- The amount and type of carbohydrates may vary and in one example, the carbohydrates are at a concentration of up to 6 g/L and up to 30 g/L. The current formulation as described in the tables has as carbohydrates 13.5 g/L of glucose and 11.5 g/L of sugar, and in an example may range from about 8.0 g/L to about 15.0 g/L of at least one additional sugar. The level of carbohydrates may be increased to as high as 70 g/L to appeal to a more mainstream product and it may be lowered to almost 0 g/L to appeal to diabetics and the elderly. Those ranges of glucose and sugar can vary from their mid-range value at 5%, 10%, 15%, 20%, and 25% differences above and below.
- The size of the liposomes are important for absorption as discussed above and can vary as noted above and is preferred about at 225 to 450 nm, but can range in an example from 200 to 500 nm. Although some available commercial products have smaller sized liposomes as alleged by their manufacturers, such as 100 mm, it has been determined their level of inclusion volume is low. Other oral liposome products, for example, using vitamin C, may have liposome sizes greater than 500 nm.
- In the example 7 described above, natural flavors are concentrated at about 1.5 g/L. Natural flavorings and masking flavors may be at a concentration of up to 5 g/L. The example formulation shown in the charts above has about 3.12 g/L flavorings and these values could vary from 5%, 10%, 15%, 25%, or 25% above and below those values. One example range is about 1.0 g/L to about 3.5 g/L. Stevia may be used as a natural sweetener and in example, the Stevia in the examples above is indicated at a concentration of about 0.1 to 0.2 g/L, and in the example shown in the tables, is currently about 0.15 g/L, but it is possible to go as high as 0.22 in one example. One example range is about 1.0 g/L to about 3.5 g/L.
- The liposomal rehydration salt formulation not only maintains hydration, but also operates to rehydrate those persons that are dehydrated, in some cases serious. For example, it is possible to rehydrate and avoid the intravenous (IV) fluid delivery necessary in some cases because the formulation may be orally administered to humans suffering from dehydration caused by various factors as indicated below or suffering a moderate to severe dehydration with the need for IV fluids. The formulation also will allow fluid maintenance and avoid use of IV fluids by preventing severe dehydration while maintaining body electrolytes and fluids. The formulation may be used for rehydration due to stomach bugs in children and adults and hydration to prevent hangover or rehydration while in a hangover episode. The liposomal rehydration salt formulation may prevent or avoid the need for parenteral hydration, corresponding to fluids that are injected subcutaneously such as parenteral glucose or saline.
- The liposomal rehydration salt formulation may be used for hydration or rehydration for pregnant or breast-feeding women and for persons that need hydration or rehydration due to exercise (sport), outdoor activities, extreme weather or high-altitude conditions, skin burns, flying, hangover episodes, diarrhea, vomiting, high fever, stomach bugs or other types of gastritis, norovirus, rotavirus, and other types of bacteria and infections. Hikers that are climbing steep hills or cliffs may also find the liposomal rehydration salt formulation advantageous to help in maintaining body electrolytes and in hydration or rehydration.
- The liposomal rehydration salt formulation may also be used for hydration or rehydration to different populations, including patients with parenteral and enteral nutrition, to reduce the volume and consequently the time of intravenous (IV) treatments. It may be used with celiac patients, particularly during an episode such as when a person may inadvertently eat protein to which they may be allergic such as found in wheat, rye, and barley and their body mounts an immune response. The symptoms may include abdominal bloating, pain, gas, diarrhea, pale stools and weight loss. The liposomal rehydration salt formulation may also be used with elderly patients, pediatric patients, pregnant and breast-feeding patients, and diabetic patients, particularly those under a SGLT2 inhibitor treatment corresponding to a class of prescription medications that inhibit sodium-
glucose transport protein 2 and that react to reduce blood to glucose levels. Thus, the liposomal rehydration salt formulation can be especially effective for those type of patients. Such class of medications are sometimes referred to as gliflozin drugs that inhibit the reabsorption of glucose in the kidney and therefore lower the blood sugar, sometimes too much. - The liposomal rehydration salt formulation as described may also be used for those that suffer from intestinal failure, including the Short Bowel Syndrome, also called short gut, as a malabsorption disorder caused by the lack of a functioning small intestine. Diarrhea is a typical symptom that sometimes results in dehydration, malnutrition and weight loss.
- Other populations that will benefit from the liposomal rehydration salt formulation include those that suffer from Cycling Vomiting Syndrome (CVS) with the sudden, repeated attacks as episodes of severe nausea, vomiting and physical exhaustion that could last a few hours to several days. Other persons suffering from gastroparesis as, for example, delayed gastric emptying with paresis of the stomach and food often remaining in the stomach for an abnormally long time, which may cause chronic nausea and vomiting in some cases with erratic blood glucose levels. Those suffering from Postural Orthostatic Tachycardia Syndrome (POTS) characterized when too little blood returns to the heart when moving from a lying down to a standing up position corresponding to orthostatic intolerance may benefit from the formulation. Those suffering from ulcerative colitis and colon cancer could use the liposomal rehydration salt formulation to benefit them since often they become dehydrated.
- Also, those having dysphagia and difficulty swallowing could benefit as well as those with Sjogren's syndrome, corresponding to a systemic autoimmune disease that may include dry eyes and dry mouth and often is accompanied by rheumatoid arthritis and lupus. Those with lupus or similar immune disorders may also benefit from the liposomal rehydration salt formulation. Especially beneficial would be those suffering from Crohn's Disease and lupus with typical abdominal cramping and pain as part of a chronic Inflammatory Bowel Disease (IBD) and inflammation of the digestive or gastrointestinal (GI) tract. Crohn's Disease is usually limited to the end of the small intestine, as compared to ulcerative colitis, which is usually limited to the large intestine such as the colon and rectum. The liposomal rehydration salt formulation is beneficial for sufferers of either disorder. Those having kidney disease with dangerous levels of fluid, electrolytes and waste build up will benefit from the use of the liposomal rehydration salt formulation.
- Those suffering from HIV are especially benefitted since often treatment for HIV and AIDS causes vomiting and diarrhea. Diarrhea is a typical side effect that accompanies use of HIV medications used for AIDS treatment. Often this includes nausea and headache with some fever, accompanied by vomiting and diarrhea. The liposomal rehydration salt formulation is especially beneficial in this type of treatment not only to help maintain electrolytes, but for rehydration. Some antiretroviral drugs for AIDS may increase blood sugar and diabetes and the liposomal rehydration salt formulation is beneficial.
- Those with the Inflammatory Bowel Disease (IBD) such as Crohn's Disease and ulcerative colitis would benefit as well as those with an ostomy, i.e., a stoma as a surgically created opening between the intestines and abdominal wall, and thus typically requiring a bag or pouch. This may can cause glucose levels and other electrolyte changes in the body, especially in the blood and intestines. Those suffering from microvillus inclusion disease also termed Davidson's Disease also suffer from chronic, intractable diarrhea causing metabolic acidosis and severe dehydration and thus would benefit from use of the liposomal rehydration salt formulation. Those suffering from cystic fibrosis (CF) would benefit from its use. Although CF is a genetic order affecting the lungs, it may also affect the pancreas, liver, kidneys and intestines causing difficulty in breathing. It can also cause fatty stool. The liposomal rehydration salt formulation can be used in many different types of cancer treatment and especially those suffering from HIV symptoms.
- The liposomal rehydration salt formulation has superior taste, higher absorption, less intake and lower sugar than other drinks and formulations both using and not using liposomal technology. Testimonies have stated that individuals feel better hydrated after taking the disclosed liposomal rehydration salt formulation and have fewer headaches and less need for IV fluids. Taken regularly, it especially may provide those suffering from gastroparesis, Crohn's Disease, ulcerative colitis, POTS, SBS, and colorectal cancer to reduce IV hydration and hospital visits, increase energy, reduce palpitations, feel less thirst, experience fewer headaches, eliminate cramps and reduce dizziness. It is found that the liposomal rehydration salt formulation hydrates in one-third of the time and requires only one-third of the intake as compared to many other hydration drinks. The current formulation also uses 46% less sugar than many commercially available hydration drinks. The current formulation aids those that live with the risk of dehydration and it is better than water since water is a very poor hydrator for moderate and severe situations and may cause loss of fluid greater than the amount of fluid consumed, thus leading to electrolyte imbalance. Even coconut water often may not contain enough electrolytes for maintaining proper hydration in severe and chronic dehydration situations. Usually, sports drinks do not contain enough electrolytes because they are designed for mild dehydration situations. The electrolyte powders and tablets that are commonly available present absorption limitations and bad taste. Many commercially available oral rehydration solutions (ORS) are also old technology as compared to the current liposomal rehydration salt formulation that uses nano-electrolytes for higher fluid absorption, less intake requirements and better taste. The formulation can be diluted with water, juices and other drinks, depending on the electrolyte level required.
- It is possible in some cases to add small amounts of other functional ingredients as part of the liposome technology, including vaccines, drugs, amino acids, mineral salts, vitamins, nutraceuticals, probiotics, prebiotics, and other flavors, including nutritive and non-nutritive sweeteners. The amounts would vary of course depending on end uses.
- Many modifications and other embodiments of the invention will come to the mind of one skilled in the art having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is understood that the invention is not to be limited to the specific embodiments disclosed, and that modifications and embodiments are intended to be included within the scope of the appended claims.
Claims (21)
1. A liposomal rehydration salt formulation, comprising phospholipids at a concentration of about 1.0 g/L to 10.0 g/L, salts, water, and a percentage inclusion ratio of salts (salts retained within total salts/liposomes) of at least 50% and a sodium electrolyte of about 12 mEq/L to 90 mEq/L, wherein said formulation has an actual osmolarity lower than 130 based on the at least 50% encapsulation of the salts and said liposomes comprise a particle diameter ranging from 200 nm to 500 nm.
2. The liposomal rehydration salt formulation of claim 1 , wherein said sodium electrolyte is from about 35 mEq/L to 55 mEq/L.
3. The liposomal rehydration salt formulation of claim 1 , further comprising about 15 mEq/L to 25 mEq/L of potassium electrolyte.
4. The liposomal rehydration salt formulation of claim 1 , wherein said phospholipids are selected from the group consisting of phosphatidylcholines (PCs), phosphatidylserines (PSs), phosphatidylethanolamines (PEs), phosphatidylglycerols (PGs), phosphatidylinositols (PIs), phosphatidic acids (PAs), and mixtures thereof.
5. The liposomal rehydration salt formulation according to claim 1 , wherein said formulation further comprises an antioxidant selected from the group consisting of phytosterol, tocopherol, and mixtures thereof.
6. The liposomal rehydration salt formulation of claim 1 , wherein said salts are selected from the group consisting of sodium chloride at a concentration of 0.7 g/L to 2.8 g/L, potassium citrate at a concentration of 0.8 g/L to 2.5 g/L, sodium citrate at a concentration of 0.5 g/L to 2.9 g/L, and mixtures thereof.
7. The liposomal rehydration salt formulation of claim 1 , wherein said formulation further comprises about 10 g/L to 17 g/L of glucose and about 8.0 g/L to 15 g/L of at least one additional sugar.
8. The liposomal rehydration salt formulation of claim 1 , wherein said formulation further comprises Stevia at a concentration of about 0.1 g/L to 0.25 g/L.
9. The liposomal rehydration salt formulation of claim 1 , wherein said formulation further comprises natural flavours at a concentration of about 1 g/L to 3.5 g/L.
10. A method of preventing severe dehydration and maintaining body electrolytes and fluids in a human, comprising orally administering a liposomal rehydration salt formulation comprising phospholipids at a concentration of about 1.0 g/L to 10.0 g/L, salts, water, and a percentage inclusion ratio of salts (salts retained within total salts/liposomes) of at least 50% and a sodium electrolyte of about 12 mEq/L to 90 mEq/L, wherein the formulation has an actual osmolarity lower than 130 based on the at least 50% encapsulation of the salts and the liposomes comprise a particle diameter ranging from 200 nm to 500 nm.
11. The method according to claim 10 , wherein the liposomal rehydration salt formulation is formulated for oral administration for use by humans that are pregnant or breast-feeding or engaged in one or more of sport exercises, outdoor activities, extreme weather activities, climbing and flying.
12. The method according to claim 10 , wherein the liposomal rehydration salt formulation is formulated for oral administration for use by patients having one or more of stomach ailments, skin burns, parenteral or enteral nutrition ailments, celiac disorders, diabetes, SGLT2 inhibitor treatment disorders, intestinal failure, Short Bowel Syndrome, Cycling Vomiting Syndrome, Gastroparesis, Postural Orthostatic Tachycardia Syndrome, Ulcerative Colitis, Colon Cancer, Dysphagia, Sjogren Syndrome, Crohn's disease, Lupus, Alzheimer's disease, Renal complications, HIV, Inflammatory Bowel Disease, an Ostomy, Microvillus Inclusion Disease, and Cystic Fibrosis.
13. The method of claim 10 , wherein said sodium electrolyte is from about 35 mEq/L to 55 mEq/L.
14. The method of claim 10 , wherein the liposomal rehydration salt formulation comprises a potassium electrolyte and administering about 15 mEq/L to 25 mEq/L of the potassium electrolyte.
15. The method of claim 10 , wherein the liposomal rehydration salt formulation comprises about 10 g/L to 17 g/L of glucose and 8.0 g/L to 15 g/L of at least one additional sugar.
16. A method of rehydrating a human suffering from dehydration comprising orally administering a liposomal rehydration salt formulation comprising phospholipids at a concentration of about 1.0 g/L to 10.0 g/L, salts, water, and a percentage inclusion ratio of salts (salts retained within total salts/liposomes) of at least 50% and a sodium electrolyte of about 12 mEq/L to 90 mEq/L, wherein the formulation has an actual osmolarity lower than 130 based on the at least 50% encapsulation of the salts and the liposomes comprise a particle diameter ranging from 200 nm to 500 nm.
17. The method according to claim 16 , wherein the liposomal rehydration salt formulation is formulated for oral administration for use by humans that are pregnant or breast-feeding or engaged in one or more of sport exercises, outdoor activities, extreme weather activities, climbing and flying.
18. The method according to claim 16 , wherein the liposomal rehydration salt formulation is formulated for oral administration for use by patients having one or more of stomach ailments, skin burns, parenteral or enteral nutrition ailments, celiac disorders, diabetes, SGLT2 inhibitor treatment disorders, intestinal failure, Short Bowel Syndrome, Cycling Vomiting Syndrome, Gastroparesis, Postural Orthostatic Tachycardia Syndrome, Ulcerative Colitis, Colon Cancer, Dysphagia, Sjogren Syndrome, Crohn's disease, Lupus, Alzheimer's disease, Renal complications, HIV, Inflammatory Bowel Disease, an Ostomy, Microvillus Inclusion Disease, and Cystic Fibrosis.
19. The method of claim 16 , wherein said sodium electrolyte is from about 35 mEq/L to 55 mEq/L.
20. The method of claim 16 , wherein the liposomal rehydration salt formulation comprises a potassium electrolyte and administering about 15 mEq/L to 25 mEq/L of the potassium electrolyte.
21. The method of claim 16 , wherein the liposomal rehydration salt formulation comprises about 10 g/L to 17 g/L of glucose and 8.0 g/L to 15 g/L of at least one additional sugar.
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WO2023230636A3 (en) * | 2022-05-27 | 2024-03-28 | The Coca-Cola Company | Fast hydration formulation and methods |
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Patent Citations (1)
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US20050000868A1 (en) * | 2002-09-27 | 2005-01-06 | William Weigel | Volumetric fluid balance control for extracorporeal blood treatment |
Cited By (2)
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US10751283B2 (en) | 2014-01-14 | 2020-08-25 | Capability Building, Inc. | Liposomal rehydration salt formulation and associated methods of use |
WO2023230636A3 (en) * | 2022-05-27 | 2024-03-28 | The Coca-Cola Company | Fast hydration formulation and methods |
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US20160331778A1 (en) | 2016-11-17 |
AU2015207485B2 (en) | 2018-01-25 |
US20180028561A1 (en) | 2018-02-01 |
AU2015207485A1 (en) | 2016-09-01 |
WO2015107241A1 (en) | 2015-07-23 |
US10238687B2 (en) | 2019-03-26 |
BR112016016269A2 (en) | 2017-08-08 |
AR094658A1 (en) | 2015-08-19 |
US20180021372A1 (en) | 2018-01-25 |
MX2016009229A (en) | 2017-03-06 |
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