PREPARATION OF CO-DRIED ALUMINIUM OXYHYDROXIDES

Abstract: Adsorptive, protein-binding aluminium oxyhydroxide is prepared by mixing an aqueous suspension of carbonate-free, highly hydrated, aluminium oxyhydroxide with a water soluble additive that provides coordinating moieties with the alumini­ um compound and drying the resultant mixture. The protein-­ binding aluminium oxyhydroxides can be made re-suspend­ able by acidifying to a pH from 4 to 6.5, the acidification being effected either before or after drying.

Description: Preparation of co-dried aluminium oxyhydroxides This invention is concerned with a process for the preparation of co-dried aluminium oxyhydroxides which are useful as adsorptive, protein-binding agents and with compositions comprising such aluminium oxyhydroxides for topical application to the skin. It is well known to those skilled in the art that aluminium hydroxide gels are irreversibly degraded upon drying. The dehydration processing causes the loss of "water-of-constitution", among other entities, resulting in the destruction of most of the positive attributes characteristic of such gels, which properties serve as the very basis of their use in many applications. Illustrative degradative changes which can result are the following: (1) alteration of the physiochemical structure of the products affecting their surfaces as well as their chemical reactivities; (2) loss of adsorbent capacity; (3) impairment of suspendability; (4) increased density; (5) increased particle size; and (6) reduced viscosity. The degradation of aluminium hydroxide gels upon dilution with water is discussed in "A Vehicle For Stabilizing Aluminum Hydroxide Gel", by Kerkhof, N.J.; Hem, S.L. and White, J.L., JOURNAL OF PHARbACRUTICAL SCIENCES, 75, Vol. 64, No. 12, pp. 2030-2032, Dec. 1975. U,S. Patents 4,112,072 and 4,115,553 are directed to producing dried antacids. These patents describe the co-drying of certain basic reactive aluminium bicarbonate-carbonate compounds with polyols to form novel antacid tablets. U.S. 3,599,150 concerns a freeze stable suspension of an aluminium hydroxide gel. The suspension has an alum-precipitated aqueous extract or aqueous pyridine extract of an antibody producing antigenic substance absorbed thereon in an aqueous solution containing a water-soluble non-toxic polyhydric alcohol and water-soluble non-toxic polymers. This patent, however, is not concerned with co-drying of the aluminium hydroxide gel. Non-reactive aluminium oxyhydroxides in the wet state, i.e., suspended in water1 are known to be good adsorbers. For example, such suspensions are used in vaccines as toxin adsorbers (an adsorbent is a material that attracts and holds to its surface a gas, liquid, or solid). Heretofore, these gels were useful only in the wet state. It was recognized that it was uneconomical to "ship large quantities of water around" with the aluminium hydroxide and that it would be advantageous to concentrate the aluminium hydroxide and resuspend it when needed. Attempts to dry such suspensions in order to concentrate them have heretofore not met with success due to the degradation of aluminium hydroxide upon drying as discussed above. We have now found that by using certain additives which are capable of providing coordinating moieties with aluminiums aqueous suspensions of aluminium oxyhydroxide can be dried to give an adsorptive, proteinbinding product and that such a product which is also re suspendable in water can be obtained by acidifying the aluminium oxyhydroxide-additive mixture. According to the present invention, there is provided a method for the preparation of adsorptive, protein-binding aluminium oxyhydroxide, which comprises mixing an aqueous suspension of a carbonate-free, highly hydrated, aluminium oxyhydroxide which is relatively inert towards weak alkalis and acids, with an additive which is soluble in water and is capable of providing coordinating moieties with aluminium, and drying the mixture to form solid particles. The aluminium oxyhydroxide used as starting material in the process according to the invention may be any inert aluminium hydroxide in which only the aluminium and the hydroxy and/or oxy entities are present, such as, for example, boehmite (alpha-alumina monohydrate) and diaspore (beta-alumina monohydrate). These compounds are distinguished from reactive-grade aluminium hydroxide" which contains carbonate/bicarbonate. Such reactive compounds which find wide use as, inter alia, antacids are distinguished from inert aluminium hydroxide by simple carbon dioxide evolution analysis. The additive mixed with the aluminium oxyhydroxide must be capable of furnishing coordinating moieties with aluminium and must be soluble in water. If the product of the co-drying method of the present invention is to be utilized as an agent in a skin composition, the additive must further be topically acceptable, i.e. safe for use on the skin. The additive can be a polyhydric alcohol, sugar, amino acid, polysaccharide or polyfunctional nitrogen-containing compound. Suitable polyhydric alcohols include, for example, glycerol, sorbitol, mannitol, polyethylene glycol (Carbowax), polypropylene glycol, butylene glycol and xylitol. Suitable sugars include, for example1 lactose, sucrose and glucose. Suitable polyfunctional nitrogen-containing compounds include, for example, amino acids, such as L-glutamic acid, glycine and beta-alanine, and urea. If an amino acid is used in a suitable strength, i.e. concentration, it can act both as an additive and as the acidifier when a re-suspendable product is desired. Suitable polysaccharides include, for example, corn starch, "VEEGUM", ',CERULOSE", ',CARBOPOLS" and "CELLOSIZE". The weight ratio of additive to aluminium oxyhydroxide, calculated as aluminium oxide present in the suspension prior to drying is suitably from 10:1 to 3:2, and preferably from 6:1 to 3:2. Based on the product, after drying, the additive can amount to from 5 to 30 % by weight of the total product. The point of determination of the amount of additive, either before or after drying, is not per se critical and only has significance when volatile additives are utilized. A volatile additive will dissipate to some degree during drying depending on its volatility and the drying temperature. The weight ratios of additive to aluminium oxide as given above assume no loss of additive during drying. It would be a simple matter for one practising this invention to calculate the estimated loss of additive due to evaporation and then add extra additive in anticipation of such loss. For a non-volatile additive, such as corn starch, this procedure is, of course, unnecessary. The mixture of additive and aluminium oxyhydroxide compound is subjected to co-drying at appropriate temperatures. High drying temperatures should not, however, be used since there is a tendency to break bonds at high temperatures. It is advantageous to drive off as much moisture as possible without over-drying the mixture. It is preferred to dry the mixture to attain from 55 to 65 % by weight aluminium oxyhydroxide, calculated as aluminium oxide. Any convenient drying method can be employed, such as spray drying, vacuum drying, and hot air circulating ovens. The type of drying used will generally determine the particle size of the resultant solids. It is preferred in many instances to form a fine powder. Such powder can, for example, be produced using a spray drying technique or other drying techniques which produce larger particles which are subsequently comminuted by various grinding techniques known in the art. Although it is usually desired to minimize the amount of additive, such amount is directly proportional to the protein-binding capacity of the product. Protein binding is enhanced by increasing the surface area of the aluminium-containing compound particles, i.e., fine particle size. The suspendability of the dried products of this invention is inversely proportional to the pH of their respective suspensions. The more concentrated the product, the less expensive the shipping costs due to elimination of unnecessary water being carried along with the useful product. Thus it is advantageous to obtain a product that is readily re-suspendable in water. To obtain a protein-binding, adsorptive agent that is re-suspendable, acid must be utilized. Acidification can be effected either prior to co-drying or after co-drying. It is preferred to acidify prior to co-drying in order to produce a concentrated resuspendable solution. In this case, the aluminium oxyhydroxide in aqueous suspension is acidified to give a pH for the suspension of from 4 to 6.5, preferably from 5 to 6. The acidified suspension is then mixed with the additive and co-dried to the desired degree. Alternatively, the aluminium oxyhydroxide aqueous suspension can be mixed with additive and then acidified to the pH range as given above prior to co-drying. The acidification can be effected with any moderately strong acid, for example hydrochloric acid, nitric acid or sulphuric acid Acidification can also be carried out with compounds which yield acids upon hydrolysis, such as All3. Acidification can also be effected after codrying. In this case, the co-dried product is mixed with water to form a suspension and the latter is acidified to the pH range as given above. The adsorptive, protein-binding aluminium oxyhydroxide product produced by the method of the present invention can be employed in topical skin compositions. It can be used alone or in combination with other ingredients to form compositions which can be used as sun screens, wrinkle fillers, acne medications, poison ivy remedies, burn remedies, antifungicides, antiseptics, analgesics, cosmetics, for example, lipsticks, and skin creams. The other ingredients used in conjunction with the product of the present invention to form topical skin compositions include emulsifiers, such as a combination of glycerol monostearate, triethanolamine and stearic acid; thickeners, such as stearic acid; emollients, such as isopropyl myristate; and humectants, such as glycerine Typical formulations are, for example, as follows: Co-Dried Powder Produced in Accordance With The Present Invention - Approximate Analysis wt. % Al2O3 60.10 wt. % Glycerine 17.30 wt. h Chloride 3.40 wt. % Na 0.45 wt.% SO4 0.71 wt. % Water 19.04 (some water may exist as OH-) pH (4% Suspension) 5.1 Bulk Density 0.77 g/cc Protein Binding Capacity 1.50 mg/mg Al2O3 at pH 5.5 Ointment Al2O3 - Glycerine Powder as given above 3.2 wt. % Mineral Oil 15.0 wt. % Petrolatum 76.8 wt. % Polyoxyethylene 4 Sorbitan Monostearate 5.0 wt. % ("TWEEN 61") Powder A1203 - Glycerine Powder as given above 3.2 wt. so Talc 93.8 wt. % Magnesium Stearate 3.0 wt. % Creams wt. % wt. % A120 - Glycerine Powder as given above 5.0 5.0 "ARLACEL 165" (Glycerol Monostearate and Polyoxyethylene Stearate) 3.5 3.5 Mineral Oil 5.0 3.0 Isopropyl Myristate 3.0 6.0 Propylene Glycol 2.0 1.0 Cetyl Alcohol 1.5 4.0 Methyl Paraben 0.2 0.2 Propyl Paraben 0.05 0.05 "MYRJ 52" (Polyoxyethylene 40 Stearate) - 0.5 Titanium Dioxide - 0.2 Deionized Water 79.75 76.55 The present invention gives an aluminium oxyhydroxide agent having the following attributes: : (1) oil absorption (an absorbent is a material that "sucks up" or incorporates liquids, gases, etX (2) thixotropic; (3) protein-binding; (4) resistant to being washed away; (5) aesthetically pleasant; (6) stable; (7) non-tacky; (8) non-greasy; (9) non-irritating; (10) non-toxic; (11) compatible with oxidizing agents, for example1 hydroperoxide and benzoperoxide; (12) having a broad pH range; and (13) re-suspendable (when acidified). In order that the invention may be more fully understood, the following examples are given by way of illustration only: Examples 1-10 Effect of Glycerol Levels on Re-suspendability of Co-Dried Products Examples 1-5 (without HCl) Five different A12O3/glycerol weight ratio levels were utilized for examination of re-suspendability; 3/0, 6/1, 3/1, 2/1, 1.5/1. To each batch of Al2O3, glycerol was added according to the formula: (wt. Al2O3) (%Al2O3 gel) (0.01) Ratio Al2O3/glycerol desired The source for Al2O3 used throughout all the examples herein was Reheis Chemical Company "F-5000" gel. "F-5000" is a carbonate-free, highly hydrated, aluminium oxyhydroxide gel which is relatively inert towards weak alkalis and acids. 5500 grams of 9.6 wt.t A1203 were added to an 18 liter Nalgene polypropylene vessel. Ten liters of well water were added to the gel and the mixture was homogenized with a Premier dispersator for two hours. From this slurry, five aliquots of 3000 grams each were taken, and each was placed in an 8 liter Nalgene polypropylene vessel. Example 1 To the first aliquot was added 17b1 grams of glycerol according to the above formula. The slurry was agitated for an hour and screened through a &num;40 sieve before spray drying. Before the slurry was spray dried, two liters of well water were added to the slurry to improve pumpability. The slurry was spray-dried at 120-125 C in a 3 foot cir cular Bowen spray dryer employing a two-fluid nozzle head. Air pressure was set at 80 psig and feed rate at 100 ml/min. This procedure yielded about 150 grams of finely divided, free-flowing, white powder with a pre-spray dry A1203 to glycerol rate of 6/1 (see Table 1). To demonstrate the resuspendability of the A1203 glycerol co-dried system with HCl, 2 grams of the above powder was added to 25 grams deionized water in a 4" x ln glass vial. With its cap in place, the vial was shaken ten times and three drops (approximately 0.14 grams) of 31% HC1 was added to the vial by a medicine dropper. The vial was again shaken ten times. The vial approximated 4 wt% A1203 (Example 1A). Resuspendability of an 8% system was also tested using 4 grams of powder and 5 drops (ap proximately 0.24 grams) of 31% HC1 in 25 grams deionized water (Example 1B). After standing overnight, the pH's of the vials were measured with a Beckman SS-3 pH meter standardized at pH S and pH 7. Example 2 This example is identical to the above Example 1 with the exception that 34.1 grams of glycerol were added to the slurry for a projected 3/1 ratio of A1203 to glycerol. Spray drying parameters and resuspendability techniques for 49 and 8% resuspensions were identical to Example 1 and for succeeding Examples 3-5. Example 3 In this example 51.2 grams of glycerol was used to achieve a 2/1 ratio of A1203 to glycerol. Example 4 In this example 68.2 grams of glycerol was used with the resultant slurry having a 3/2 ratio of A1203 to glycerol. Example 5 No glycerol was used in this slurry which served as the 3/0 control. The above spray dried slurries were analyzed for % A1203 and reported in Table I herein. Resuspendability of the A1203-glycerol co-dried systems with HC1 added on resuspension is shown in Table II herein. Examples 6-10 (with HCl) 5000 grams of 9.6 wt.% A1203 were added to an 18 liter Nalgene polypropylene vessel¯. To this, three liters of well water were added. The pH of the slurry was then adjusted to 4.8 with 62 ml of 31% HC1 under constant agitation with a Premier dispersator. The mixture was homogenized for two hours. From this slurry, five aliquots of 1800 grams each were taken and placed in an 8 liter Nalgene polypropylene vessel. Example 6 To the first 1800 gram aliquot was added 18 grams of glycerol under constant agitation with the dispersator. The slurry was agitated one hour, and then screened through a µ40 mesh sieve before spray drying (No extra well water was added to the slurry since it was pumpable). The spray drying parameters followed exactly those enumerated above in Example 1. -130 grams of finely divided, free-flowing powder resulted with a 6/1 pre-spray dry A1203 to glycerol ratio (see Table II). Resuspendability of this system was achieved by adding 2 grams of the powder to 25 grams deionized water in a 4" x 1" glass vial. The vial was shaken ten times and left to stand overnight. After a minimum of 24 hours, pH's and descriptions were recorded. Example 7 This example was identical to Example 6 except 36 grams of glycerol was added to the slurry to yield a 3/1 ratio. Dilution, spray drying parameters and resuspendability techniques for 4% resuspensions were identical to Example 6 for this and the succeeding Examples 8 through 10. Example 8 The third aliquot received 54 grams of glycerol for an A1203/glycerol ratio of 2/1. ¯ .'. - Example 9 72 grams of glycerol were added to the fourth 1800 gram portion for a 3/2 ratio A1203 to glycerol. Example 10 To the last aliquot of slurry, no glycerol was added. The spray dried slurries in each of the above Examples 6-10 produced 130-140 grams of finely divided, free-flowing, white powder. Analyses of these powders is given in Table III herein. Table IV given herein describes resuspendability of the A1203-glycerol-HC1 system at various glycerol concentrations. Examples 11-15 Effect of pH on Resuspendability In the following examples, the effect of pH on A1203-glycerol-HCl co-driedsystems is demonstrated. Varying amounts of HC1 was used prior to spray drying to achieve powders of different pH values. To 6000 grams of 9. 6t A1203 gel in an. 18 liter Nalgene pblypropylene vessel was added 3600 grams of well water and the resultant mixture was slurried with a Premier Jispesator for two hours. This slurry was then split into five 1800 grams aliquots each and put into 8 liter Nalgene polypropylene vessels. Each of the five portions was acidified to a different extent as shown in Examples 11 through 15. Example 11 To the first 1500 gram aliquot was added 36 grams glycerol and 15.7 ml 31% HC1 under constant agitation from a dispersator. The pH was measured and found to be 4.3. 130 grams of finely divided, free-flowing, white powder resulted after spray drying at parameters mentioned in Example 1. Resuspension of this powder and the powders of Examples 12 through 15 were according to the procedures of Example 6. Example 12 - To this aliquot was added 36 grams of glycerol and 138 ml 31% HC1. After agitation, the pH was read as 4.8. Example 13 36 grams of glycerol and 12.7 ml HC1 were added to the third aliquot to give a final pH of 5.5. Also, one liter of well water was added to make the slurry pumpable. Example 14 36 grams of glycerol, 8.3 ml 31 EIC1 and three liters of well water were added to this sample. Example 15 36 grams of glycerol, 8.3 ml 31% HC1, three liters of well water1 and no HC1 were added to this sample before spray drying. The results of the resuspendibility tests at different pM' s are given in Table V herein. Examples 16-20 Effect of Concentration on Resuspendability Superior resuspendability of this invention over a wide range of concentrations are shown below using A1203glycerol-HCl co-dried systems. Each of the examples outlined below (Examples 16 through 20) used powder synthe sized in accordance with the procedures of Example 7. The results for Examples 16-20 are given in Table VI herein. Example 16 One gram of Example 7 powder and 25 grams of deionized water were put into a 4" x 1" glass vial and shaken ten times. This represented the 2% A1203 example. Except for powder quantities, all resuspensions were performed identically and followed the procedures given in Example 6. Example 17 This example is a duplicate of Example 7. Example 18 Three grams of powder gave approximately a 6% A1203 resuspension. Example 19 Four grams of powder resulted in an 8% resuspension. Example 20 Five grams of powder resuspended for a 10% A1203 level. Examples 21-33 Order of Component Addition in Relation To Spray Drying on Resuspendability Resuspendability studies were performed on four different variations of co-dried powders: A1203 alone, A1203 co-dried with glycerol, A1203 co-dried with glycerol and HC1, and A1203 co-dried with HC1-. To each of these powders glycerol, HC1, or both were added after spray drying. The resulting thirteen examples examined at 48 and & A1203. 5000 grams of 9.6 wt.% A1203 were added to an 18 liter Nalgene polypropylene vessel. Nine liters of well water was added to the gel and the mixture was homogenized with a Premier dispersator for two hours. This batch was then split into two unequal sized aliquots; one, 7625 grams and the other, 6120 grams. The larger portion was acidified to pH 4.8 with 27 ml of 31t HC1 in an 8 liter Nalgene polypropylene vessel. The smaller portion received no HC1. The acidified batch was split into two equal portions of 3800 grams, each put into an 8 liter Nalgene polypropylene vessel. To one of these 3800 gram batches was added 43.4 grams of glycerol. This batch was agitated for one hour. The other 3800 gram batch received no glycerol. The unacidified half was also split into two aliquots of about 3060 grams each. Again, each was placed in an 8 liter Nalgene polypropylene vessel. One portion received 35.0 gram glycerol according to the formula given for Examples 1-5, and one portion received no glycerol. The regime for Examples 21-33 is given in Table VII herein; the results for Examples 21-33 are given in Tables VIII and IX herein. The slurries were all spray dried according to Example 1, but 2 liters of well water had to be added to the unacidified slurries to make them pumpable. Examples 21-26 Spray Dried A1203 Plus UnCo-Dried Adjuvants Example 21A To a 4 x X 1" glass vial containing 25 grams of deionized water was added two grams of -A1203 powder as prepared above. The vial was shaken ten times and then 4 drops of 31% HC1 were added to the vial by a medicine dropper and shaken again for ten times. The vial was left overnight at which time a pH reading was taken and observations were made. This represented a 4t A1203 sample. Examples 22 through 26 follow the above procedure with the stated changes. Example 21B An 8% A1203 sample was also made up with 4 grams of powder in 25 grams of deionized water plus 5 drops HC1. Example 22A 4% A1203 and 3 drops HC1. Example 22B 8% A1303 and 4 drops HC1. Example 23A 4% A1203, 3 drops glycerol (0.2 grams), and 4 drops HC1. Amount of glycerol to each vial was figured according to formula given in Examples 1-5. Example 23B 8t A1203, 6 drops glycerol (0.4grams), and 5 drops HC1. Example 24A 4% A1203, 3 drops HC1, 3 drops glycerol. Example 24B 8% Al2O3, 4 drops HC1, and 3 drops glycerol. Example 25A 4% A1203 and 6 drops glycerol. Example 25B 8% A1203 and 6 drops glycerol. Example 26A 4% A1203; no additives. Example 26B 8% A1203; no additives. Examples 27-29 A1203-glycerol co-dried powder was used in Examples 27 to 29. These resuspensions were prepared according to the procedure in Example 21A. Example 27A 4% A1203 and 3 drops HC1. Example 27B 8% A1203 and 4 drops HC1. Example 28A 4% A1203 and 4 drops HC1. Example 28B 8% A1203 and 5 drops HC1. Example 29A 4% A1203; no additives. Example 29B 8% A1203; no additives. Examples 30-31 A1203-Glycerol-HCl Co-Dried Systems -- No Additives A1203-Glycerol-HCl Co-Dried powder was used in Examples 30A and 30B. These resuspensions also followed the procedure given in Example 21A. Example 30A 4% A1203 Example 3OB- 8% A1203 Example 31A 4% A1203 using powder prepared according to Example 11. Example 31B 8% A1203 using powder prepared according to Example 11. Examples 32-33 A1203-HC1 Co-Dried Systems A1203-HCt Co-Dried powder was used in Examples 32 and 33. These resuspensions followed the procedure given in Example 21A. Example 32A 4% A1203 and 3 drops glycerol. Example 32B 8% A1203 and 6 drops glycerol. Example 33A 4% A1203; no additives. Example 33B 8% A1203; no additives. Examples 34-50 Resuspendability of A1203-Adjuvant Co-Dried Systems Examples 34-50 show the superior resuspendability of A1203 gel co-dried with a number of additives, thirteen of eighteen having a positive effect on resuspendability. 5500 grams of A1203 gel and ten liters of well water were slurried with a dispersator in an 18 liter reaction vessel for two hours. Four 4000 gram aliquots were taken from this main batch and each was mixed in four 8-liter reaction vessels. This diluted the gel from 9.6% A1203 to 3.4t A1203. -All slurries possessed 3/1 Ai203 to additive ratios. Analyses for the powders used in Examples 34-50 are given in Table X herein. The results for Examples 34-50 are given in Tables XI and XII herein. Example 34A To one of the 4000 gram aliquots was added 45.5 grams of sucrose according to the formula given for Examples 1-5. The slurry was mixed in a dispersator for one hour. Two liters of additional well water were added to make the gel pumpable. The slurry was then spray dried and resuspended at 4% according to Example 1. The following Examples 35 to 50 follow the above example except that in Examples 38 through 50, 3000 grams of slurry and 34.1 grams of additive were used. The additives utilized were as follows: sucrose - sucrose USP - lactose - Fisher ACSt - lactose sorbitol - ICI 70 sorbitol solution polypropylene glycol Carbowax 200 - Union Carbide "CARBOWAX 200"; Grade 1, 2 propanediol Carbowax 400 - Union Carbide "CARBOWAX 400" Carbowax 600 - Union Carbide "CARBOWAX 600" stearic acid - Baker certified stearic acid citric acid - Pfizer citric acid USP potassium citrate - Fisher certified potassium citrate corn starch - Sargent-Welsh corn starch Gelatin - Atlantic Gelatin edible 200B glycine - Walker glycine USP beta-alanine - Fisher beta-alanine purified grade L-Glutamic acid - Fisher certified glutamic acid Veegum - "VEEGU" regular grade R.T. Vanderbilt Inc. Urea - Fisher ACS grade PVP K-30 - General Aniline & Film Corp. PVP (polyvinylpyrolidine) K-30 USP PVP K-60 - General Aniline & Film Corp. PVP (pplyvinylpyrolidine) Examples 51-71 Protein Binding A known excess of protein standard was mixed with the sample. The non-adsorbed protein was spectrometrically determined and subtracted from the total added protein. Protein Reagent A protein reagent was prepared by pipetting 30 ml of deionized water into a 100 ml breaker. 1.596 grams of bovine albumin Fraction V powder, Armour Pharmaceutical Company, was added to the water. The resultant mixture was gently stirred to effect solution. The solution was then filtered through Whatman &num;4 filter paper and stored in a glass stoppered flask. Preparation of Standard Curve Protein reagent as prepared according to the above was pipetted in amounts of 0.5, 1.0, 1.5 and 2.0 mi respectively into four different 50 ml volumetric flasks and each flask was diluted to the mark with deionized water. The four standards were each well mixed. Each standard contained 0.25, 0.50, 0.75 and 1.00 mg. protein per/ml respectively. Absorbance of each standard was obtained at a wavelength of 280 nm using 10 mm silica cells on a Beckman Model 25 spectrophotometer using deionized water as a blank. A standard graph was prepared by plotting absorbance vs. concentration of each protein standard (mg. Protein/ml) on linear graph paper. The best possible straight line to fit most of the points and the origin was drawn. Procedure To at least three significant figures two and four grams of the A1203 samples were weighed into two separate 50 ml glass stoppered centrifuge tubes (concentration of each sample was approximately 40 mg and 80 mg A1203). A sufficient amount of deionized water was added from a burette so that grams of sample plus milliliters of water equaled 17.0 mls (if the density of the suspension was significantly different from one, corrections were made for the sample volume). The samples were shaken gently to disperse the suspension. 3.00 ml (150 mg of protein) of protein reagent (Bovine Albumin F.V, 5% Solution) solution was then added. The tubes were then mixed gently and placed on a Burrell wrist action shaker. The tubes were shaken gently at a setting of 2 for 15 minutes. The tubes were centrifuged for 15 minutes at 2000 to 2500 RPM. The supernatant was filtered through a millipore HA (0.45}ism) membrane filter paper. 10 ml of clear filtrate was pipetted into a 100 ml volumetric flask and diluted to volume with deionized water. The absorbance for each sample at 280 nm wavelength was read using 10 mm silica cells, the model 25 spectrophotometer and deionized water as a blank. The concentration of each non-adsorbed protein sample was obtained in mg/ml at approximately 40 mg A1203 and 80.0 mg A1203 level from the standard graph. Calculations &commat; approximately 40 mg A1203 level, mg Protein adsorbed = mg A1203 150 - mg/ml Protein from graph x 2 x 100 mg. of A1203 in suspension And, &commat; approximately 80 mg A1203 level, mg Protein adsorbed = mg A1203 150 - mg/ml Protein from graph x 2 x 100 mg of A1203 in suspension Results The average of both the mg Protein/mg A1203 were taken at approximately 40 mg A1203 and 80 mg A1203 23 level and reported as mg Protein/mg A1203. Using the above procedure, protein-binding capacities were determined for various co-dried compounds in Examples 51-71 and the results are given in Table XIII herein. Since surface area plays a major role in the adsorption measured in this test, micronization might increase the values of the co-dried systems and not the Al2O3 dried without additivies. Examples 72-91 Protein Binding The same test procedure as in Examples 51-71 was utilized in Examples 72-91 except the pri was adjusted to 5.5 The glycerine control (100% glycerine) test was not applicable, since both it and the protein solution were soluble in mixed form. A plot of protein binding capacity vs. glycerine for co-dried A1203-glycerine without acid is given in the single Figure of the accompanying drawing (Example Nos. 72-75). The results for Examples 72-91 are given in Table XIV herein. Examples 92-100 In Examples 92-100, co-dried systems of A1203- glycerine prepared in accordance with this invention were evaluated with and without the addition of acid (HCl). The results for Examples 92-100 are given in Table XV herein. It is evident from Table XX that re-suspendability was afforded to only those systems employing acid. The use of acid also increased the protein binding capacity of the co-dried systems. Table I Example No. Al2O3 Al2O3(/Glycerol Ratio in Slurry 1 61.4 6/1 2 60.1 3/1 3 58.6 2/1 4 57.9 3/2 5 64.47 3/0 ?able IT. Ease ptI A1203/Glycerol No. Measured Ratio In Slurry * Description 1A 4.7 6/1 fluid gel 1B 6.0 6/1 thick fluid gel 2A 5.1 3/1 gel 2B 6.3 3/1 gel 3A 4.7 2/1 fluid gel 3B 6.3 2/1 gel 4A 4.0 3/2 fluid gel 4B 6.3 3/2 gel 5A 4.7 3/1 fluid gel 5B- 6.2 3/0 with 0.2 cm unsuspended powder * All resuspensions described at a minimum of 1 dayr maximum of 30 days. Table III Example Al2O3/Glycerol Ratio No. tA12o3 glycerol Slurry Powder 6 62.18 10.5 6/1 5.9/1 7 59.20 16.5 3/1 3.6/1 8 56.70 19.7 2/1 2.9/1 9 55.77 22.9 3Y2 4.9/2 10 64.47 ---- 3/0 3/0 Table IV Example Measured No. pH Description 6 5.8 gel 7 5.8 gel 8 5.6 gel 9 5.7 gel 10 5.9 0.5 cm unsuspended powder in 6 cm supernatant Table V Example Measured A1203/Glycerol No. pH in Slurry Description 11 5.5 3/1 gel 12 5.9 3/1 gel 13 6.4 3/1 fluid gel 14 7.2 3/1 0.5 cm unsus pended powder and 6 cm super natant 15 7.9 3/1 same as Example 14 Table VI Example Measured Approx. % A12O3 No. pH Concentration in Vial Description 16 5.7 2 fluid gel 17 5.7 4 gel 18 5.7 6 gel 19 5.8 8 very thick gel 20 5.7 10 very thick gel Table VII EMI27.1 <tb> <SEP> A1203 <SEP> Gel <SEP> + <SEP> well <SEP> water <tb> <SEP> unacidified <SEP> acidified <tb> <SEP> glycerol <SEP> no <SEP> gi <SEP> cerol <SEP> glycerol <SEP> no <SEP> ivcerol <tb> A1203 <SEP> + <SEP> glycerol <SEP> A1203 <SEP> A12 <SEP> + <SEP> glycerol <SEP> A1202 <SEP> + <SEP> HC1 <tb> <SEP> + <SEP> aC1 <tb> <SEP> pH <SEP> of <SEP> 48 <SEP> pH <SEP> of <SEP> 4% <SEP> pH <SEP> of <SEP> 4% <SEP> pH <SEP> of <SEP> 4% <tb> resuspension=9.0 <SEP> resuspension=8.6 <SEP> resuspension=6.9 <SEP> resuspension=6,6 <tb> Table VIII Example Measured No. pH ¯ % A1203 Resuspension * Description 21A 4.6 4 fair 0.5 cm settled powder belpw hazy liquid 21B -5.0 8 fair 2 cm clear liquid above unsuspended powder 22A 5.5 4 fair 1 cm settled pow - der above hazy liquid 22B 6.2 8 fair 2 cm clear liquid above unsuspended powder 23A 4.2 4 fair 0.5 cm settled powder -below hazy powder 23B 5.7 8 good thick suspension 24A 5.2 4 fair 1.5 cm settled powder below hazy liquid 24B 6.2 8 fair 1.5 cm clear liquid above settled powder 25A 8.4 4 no unsuspended powder 25B 8.5 8 no unsuspended powder 26A 8.5 4 no unsuspended powder 26B 8.4 8 no unsuspended powder 27A 5.2 4 good gel 27B 6.5 8 good very thick gel 28A 4.1 4 good fluid gel 28B 6.2 8 good very thick gel Table VIII (Cont'd) Example Measured No. pH 90 A1203 Resuspension * Description 29A 8.9 4. no unsuspended powder 29B 8.9 8 no unsuspended powder 30A 6.3 4 no unsuspended powder 30B 6.5 8 no unsuspended powder 31A 5.6 4 good gel 3lB 5.8 8 good very thick gel 32A 6.3 4 no unsuspended powder 32B 6.5 8 no unsuspended powder 33A 6.3 4 no unsuspended powder 33B 6.5 8 no unsuspended powder * All descriptions made at minimum 1 day, maximum 30 days. Table IX Reevaluation Of Resuspendability Taken About Six Weeks Later Than Those Taken In Table VIII Example No. % A1203 Resuspension * Description 21A 4 good gel 21B 8 good gel 22A 4 fair 1.5 cm clear liquid above 4 cm resus pended powder 22B 8 fair 0.5 cm clear liquid above 5 cm resus pended powder 23A 4 good gel 23B- 8 good gel 24A 4 good fluid gel 24B 8 fair 1 cm clear liquid above 4.5 cm resus pended powder 25A 4 no unsuspended powder 25B 8 no unsuspended powder 26A 4 no unsuspended powder 26B 8 no unsuspended powder 27A 4 good gel 27B 8 good very thick gel 28A 4 good gel 28B 8 s good very thick gel 29A 4 no unsuspended powder Table IX (Cont'd) Example No. % Al2O3 Resuspension * Description 29B 8 no unsuspended 30A 4 fair 1 cm clear liquid above 4.5 cm resus pended powder 30B 8 fair 1.5 cm clear liquid above 4 cm resus pended powder 31A 4 good gel 31B 8 good very thick gel 32A 4 no unsuspended powder 32B 8 no unsuspended powder * All descriptions made at minimum 1 day, maximum 30 days. Table X Additive %A1203 none - 65.31 sucrose 56.07 lactose 56.36 sorbitol 56.74 propylene glycol 63.74 urea .59.29 Carbowax 600 56.83 Carbowax 400 56.42 Veegum 54.40 corn starch 51.26 PVP K-30 55.35 citric acid 57.66 stearic acid 63.66 gelatin 57.75 PVP K-60 55.68 Carbowax 200 54.21 glycine 58.61 L-glutamic acid 58.72 beta-alanine 58.46 potassium citrate 56.97 Table XI Example Wt.% Al2O3 Drops HCl No. Additive Resuspension (31%) Added 34B sucrose 8 3 (0.14 g) 34C sucrose 4 3 34D sucrose 8 5 (0.24 g) 35A lactose 4 3 35B lactose 8 5 35C lactose 4 3 35D lactose 8 3 36A sorbitol 4 3 36B sorbitol 8 5 36C sorbitol 4 3 36D sorbitol 8 3 37A propylene glycol 4 3 37B propylene glycol 8 5 37C propylene glycol A 3 37D propylene glycol 8 3 38A Carbowax 200 4 3 38B Carbowax 200 8 3 38C Carbowax 200 4 3 38D Carbowax 200 8 5 39A Carbowax 400 4 3 39B Carbowax 400 8 5 39C Carbowax 400 4 3 39D Carbowax 400 8 3 40A Carbowax 600 4 3 40B Carbowax 600 8 5 Table XI (Cont'd) Example Wt.% A1203 Drops lECi No. additive Resuspension (31%) Added 40C Carbowax 600 4 3 40D Carbowax 600 8 3 41A stearic acid 4 3 41B stearic acid 8 5 41C stearic acid 4 3 41D stearic acid 8 3 42A citric acid 4 5 42B citric acid 8 3 42C citric acid 4 3 42D citric acid 8 3 43A potassium citrate 4 3 43B potassium citrate 8 5 43C potassium citrate 8 3 44A corn starch 4 3 44B corn starch 8 5 44C corn starch 4 3 44D corn starch 8 3 45A urea 4 5 45B urea 8 3 45C urea 4 3 45D urea 8 3 46A glycine 4 3 46B glycine 8 5 Table XI (Cont'd) Example Wt.% A1203 Drops HC1 No. Additive Resuspension (318) Added 46C glycine 4 3 46D glycine 8 3 47A beta-alanine 4 3 47B beta-alanine 8 5 47C beta-alanine 4 3 47D beta-alanine 8 3 48A L-glutamic acid 4 3 48B L-glutamic acid 8 5 48C L-glutamic acid 4 0 48D L-glutamic acid 8 3 49A gelatin 4 3 49B gelatin 8 5 49C gelatin 8 3 50A Veegum 4 3 50B Veegum 8 5 50C Veegum 4 3 50D Veegum 8 3 Table XII Example Adjusted Ntb Additive pM %A1203 Resuspension *Description 34A sucrose 5.2 4 good thick gel 34B sucrose 6.7 8 good fluid gel 34C sucrose 6.0 4 good thick gel 34D sucrose 5.6 8 good very thick gel 35A lactose 5.5 4 good thick gel 35B lactose 5.6 8 good thick gel 35C lactose 6.3 4 good thick fluid gel 35D lactose 6.6 8 good fluid gel 36A sorbitol 5.5 4 good gel 36B sorbitol 6.4 8 good very thick gel 36C sorbitol 6.3 4 good fluid gel 36D sorbitol 6.5 8 good gel 37A propylene 5.2 4 good gel glycol 37B propylene 6.5 8 fair 0.5 cm clear glycol liquid on 5 cm powder 37C propylene 6.5 4 no unsuspended glycol powder 37D propylene 6.7 8 fair 0.5 cm clear glycol liquid on 5 cm powder 38A Carbowax 200 5.5 4 good thick fluid gel 38B Carbowax 200 6.4 8 good thick fluid gel 38C Carbowax 200 5.8 4 good gel Table XII (Cont'd) Example Adjusted Nc. Additive pH %Al2O3 Resuspension *Description 38D Carbowax 200 5.6 8 good gel 39A Carbowax 400 4.6 4 good thick fluid gel 39B Carbowax 400 6.1 8 good very thick gel 39C Carbowax 400 6.0 4 good gel 39D Carbowax 400 6.4 8 good thick fluid gel 40A Carbowax 600 4.7 4 good thick fluid gel 40B Carbowax 600 5.1 8 good gel 40C Carbowax 600 5.4 4 good thick fluid gel 40D Carbowax 600 6.2 8 no unsuspended powder 41A stearic acid 4.1 4 no unsuspended powder with hazy liquid 41B stearic acid 5.1 8 no same as above 41C stearic acid 4.3 4 no same as above 41D stearic acid 5.2 8 no same as above 42A citric acid 2.5 4 no unsuspended powder 42B citric acid 2.5 8 no same as above 42C citric acid 2.6 4 no same as above 42D citric acid 2.7 8 no same as above 43A potassium 5.8 4 no same as above citrate 43B potassium 6.6 8 no same as above citrate Table XII (Cont'd) Example Adjusted No. Additive pH %Al2O3 Resuspension *Description 43C potassium 8.3 8 no same as above citrate 44A corn starch 4.8 4 good fluid gel 44B corn starch 5.1 8 good thick fluid gel 44C corn starch 6.1 4 no unsuspended powder 44D corn starch 6.2 8 no same as above 45A urea 4.9 4 good fluid gel 45B urea .5.7 8 good very thick gel 45C - urea 5.6 4 good thick gel 45D urea 6.5 8 no unsuspended powder 46A glycine 5.2 4 good gel 46B glycine 5.4 8 - good gel 46C glycine 5.6 , 4 good gel 46D glycine 6.6 8 fair 1 cm clear liquid above 4.5 au powder 47A beta-alanine 5.0 - 4 good fluid gel 47B beta-alanine 6.0 8 good gel 47C beta-alanine 6.2 4 good gel 47D beta-alanine 6.7 8 fair 0.5 an clear liquid above powder 48A Glutamic 3.7 4 good gel acid 48B L-glutamic 3.9 8 good thick fluid acid gel Table XII (Cont'd) Example Adjusted No. Additive pH gA1203 Resuspension *Description 48C L-glutamic 4.9 4 no unsuspended powder 48D L-glutamic 4.1 8 good thick fluid gel 49A gelatin 5.3 4 no same as above 49B gelatin 6.1 8 no same as above 49C gelatin 6.6 8 no same as above 50A Veegum 5.5 4 no same as above 50B Veegum 6.3 8 no same as above 50C Veegum 6.6 4 no same as above 50D Veegum 6.7 8 no same as above Table XIII Protein Binding Capacity of Al2O3 with Additives* Example mg. of Protein adsorbed No. Sample description %Al2O3 mg og Al2O3 51 Al2O3 slurry (no additive) 3:37 1.34 52 A1203 w/L-glutamic acid 58.72 0.48 53 A1203 w/Carbowax-600 56.83 0.25 54 A1203 w/beta-alanine 58.46 0.24 55 A1203 w/Carbowax-400 56.42 0.21 56 Al2O3 w/stearic acid 63.62 0.20 57 A1203 w/K-citrate 56.92 0.20 58 A1203 w/citric acid 57.66 0.17 59. - A1203 w/Glycine 58.61 0.17 60 A1203 w/propylene glycol 63.74 0.14 61 A1203 w/ urea 59.29 0.13 62 A1203 w/sucrose 56.07 0.12 63 A1203 w/Carbowax-200 59.21 0.1 64 A1203 (No additive) 65.31 O.11 65 A1203 w/sorbitol 56.74 0.11 66 A1203 gelatin 57.75 0.10 67 A1203 w/PVP (K-60) 55.68 0.09 68 A1203 w/PVP (K-30) 55.35 0.08 69 A1203 w/lactose 56.36 0.04 70 Al2O3 w/Veegum 54.40 0.0 71 A1203 w/corn starch 51.26 0.0 * Al2O3 powder with 3:1 additive ratio Protein Binding Example Co-Dried % % Approx. Actual Nat'1 PB # No. Additive Al2O3 Additive Al2O3 Al2O3 pH Nat'1 pH pH 5.51 mg Protein mg Al2O3 72 None 65.3 0 - - 8.6 0.11 0 73 Glycerine 61.4 10.75 6/1 5.7/1 0.09 0.54 74 Glycerine 60.1 21.5 3/1 2.8/1 8.5 0.11 0.95 75 Glycerine 57.9 43 1.5/1 1.3/1 0.26 1.25 76 Glycerine/ HCl 3/1 5.5 1.7 1.7 77 Glycerine/ HCl 62.1 15.7 4.0/1 4.7 1.7 78 None 65.3 0 - - 8.6 0.11 0 79 Glycerine 60.1 21.6 3/1 2.8/1 8.5 0.11 0.95 80 Carbowax 400 56.4 3/1 8.1 0.21 0.73 81 Lactose 56.4 3/1 8.8, 0.04 0.67 8.7 82 Glycerine 58.6 3/1 8.1 0.17 0.58 83 Sorbitol 56.7 3/1 8.8, 0.11 0.36 8.7 Protein Binding Exemple Co-Dried % % Approx. Actual Nat'1 PB # PB # No. Additive Al2O3 Additive Al2O3 Al2O3 pH Nat'1 pH pH 5.51 mg Protein mg Al2O3 84 Propylene 8.7, glycol 63.7 3/1 8.6 0.14 0.34 85 Citric Acid 57.7 3/1 3.4 0.17 0.08 86 Stearic Acid 63.6 3/1 7.8 0.20 0.05 87 Corn Starch 51.3 3/1 8.2 0 0 88 Gelatin 57.8 3/1 8.0 0.10 0 89 K Citrate 57.0 3/1 9.4 0.20 0.1 90 Arlacel 58.0 3/1 8.2 0 165** 91 Arlacel 55.9 3/1 0.17 165** Examples 92-100 Co-Dried Al2O3 and Glycerol - With and Without HCl Table XV Protein Binding pH of Example Al2O3/Glycerol % Al2O3 in mg Protein/ 4% Al2O3 No. HCl Ratio in Slurry Powder mg Al2O3 Suspension Resuspendability 92 No HCl 3/1 58.9 0.04 9.0 Poor 93 No HCl 3/0.5 61.4 0.09 8.5 Poor 94 No HCl 3/1 60.1 0.11 8.5 Poor 95 No HCl 3/1.5 58.6 0.15 8.5 Poor 96 No HCl 3/2 57.9 0.26 8.5 Poor 97 No HCl 3/1 62.48 0.4 8.5 Poor 98 HCl 3/1 62.48 1.7 4.7* Good 99 HCl 3/1 ¯¯ 1.6 * Good 100 HCl 3/1 58.13 1.78 6.2 Good

Claims: Claims: 1. A method for the preparation of adsorptive, protein-binding aluminium oxyhydroxide, which comprises mixing an aqueous suspension of a carbonate-free, highly hydrated, aluminium oxyhydroxide which is relatively inert towards weak alkalis and acids, with an additive which is soluble in water and is capable of providing coordinating moieties with aluminium, and drying the mixture to form solid particles. 2. A method according to claim 1, in which the additive is a polyhydric alcohol, sugar, amino acid, polysaccharide or polyfunctional nitrogen-containing compound. 3. A method according to claim 1 or 2, in which the additive is added in such amount that the weight ratio of additive to aluminium oxyhydroxide, calculated as aluminium oxide in the suspension before drying, is from 10:1 to 3:2. 4. A method according to any of claims 1 to 3, in which the mixture is dried such that the proportion of aluminium oxyhydroxide, calculated as aluminium oxide, in the product is from 55 to 65 0% by weight. 5. A method according to any of claims 1 to 4, which further comprises mixing water with the dried aluminium oxyhydroxide and acidifying the resulting mixture to a pH of from 4 to 6.5 to produce a resuspendable, adsorptive, protein-binding aluminium oxyhydroxide. 6. A method according to any of claims 1 to 4, in which, before drying and either before or after mixing the aluminium oxyhydroxide suspension with the additive, the suspension is acidified to a pH of from 4 to 6.5 to produce a re-suspendable, adsorptive, protein-binding aluminium oxyhydroxide. 7. A method according to claim 5 or 6, in which the pH is from 5 to 6. 8. An adsorptive, protein-binding aluminium oxyhydroxide when produced by the method claimed in any of claims 1 to 7. 9. A composition for topical application to the skin which comprises an adsorptive, protein-binding aluminium oxyhydroxide as claimed in claim 8.

Inventors: RUBINO, ANDREW M., SICILIANO, ARTHUR
Applicants: REHEIS, INC.
Application year: 1982
Main classification: C01F7
IPC codes: A61Q19, A61K33, C01F7, A61K8