US3130125A - Preparation of medicated benzyl dextran gradual release therapeutic products containing up to five percent benzyl alcohol - Google Patents
Preparation of medicated benzyl dextran gradual release therapeutic products containing up to five percent benzyl alcohol Download PDFInfo
- Publication number
- US3130125A US3130125A US223839A US22383962A US3130125A US 3130125 A US3130125 A US 3130125A US 223839 A US223839 A US 223839A US 22383962 A US22383962 A US 22383962A US 3130125 A US3130125 A US 3130125A
- Authority
- US
- United States
- Prior art keywords
- benzyl
- dextran
- medicament
- percent
- benzyl dextran
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 229920002307 Dextran Polymers 0.000 title claims description 66
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 title claims description 18
- 235000019445 benzyl alcohol Nutrition 0.000 title claims description 6
- 230000001225 therapeutic effect Effects 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title description 3
- 239000003814 drug Substances 0.000 claims description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 11
- 239000012530 fluid Substances 0.000 claims description 10
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical class [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 3
- 230000037406 food intake Effects 0.000 claims description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 2
- 229960002086 dextran Drugs 0.000 description 62
- -1 benzyl dextran Chemical compound 0.000 description 48
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 15
- 230000003111 delayed effect Effects 0.000 description 14
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 8
- 229940073608 benzyl chloride Drugs 0.000 description 8
- 239000008187 granular material Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- PYHRZPFZZDCOPH-UHFFFAOYSA-N amphetamine sulfate Chemical compound OS(O)(=O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-UHFFFAOYSA-N 0.000 description 5
- 229960000632 dexamfetamine Drugs 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 4
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 235000012970 cakes Nutrition 0.000 description 3
- 229960000846 camphor Drugs 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 2
- 229960003291 chlorphenamine Drugs 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- 229960003910 promethazine Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PYHRZPFZZDCOPH-QXGOIDDHSA-N (S)-amphetamine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C[C@H](N)CC1=CC=CC=C1.C[C@H](N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-QXGOIDDHSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 239000000026 Pentaerythritol tetranitrate Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229940124346 antiarthritic agent Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 235000021463 dry cake Nutrition 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960004815 meprobamate Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960004321 pentaerithrityl tetranitrate Drugs 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001003 psychopharmacologic effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Definitions
- This invention relates to delayed release medicaments, and more particularly to delayed release medicaments prepared with benzyl dextran.
- This is accomplished by administering the medicarnent in combination with benzyl dextran, and particularly benzyl dextran of the character described below.
- benzyl dextran and particularly benzyl dextran of the character described below.
- benzyl dextran-medicament composition Large dosages of the benzyl dextran-medicament composition are administered in extended periods and by regulating the amount of the medicament or the type of the benzyl dextran used, or both, the medicament Will be released in the body to give the particular desired concentration over a particular desired period of time.
- dextran is applied to a class of polymers of glucose having chain-like structures and usually of very high molecular weight, produced by fermentation.
- the structure of dextran varies somewhat depending upon its method of production.
- dextran having a ratio of repeating alpha-1,6 to alpha non-1,6 glycosidic links from 2:1 to 32:1 has been found to be particularly suitable.
- the dextran used to produce synthetic blood-volurne expanders falls within this range and has a ratio of repeating alpha-1,6 to alpha non-1,6 glycosidic links of 19:1.
- the molecular weight of the dextran used in making benzyl dextran for delayed release medicaments should fall preferably within the range of three million to sixty million, determined by light scattering, which is the average molecular weight range for most of the dextrans ob tained by normal fermentations.
- the rate of release of the medicament from the benzyl dextranmedicament composition is increased as the molecular weight is reduced. Where it is desired to speed up the rate of release this can be accomplished by hydrolysis of the native dextran controlled so as to give dextran of any particular molecular weight range.
- the degree of substitution of the benzyl in the benzyl dextran also has an important bearing on the rate of release of the medicament from the benzyl dextran-medicament compositions.
- the rate of release is decreased as the degree of substitution is raised and increased as the degree of substitution is decreased.
- a de ree of substitution ranging from 0.8 to 1.0 has been found to be most desirable, a D5. below 0.8 giving too rapid release for most practical purposes, and above 1.0 not giving fast enough release.
- benzyl dextran having a D5. of benzyl outside of this range is useful.
- a benzyl dextran designed to give gradual release of medicament in the body over a period of eight to sixteen hours, should have a molecular weight ranging from three million to sixty million, a ratio of repeating alpha-1,6 to alpha non-1,6 glycosidic links of 2:1 to 32:1, and preferably 1911, and in which 2632% of the replacable hydrogens on the hydroxyl groups have been replaced by benzyl groups (i.e., a BS. of 0.8l.0).
- the benzyl dextran used in the benzyl dextran-medicament composition can be produced in various ways but preferably by reacting a benzyl halide (Cl, Br, or I) with native dextran in the presence of a strong base (NaOH, KOH) in an aqueous system.
- Benzyl chloride is the preferred benzyl compound and sodium hydroxide the preferred base.
- benzyl dextran having a benzyl DB. of 0.8-1.0 these reactants are used in the ratio of 4-8 moles of NaOH, 3-5 moles of benzyl chloride, and 100 moles of water, per mole of dextran.
- the dextran is first dissolved in the water, one-half of the sodium hydroxide added, as a 40% aqueous solution, and the resulting solution heate to C. with constant stirring. At this temperature one-third of the benzyl chloride is slowly added and the resulting mixture heated under reflux at -100 C. until the odor of benzyl chloride is no longer detected. During this period the partially substituted benzyl dextran separates as an insoluble soft gum. Water is added to the reaction before any liquid is removed. This operation reduces the concentration of by-products produced in this step of the operation.
- the second half of the sodium hydroxide in 40% aqueous solution is then added to the soft gum remaining in the reaction vessel and the mixture heated to 90 C.
- a second one-third portion of the benzyl chloride is next added and the mixture heated under reflux at 95100 C. until the odor of benzyl chloride is no longer detected.
- the remaining one-third of benzyl chloride is then added and refluxing continued until the odor of benzyl chloride is no longer detected.
- reaction mixture containing two moles of dextran will normally require refluxing for about thirty minutes, While one containing 10 moles of dextran will usually require refluxing for approximately one hour to complete the reaction.
- the benzyl dextran is then recovered and purified by any convenient method, as for example, by Washing with water followed by steam distillation.
- a preferred method consists of washing with water, solution in an isopropanolmiscible solvent (i.e. monoethyl ether of ethylene glycol), precipitation with isopropanol and-drying.
- the benzyl dextran obtained by the latter method is a substantially white free-flowing amorphous powder having a benzyl D.S. ranging from 0.8 to 1.0 and molecular weight ranging from three million to sixty million, and other impurities and ready for use in preparing delayed release benzyl dextran-medicament compositions.
- Benzyl dextran prepared and recovered as above described will usually contain not in excess of 1% impurities, and it is such a grade of benzyl dextran that is purposely used in order to reduce to a minimum the toxic ingredients of the benzyl dextran.
- Benzyl dextran obtained by the first mentioned and other processes frequently is mixed with substantial amounts of benzyl alcohol and other impurities such as benzyl ethers and hence may require further purification, depending upon the character and amount of impurities present. The requirement for and character of additional purification is to a large extent dependent upon the requirements of the United States Food and Drug Administration.
- the presence of as much as 20% of benzyl impurities does not significantly alter the rate of release of a medicament from a benzyl dextran-medicament composition in which the benzyl dextran having a benzyl D5. of 0.8l.0, although the maximum amount of these impurities allowed, from a toxicity standpoint, is considered to be about 1%.
- the softening temperature of the benzyl dextran is lowered and the presence of 5% or more of benzyl alcohol still further reduces the softening temperature with the result that the benzyl dextran granules flow into a plastic mass at 37 C., and thereby reduce the total surface area to such an extent that the medicament is not readily released from the benzyl dextranmedicament composition.
- the meohanism of the combination of the benzyl dextran and medicament is not definitely known. It is believed, however, that the medicament is held in suspension within the tightly coiled molecules of the benzyl dextran without substantial loss through decomposition, vaporization or sublimation during the processing and subsequent storage can be used with the benzyl dextran and administered as a delayed release medicament, the only limitation being that the medicament selected be such that it can be homogeneously suspended in the benzyl dextran and entrapped within its coiled molecules.
- Analgesics and antiarthritics such as acetophenetidin with aspirin and caifein and meperidine; antiacids and antidiarrhetics such as magnesium trisilicate; antibiotics such as penicillin, tetracycline, chloramphenicol, erythromyoin; anticholinergics such as atropine-phenolbarbital; antihistaminics such as chlorprophenpyridamine, promethazine; cardiotonics such as pentaerythritol tetranitrate; diuretics such as acetazoleamide; psychopharmacological drugs such aschlorpromaxine, dextroamphetamine, meprobamate; steroid hormones such as estrogens, hydrocortisone; vasoconstrictors such as phenylephrine; vitamin preparations such as B etc. represents examples of medicaments which can be used with the benzyl dextran in the formulating of delayed release medicaments.
- the amount of medicament combined with the benzyl dextran depends to a considerable degree on the desired dosage of the medicament and the influence of the concentration of the medicament on its rate of release from the combination. In the case of dextroamphetamine 5 to 15% of the medicament in the combination has been found satisfactory. Larger amounts may, of course, be used unless the character of the medicament is such that the amount released at any time might be hazardous to the patient. In such cases, however, the benzyl D.S. may be increased so as to slow up the rate of release.
- benzyl dextran in delayed release medicaments, namely, that the benzyl dextran can be tailor-made to fit the particular medicament and the particular type of treatment required for best results.
- a delayed release medicament can be prepared to fit any usual requirement.
- the medicament can be incorporated with the benzyl dextran in any suitable manner Which will assure homo: geneity and entrapment within the benzyl dextran molecules.
- One convenient method of doing this has been by preparing a fluid paste of the benzyl dextran in methanol using the minimum quantity of methanolone to three parts of methanol by weight to one part of benzyl dextran.
- the medicament is then incorporated with the fluidized benzyl dextran in the desired quantity and thoroughly blended by stirring and heating up to 60 C. If the medicament is solid it is generally necessary to incorporate it in solution or suspension form in order to assure thorough mixing.
- a preferred method is to introduce the medicament in aqueous or methanolic solution or solution in other volatile solvent from which the medicament is not readily precipitated by methanol.
- the fluid mass after thorough mixing and incorporation of the medicament, is dried in vacuo at 60 C., or other temperature at which the solvents are readily removed With? out undesirably affecting either the benzyl dextran or medicament. After drying the mixture is crushed, preferably to pass a #10 mesh screen and retained on a #20 mesh screen.
- the product can then be administered in the desired dosages in either capsules or in tablet form.
- the delayed release characteristics of the benzyl dextran with the medicament are then determined by extracting the medicament wtih simulated gastro-intestinal fluids under a standard set of conditions. The percent of the total medicament extracted during a series of specific periods of time is plotted on graft paper and the curve compared to specifications. These determinations are carried out as follows:
- One thousand milligrams of the benzyl dextran medicament in granular form, prepared as above described, are dispersed in ml. of simulated gastric fluid, pH 1.5 (U.S.P.) in a 250 ml. Erlenmeyer flask, which is then placed on a reciprocating shaker at 37 C. for fifty-five minutes.
- the residual medicament from this extraction is then dispersed in simulated intestinal fluid, pH 7.5 (U.S.P.) and extracted as described above for the periods of time indicated in the schedule below.
- the extracts are then assayed for the medicament by any suitable means.
- the table below shows results obtained as above described for a benzyl dextran-dextro-amphetamine hydrochloride composition containing 5l5% of the medicament, the benzyl dextran having a benzyl D8. of 0.8-1.0 and a molecular Weight ranging from three million to sixty million.
- Example 1 Small amounts of methanol were mixed into benzyl dextran having a benzyl D.S. of 0.8-1.0 (18.0 g., -40 mesh) until a soft plastic mass was obtained (approximately 20 ml. methanol required). Amphetamine sulphate (2.0 g.) was dissolved in water (2 ml.) and the solution was mixed into the plastic mass. The resulting mixture of benzyl dextran-anphetarm'ne sulphate was then dried at 60 C. under vacuum and the dried cake was crushed to -20 to +40 mesh granules for testing. The results are shown in Table 11 below.
- Example 11 This composition was prepared exactly as described in Example I except that half the amount of amphetamine sulphate was used and the latter was dissolved directly in the methanol suspension (no water used). The results are shown in Table II below.
- Example III This composition was prepared as described in Example I except that less methanol was used (5 ml. total) and a ratio of 8.5 parts of benzyl dextran to 1.5 parts of amphetamine sulphate was used. The results are shown in Table 11 below.
- Example IV Dextroamphetamine (0.53 g.) was added to methanol (10 ml.) and the solution was mixed into benzyl dextran of the character used in Example I (10.0 g., -40 mesh), adding it in small amounts. The resulting soft mass was dried at 60 C. under vacuum and the dried cake was crushed to -20 to +40 mesh granules. The results are shown in Table II below.
- Example V Small amounts of dioxalane were mixed into benzyl dextran of the type used in Example I (10.0 g., -40 mesh) until a total of 10 ml. was added. The past was heated to 90 C. and the amphetamine sulphate (1.3 g.) was added. The soft mass was dried at 60 C. under vacuum, an dthe dry cake was crushed to -10 to +20 mesh granules.
- Example VI In this example a delayed release medicament was prepared with chlorprophenpyridamine following the procedure described in Example I, using a benzyl dextran having a molecular weight ranging from three million to sixty million, and a benzyl D.S. ranging from 0.8 to 1.0. The final dried cake was crushed to -20 to +40 mesh granules. Administered in capsule form, it gave a satisfactory rate of release of the medicament over a period of 8 to 12 hours.
- Example VII In this example a delayed release medicament was prepared as described in Example VI using promethazine with similar results.
- Example VIII In this experiment a dextroamphetamine sulphatebenzyl dextran delayed release medicament prepared as described in Example I was used. To achieve a dosage of 10 mg. of d-amphetamine sulphate (a desirable dosage figure in the light of present knowledge) 66.7 mg. of the d-amphetamine benzyl dextran was found to be necessary. This amount of material was mixed with a suitable excipient for filling into hard gelatine capsules. A suitable formulation is as follows:
- the benzyl dextran-medicament particles can be incorporated in tablet form, according to the practice of the trade, using inert excipients.
- a method of producing a therapeutic composition for oral ingestion to provide a gradual release of medicament over an extended period of time in the intestinal tract comprising preparing a fluid paste of benzyl dextran and methanol and incorporating into the benzyl dextran paste a medicament and drying the resulting mixture, the improvement consisting of employing a benzyl dextran having a molecular weight between 3,000,000 and 60,- 000,000 and having a D3. of benzyl ranging between 0.8 and 1.0, and wherein the particle size of the dried product is on the order of -20 to +40 mesh and which product contains up to 5% benzyl alcohol.
Description
United States Patent PREPAQATIQN GF NEDECATED BENZYL DEX- TRAN GRADUAL RELEASE TI ERAPEUTEC PRGDUCTS CGNTAINHQG U1 Ti) FIVE PERCENT BENZYL ALCUHCL Herman Hecirel, Oxford, and Rohert T. Jefferson, West Carroliton, Ohio, assignors to The Central Pharmacal Company, Seymour, ind, a corporation of Indiana No Drawing. Filed Sept. 14, 1962, Ser. No. 223,839
2 Claims. (Cl. 167-82) This invention relates to delayed release medicaments, and more particularly to delayed release medicaments prepared with benzyl dextran.
For numerous purposes it is necessary to administer medicaments over extended periods of time in order to accomplish the desired result. In most cases it is necessary to administer the medicament at stated intervals in order to maintain a useful concentration of the medicament in the body without at the same time having present toxic amounts. It is well known that almost any medicament will produce harmful instead of beneficial results when excessive quantities are introduced into the blood stream of the body, and that too small quantities produce little, if any, beneficial effect, and may even prove harmful in establishing immunity against the medicament. it is accordingly necessary to exercise extreme care in the administration of all medicaments, and in particular those of a high degree of toxicity.
The necessity of maintaining a regulated level of a medicament in the blood stream has in the past made it essential to administer regulated amounts of the medicament at fairly frequent regulated intervals, the amounts and time intervals being dependent upon the particular medicament. In cases where the medicament has a high degree of toxicity or where the rate of excretion from the body is high it has been necessary to administer the drug at quite frequent intervals with resultant inconvenience and cost to the patient, as Well as to the physician or nurse.
It is an object of this invention to provide a practical economical means of administering medicaments in a manner so that the required levels of the medicament can be maintained in the body Without harm to the patient and without the necessity for frequent dosages of the medicament. This is accomplished by administering the medicarnent in combination with benzyl dextran, and particularly benzyl dextran of the character described below. By suitably regulating the composition as hereinafter described it is possible to regulate the rate of release of the medicament as desired so that much less frequent dosages are required in order to maintain a particular desired effective concentration of the medicament in the body of the patient being treated. Large dosages of the benzyl dextran-medicament composition are administered in extended periods and by regulating the amount of the medicament or the type of the benzyl dextran used, or both, the medicament Will be released in the body to give the particular desired concentration over a particular desired period of time.
The term dextran is applied to a class of polymers of glucose having chain-like structures and usually of very high molecular weight, produced by fermentation. The structure of dextran varies somewhat depending upon its method of production. For use in preparing benzyl dextran suitable for delayed release medicament compositions dextran having a ratio of repeating alpha-1,6 to alpha non-1,6 glycosidic links from 2:1 to 32:1 has been found to be particularly suitable. The dextran used to produce synthetic blood-volurne expanders falls within this range and has a ratio of repeating alpha-1,6 to alpha non-1,6 glycosidic links of 19:1.
The molecular weight of the dextran used in making benzyl dextran for delayed release medicaments should fall preferably within the range of three million to sixty million, determined by light scattering, which is the average molecular weight range for most of the dextrans ob tained by normal fermentations. In general, the rate of release of the medicament from the benzyl dextranmedicament composition is increased as the molecular weight is reduced. Where it is desired to speed up the rate of release this can be accomplished by hydrolysis of the native dextran controlled so as to give dextran of any particular molecular weight range.
The degree of substitution of the benzyl in the benzyl dextran also has an important bearing on the rate of release of the medicament from the benzyl dextran-medicament compositions. In general, the rate of release is decreased as the degree of substitution is raised and increased as the degree of substitution is decreased. For most uses, a de ree of substitution ranging from 0.8 to 1.0 has been found to be most desirable, a D5. below 0.8 giving too rapid release for most practical purposes, and above 1.0 not giving fast enough release. For some purposes, however, benzyl dextran having a D5. of benzyl outside of this range is useful.
A benzyl dextran, designed to give gradual release of medicament in the body over a period of eight to sixteen hours, should have a molecular weight ranging from three million to sixty million, a ratio of repeating alpha-1,6 to alpha non-1,6 glycosidic links of 2:1 to 32:1, and preferably 1911, and in which 2632% of the replacable hydrogens on the hydroxyl groups have been replaced by benzyl groups (i.e., a BS. of 0.8l.0).
The benzyl dextran used in the benzyl dextran-medicament composition can be produced in various ways but preferably by reacting a benzyl halide (Cl, Br, or I) with native dextran in the presence of a strong base (NaOH, KOH) in an aqueous system. Benzyl chloride is the preferred benzyl compound and sodium hydroxide the preferred base. To produce a benzyl dextran having a benzyl DB. of 0.8-1.0 these reactants are used in the ratio of 4-8 moles of NaOH, 3-5 moles of benzyl chloride, and 100 moles of water, per mole of dextran.
The dextran is first dissolved in the water, one-half of the sodium hydroxide added, as a 40% aqueous solution, and the resulting solution heate to C. with constant stirring. At this temperature one-third of the benzyl chloride is slowly added and the resulting mixture heated under reflux at -100 C. until the odor of benzyl chloride is no longer detected. During this period the partially substituted benzyl dextran separates as an insoluble soft gum. Water is added to the reaction before any liquid is removed. This operation reduces the concentration of by-products produced in this step of the operation.
The second half of the sodium hydroxide in 40% aqueous solution is then added to the soft gum remaining in the reaction vessel and the mixture heated to 90 C. A second one-third portion of the benzyl chloride is next added and the mixture heated under reflux at 95100 C. until the odor of benzyl chloride is no longer detected. The remaining one-third of benzyl chloride is then added and refluxing continued until the odor of benzyl chloride is no longer detected.
The refluxing periods will vary directly with the quantities of reaction products. A reaction mixture containing two moles of dextran will normally require refluxing for about thirty minutes, While one containing 10 moles of dextran will usually require refluxing for approximately one hour to complete the reaction.
The benzyl dextran is then recovered and purified by any convenient method, as for example, by Washing with water followed by steam distillation. A preferred method consists of washing with water, solution in an isopropanolmiscible solvent (i.e. monoethyl ether of ethylene glycol), precipitation with isopropanol and-drying. The benzyl dextran obtained by the latter method is a substantially white free-flowing amorphous powder having a benzyl D.S. ranging from 0.8 to 1.0 and molecular weight ranging from three million to sixty million, and other impurities and ready for use in preparing delayed release benzyl dextran-medicament compositions. Benzyl dextran prepared and recovered as above described will usually contain not in excess of 1% impurities, and it is such a grade of benzyl dextran that is purposely used in order to reduce to a minimum the toxic ingredients of the benzyl dextran. Benzyl dextran obtained by the first mentioned and other processes frequently is mixed with substantial amounts of benzyl alcohol and other impurities such as benzyl ethers and hence may require further purification, depending upon the character and amount of impurities present. The requirement for and character of additional purification is to a large extent dependent upon the requirements of the United States Food and Drug Administration. For example, the presence of as much as 20% of benzyl impurities (benzyl alcohol and benzyl ether) does not significantly alter the rate of release of a medicament from a benzyl dextran-medicament composition in which the benzyl dextran having a benzyl D5. of 0.8l.0, although the maximum amount of these impurities allowed, from a toxicity standpoint, is considered to be about 1%. When, however, the benzyl D3. is increased above 1.0 the softening temperature of the benzyl dextran is lowered and the presence of 5% or more of benzyl alcohol still further reduces the softening temperature with the result that the benzyl dextran granules flow into a plastic mass at 37 C., and thereby reduce the total surface area to such an extent that the medicament is not readily released from the benzyl dextranmedicament composition.
The meohanism of the combination of the benzyl dextran and medicament is not definitely known. It is believed, however, that the medicament is held in suspension within the tightly coiled molecules of the benzyl dextran without substantial loss through decomposition, vaporization or sublimation during the processing and subsequent storage can be used with the benzyl dextran and administered as a delayed release medicament, the only limitation being that the medicament selected be such that it can be homogeneously suspended in the benzyl dextran and entrapped within its coiled molecules. Analgesics and antiarthritics such as acetophenetidin with aspirin and caifein and meperidine; antiacids and antidiarrhetics such as magnesium trisilicate; antibiotics such as penicillin, tetracycline, chloramphenicol, erythromyoin; anticholinergics such as atropine-phenolbarbital; antihistaminics such as chlorprophenpyridamine, promethazine; cardiotonics such as pentaerythritol tetranitrate; diuretics such as acetazoleamide; psychopharmacological drugs such aschlorpromaxine, dextroamphetamine, meprobamate; steroid hormones such as estrogens, hydrocortisone; vasoconstrictors such as phenylephrine; vitamin preparations such as B etc. represents examples of medicaments which can be used with the benzyl dextran in the formulating of delayed release medicaments.
' The amount of medicament combined with the benzyl dextran depends to a considerable degree on the desired dosage of the medicament and the influence of the concentration of the medicament on its rate of release from the combination. In the case of dextroamphetamine 5 to 15% of the medicament in the combination has been found satisfactory. Larger amounts may, of course, be used unless the character of the medicament is such that the amount released at any time might be hazardous to the patient. In such cases, however, the benzyl D.S. may be increased so as to slow up the rate of release. This illustrates one of the principal advantages of the use of benzyl dextran in delayed release medicaments, namely, that the benzyl dextran can be tailor-made to fit the particular medicament and the particular type of treatment required for best results. In other words, by selecting the particular medicament, the concentrations thereof used, and the particular benzyl D.S. a delayed release medicament can be prepared to fit any usual requirement.
The medicament can be incorporated with the benzyl dextran in any suitable manner Which will assure homo: geneity and entrapment within the benzyl dextran molecules. One convenient method of doing this has been by preparing a fluid paste of the benzyl dextran in methanol using the minimum quantity of methanolone to three parts of methanol by weight to one part of benzyl dextran. The medicament is then incorporated with the fluidized benzyl dextran in the desired quantity and thoroughly blended by stirring and heating up to 60 C. If the medicament is solid it is generally necessary to incorporate it in solution or suspension form in order to assure thorough mixing. A preferred method is to introduce the medicament in aqueous or methanolic solution or solution in other volatile solvent from which the medicament is not readily precipitated by methanol. The fluid mass, after thorough mixing and incorporation of the medicament, is dried in vacuo at 60 C., or other temperature at which the solvents are readily removed With? out undesirably affecting either the benzyl dextran or medicament. After drying the mixture is crushed, preferably to pass a #10 mesh screen and retained on a #20 mesh screen. The product can then be administered in the desired dosages in either capsules or in tablet form.
The delayed release characteristics of the benzyl dextran with the medicament are then determined by extracting the medicament wtih simulated gastro-intestinal fluids under a standard set of conditions. The percent of the total medicament extracted during a series of specific periods of time is plotted on graft paper and the curve compared to specifications. These determinations are carried out as follows:
One thousand milligrams of the benzyl dextran medicament in granular form, prepared as above described, are dispersed in ml. of simulated gastric fluid, pH 1.5 (U.S.P.) in a 250 ml. Erlenmeyer flask, which is then placed on a reciprocating shaker at 37 C. for fifty-five minutes. The residual medicament from this extraction is then dispersed in simulated intestinal fluid, pH 7.5 (U.S.P.) and extracted as described above for the periods of time indicated in the schedule below. The extracts are then assayed for the medicament by any suitable means. The table below shows results obtained as above described for a benzyl dextran-dextro-amphetamine hydrochloride composition containing 5l5% of the medicament, the benzyl dextran having a benzyl D8. of 0.8-1.0 and a molecular Weight ranging from three million to sixty million.
TABLE Total Extraction Time Extraction Extraction Fluid pH Period The following examples illustrate the preparation of additional delayed release compositions.
Example 1 Small amounts of methanol were mixed into benzyl dextran having a benzyl D.S. of 0.8-1.0 (18.0 g., -40 mesh) until a soft plastic mass was obtained (approximately 20 ml. methanol required). Amphetamine sulphate (2.0 g.) was dissolved in water (2 ml.) and the solution was mixed into the plastic mass. The resulting mixture of benzyl dextran-anphetarm'ne sulphate was then dried at 60 C. under vacuum and the dried cake was crushed to -20 to +40 mesh granules for testing. The results are shown in Table 11 below.
Example 11 This composition was prepared exactly as described in Example I except that half the amount of amphetamine sulphate was used and the latter was dissolved directly in the methanol suspension (no water used). The results are shown in Table II below.
xample III This composition was prepared as described in Example I except that less methanol was used (5 ml. total) and a ratio of 8.5 parts of benzyl dextran to 1.5 parts of amphetamine sulphate was used. The results are shown in Table 11 below.
Example IV Dextroamphetamine (0.53 g.) was added to methanol (10 ml.) and the solution was mixed into benzyl dextran of the character used in Example I (10.0 g., -40 mesh), adding it in small amounts. The resulting soft mass was dried at 60 C. under vacuum and the dried cake was crushed to -20 to +40 mesh granules. The results are shown in Table II below.
Example V Small amounts of dioxalane were mixed into benzyl dextran of the type used in Example I (10.0 g., -40 mesh) until a total of 10 ml. was added. The past was heated to 90 C. and the amphetamine sulphate (1.3 g.) was added. The soft mass was dried at 60 C. under vacuum, an dthe dry cake was crushed to -10 to +20 mesh granules.
The extraction data obtained from Examples I-V are given in Table II below.
TABLE II Amphetamine Amphet. Extr.
Extract Simu Sim. Intest. Size of Amphetlated Gastric Fluid Percent Example Granules, amine Fluid Percent Mesh Percent 1 Hr. 1.5 Hrs. 1 Hr. 2 Hrs.
Example VI In this example a delayed release medicament was prepared with chlorprophenpyridamine following the procedure described in Example I, using a benzyl dextran having a molecular weight ranging from three million to sixty million, and a benzyl D.S. ranging from 0.8 to 1.0. The final dried cake was crushed to -20 to +40 mesh granules. Administered in capsule form, it gave a satisfactory rate of release of the medicament over a period of 8 to 12 hours.
Example VII In this example a delayed release medicament was prepared as described in Example VI using promethazine with similar results.
Example VIII In this experiment a dextroamphetamine sulphatebenzyl dextran delayed release medicament prepared as described in Example I was used. To achieve a dosage of 10 mg. of d-amphetamine sulphate (a desirable dosage figure in the light of present knowledge) 66.7 mg. of the d-amphetamine benzyl dextran was found to be necessary. This amount of material was mixed with a suitable excipient for filling into hard gelatine capsules. A suitable formulation is as follows:
d-Amphetamine-benzyl dextran 0.0667
Starch #10 granules 0.1653
Magnesium stearate 00080 Total fill 0.2400
TABLE [Amphetamine sulphate content of urine (mgs.)]
Patient A Patient B Time, Hours Total recovered, 9,140 mg. Percent recovered, 94.
Total recovered, 7.83 mg. Percent recovered, 78.
If preferred, the benzyl dextran-medicament particles can be incorporated in tablet form, according to the practice of the trade, using inert excipients.
Now having described the invention, what is claimed is:
1. In a method of producing a therapeutic composition for oral ingestion to provide a gradual release of medicament over an extended period of time in the intestinal tract and comprising preparing a fluid paste of benzyl dextran and methanol and incorporating into the benzyl dextran paste a medicament and drying the resulting mixture, the improvement consisting of employing a benzyl dextran having a molecular weight between 3,000,000 and 60,- 000,000 and having a D3. of benzyl ranging between 0.8 and 1.0, and wherein the particle size of the dried product is on the order of -20 to +40 mesh and which product contains up to 5% benzyl alcohol.
2. A pharmaceutical product produced in accordance with the process of claim 1.
References Cited in the file of this patent UNITED STATES PATENTS 2,989,518 Novak June 20, 1961 3,063,905 Novak Nov. 13, 1962 3,063,906 Heckel et al Nov. 13, 1962
Claims (1)
1. IN A METHOD OF PRODUCING A THERAPEUTIC COMPOSITION FOR ORAL INGESTION RO PROVIDE A GRADUAL RELEASE OF MEDICAMENT OVER AN EXTENDED PERIOD OF TIME IN THE INTESTINAL TRACT AND COMPRISING PREPARING A FLUID PAST OF BANZYL DEXTRAN AND METHANOL AND INCORPORATING INTO THE BENZYL DEXTRAN PAST A MEDICAMENT AND DRYING THE RESULTING MIXTURE, THE IMPROVEMENT CONSISTING OF EMPLOYING A BENZYL DEXTRAN HAVING A MOLECULAR WEIGHT BETWEEN 3,000,000 AND 60,000,000 AND HAVING A D.S. OF BENZYL RANGING BETWEEN 0.8 AND 1.0 AND WHEREIN THE PARTICLE SIZE OF THE DRIED PRODUCT IS ON THE ORDER OF -20 TO +40 MESH AND WHICH PRODUCT CONTAINS UP TO 5% BENZYL ALCOHOL.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US2989518A (en) * | 1957-05-13 | 1961-06-20 | Ohio Commw Eng Co | Carboxymethyl benzyl dextran |
US3063906A (en) * | 1960-09-13 | 1962-11-13 | Central Pharmacal Company | Benzyl dextran-amphetamine and method of making same |
US3063905A (en) * | 1959-08-21 | 1962-11-13 | Central Pharmacal Company | Carboxy methyl benzyl dextran dextro-amphetamine |
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1962
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US2989518A (en) * | 1957-05-13 | 1961-06-20 | Ohio Commw Eng Co | Carboxymethyl benzyl dextran |
US3063905A (en) * | 1959-08-21 | 1962-11-13 | Central Pharmacal Company | Carboxy methyl benzyl dextran dextro-amphetamine |
US3063906A (en) * | 1960-09-13 | 1962-11-13 | Central Pharmacal Company | Benzyl dextran-amphetamine and method of making same |
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