IL27183A - Parenteral composition comprising freeze dried mannitol - Google Patents

Description

C O H E N Z E D E K & S P I S B A C H E GD. PAT E T A TT O R N EYS 24, LEVONTIN STR., P. O. B. 1169 T E L - A V I V P A T E N T S & D E S I G N S O R D I N A N C E 16111/66 SPECIFICATION PARENTERAL ^FREEZE DRIED MANN I TOU 1 COMPOS I T (ON Co ~>P- lSf*6 uam V¾B»3B aa » iP3i9 mztch nwppna ranna τ*ρ3η THE UPJOHN COMPANY, a corporation organized and existing under the laws of the State of Delaware, o 301, Henrietta Street, Kalamazoo, State of Michigan, U.S.A., DO HEREBY DECLARE ihe nature of this invention and in what manner the same is to be performed to be particularly described and ascertained in and by the following statement: This invention relates to freeze- dried parenteral products and the method for preparation there f. More particularly, this invention relates to parenteral compositions comprising mannitol as the freeze-dried cake both alone and in combination with a parenteral ly administrate medicinal agent.

Freeze- dry i ng has been used to protect medicinal compositions and other materials, such as food products, against thermal decomposition or oxidation and to protect the potency of such compositions or other materials. Freeze- d ry i ng Is used in particular to remove water or other solvents from such products as vitamins and antibiotics, to give dried products having prolonged stabi lity. Freeze-dryi ng is usually carried out by freezing a solution of the material to be dried and removing the water or solvent by sub 1 imat i on whi le the material to be dried remains in the sol id state. The removal of the water or solvent leaves a lyophi lic porous residue, hereinafter cal led the cake, : which usually readily redissolves in the water or other solvent to be used for administering the product to a patient. Freeze-drying has the advantage, compared with drying by ordinary disti llation, in that the low temperature reduces or prevents decomposition or the loss of volatile substances, the product is highly porous and thus general 1 y more readily soluble in water or solvents than the ordinarily dried product and coagulation is minimized.

Prior to the present invention, however, mannitol was not used fin the formulation of freeze-dried products, and such products as were known, not conta i n i ng mann i tol presented certain disadvantages. Such disadvantages were noted in the dried cake itself and in the freeze- dry i ng process. The cakes were subject to shrinkage in size (from the original volume of the frozen solution), discoloration, hygroscopi ci ty, physical instabi lity and fai lure to yield a clear solution on recons t i tut i on . In the drying process, there occurred melting-back and bubbling, loss of material being entrained by the rapidly moving vapor stream and critical l imits in the control of vacuum and temperature.

By means of the step of i ncorporat i ng mann i to 1 in the vehicle prior to freezing the di sadvantages previ ousl y observed in the processing and cake are not encountered.

An additional advantage in reeze-dryi ng a solution con-sisting essentially of mannitol is the provision of a cake which can serve as a placebo or control for use in clinical investigations. The quality of not shrinking when dried pro-vjdes a cake which to outward appearance is similar to the cake of the medicament containing counterpart thereby assuring a "blind" study.

"In preparing the compositions, mannitol is dissolved in pyrogen free water for injection. The concentration of mannitol in solution can be from about 1 to about 151* w/w. The solution is then steri lized, fi lled into a suitable container, frozen arid dried under vacuum. The volume of the solution fi l led into the container prior to freezing and drying wi l l ! determine the volume of the dried cake.

In the freeze-dried cake consisting essentially of mannitol additional adjuvants can be added, for example local anesthetic, preservative, coloring agent (when preparing placebos to serve as controls), and the like known in the parenteral art. In general, such additives constitute a negligible amount, about 1$ of w/w of the cake.

In preparing medicament containing compositions, the medi-cament is dissolved in the aqueous vehicle, either before or after the mannitol is added. In the dry cake mannitol com -A and adjuvants from about 'l4> to about 95$ w/w.

This invention is applicable to a wide variety of medicinal materials, such as antibiotics, enzymes, sedatives, analgesics, hypnotics, antispasmodics, anesthetics, steroids, especially water-soluble cortical hormone derivatives, and combinations of these with each othe and other medicinals.. The process is applicable whenever it is •desired to provide compositions of medicinal materials in the freeze-dried state.

The following examples are i llustrat i ve of the process of this invention but are not to be construed as limiting.

Example 1 1, 000 vials are prepared from the following types and amounts of ingredients: Mann i to! NF 50 grams Water for Injection q.s. l800 c.c.

The mannitol is dissolved in sufficient water to make 1, 800 c.c. The solution is passed through a clarifying and sterilizing filter. 1. 8 c.c. of solution is filled i nto each of 1, 000 sterile vials, the solution frozen, and the water re-moved by drying. The vials are then capped.

Example 2 130 vials are prepared from the following types and amounts of ingredients: Propylthiouracil 26 grams Sodium Hydroxide . 8 grams Mannitol 6. 5 grams solution sodium hydroxide q.s.

Water for injection q.s. 520 ml.

The sodium hydroxide is dissolved in 75 ml. of water.

The propylthiouracil is stirred into the solution and then the sodium hydroxide solution and sufficient water added to make 520 ml. of solution. The solution is the^ filtered through a clarifying and steri lizing filter, 4 ml. is filled into each of 130, 10 c.c. vials, the solution frozen, and the water re-moved by drying. The vials are then capped.

Example 3 575 vials are prepared from the following types and amounts of ingredients: Sodium Biphosphate Anhydrous 1.09 grams Sodium Phosphate Exsiccated NF 11.9 grams anni tol NF 51 grams IO52 Sodium Hydroxide Solution q.s.

Water for Injection q.s. 1150 ml.

The sodium biphosphate, sodium phosphate and manni tol are dissolved in 900 ml. of water. The pH is adjusted to pH 7.5-7.7 with 10$ sodium hydroxide solution if required.

Additional water is added to make II50 ml. of solution, 2 ml. of solution is filled into each of 575 vials, the solution is frozen and the water removed by drying. The vials are then capped.

Example 50 vials are prepared from the following types and amounts of ingredients: Neomycin Sulfate 38.5 grams Polymyxin B Sulfate (7500 u./mg.) I6.8 grams Manni tol 25.1 grams Water for Injection q.s. 660 ml.

The neomycin, polymyxin, and manni tol are triturated togethe and added to 620 ml. of water. The solution is stirred unti l all ingredients are dissolved and the sufficient water added to make 660 ml. of solution. The solution is passed through a clarifying and sterilizing filter. 1.2 ml of solution is fil led into each of 550 2 c.c. vials, the solution frozen, and the water removed by drying. The vial are then capped.

Claims (1)

1. HAVING NOW particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is : -1 - A ,pa ren tera 11 y acceptab 1 e compos i t i on compr i sing a steri le, pyrogen free, f reeze-dr i ed cake of mannitol . The composition of claim 1 wherein the freeze-dried cake ins a parenteral ly acceptable medicinal agent. The composi tion of claim 2 wherein mannitol comprises in excess of $ w/w of the freeze-dried cake. The composi tion of claim 2 wherein manni tol comprises about 5$ to about 99$ w/w of the freeze-dried cake. In a method of drying a parenteral ly admi n i s t rab 1 e medicinal product, in which said product is incorporated in an aqueous parenteral ly acceptable vehicle, said vehicle is frozen and ice is di rectly sublimed in vacuo, the step of incorporating mannitol in said vehicle prior to freezing said vehicle. The method of claim 5 wherein from about 1$ to about 15 of mannitol is incorporated and the i is by weight of mannitol to volume of vehicle. DATED THIS 27th day of December, 1966. COHEN ΖΈΏ Κ & S PIS BACH P.O.BOX 1169, TEL-AVIT Attorneys for Applicants