# US 4,578,270 A · Process for the preparation of lyophilized, adsorbed polyvalent vaccines

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- Number: US 4,578,270 A
- Document ID: US4578270A
- Status: Granted
- Kind: A
- Application number: 06/582,432
- Filed: 1984-02-22
- Granted: 1986-03-25
- Earliest claimed: 1983-02-22
- Assignees: Human Oltoanyagtermelo es Kutato Intezet
- Inventors: Zoltan Csizer; Karoly Sikos; Laszlo Bacskai; Istvan Joo; Eleonora Niedermayer; Lajos Rethy; Jozsef Zsidai
- Web page: https://patentgrep.com/patent/US4578270A

## CPC

- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 39/0016: {Combination vaccines based on diphtheria-tetanus-pertussis}
- A61K 39/0275: {Salmonella}
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K 2039/55505: {Inorganic adjuvants}
- A61K 2039/70: {Multivalent vaccine}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The invention relates to the preparation of lyophilized, absorbed polyvalent vaccines. According to the invention tetanus, diphtheria, pertussis and optionally typhus antigens concentrated to 5 to 15 doses/3 ml are adsorbed at a pH value of 3 to 6 to an insoluble carrier concentrated in the same way as the antigens, then the pH of the mixture is adjusted to a value of 5 to 6 and lyophilized together with a protective material commonly used in lyophilizing processes. Before administration the lyophilized vaccine is diluted to the concentration required by a physiological saline buffered to a pH value of 6.8 to 7 by a phosphate solution.

## Claims

### Claim 1

A process for the preparation of lyophilized, adsorbed, polyvalent vaccine against tetanus, diphtheria and pertussis, which comprises the steps of:
(a) concentrating tetanus, diphtheria, and pertussis antigens to a value of 5 to 15 doses of vaccine per 3 ml;
(b) concentrating an insoluble adsorbent carrier selected from the group consisting of aluminum hydroxide gel and aluminum phosphate so that 1.75 to 3.5 mg of adsorbent carrier are employed per dose of vaccine;
(c) adsorbing the tetanus, diphtheria, and pertussis antigens concentrated in step (a), separately or together, on the insoluble adsorbent carrier concentrated in step (b), at a pH of 3 to 6, which is not lower than the value of the isoelectric point of any of the antigens and which does not exceed a pH value at which more than 15% of the antigens adsorbed at the pH value of the isoelectric point are eluated;
(d) adjusting the pH value to 5 to 6: and
(e) lyophilizing the mixture in the presence of a protective material selected from the group consisting of proteins, polypeptides and polysaccharides.

### Claim 2 (depends on 1)

The process defined in claim 1 wherein in step (c) separate solutions of the tetanus, diphtheria, and pertussis antigens are adsorbed on the adsorbent carrier.

### Claim 3 (depends on 2)

The process defined in claim 2 wherein the tetanus antigen is adsorbed at a pH of about 3.

### Claim 4 (depends on 2)

The process defined in claim 2 wherein the diphtheria antigen is adsorbed at a pH of about 4.

### Claim 5 (depends on 2)

The process defined in claim 2 wherein the pertussis antigen is adsorbed at a pH of about 5.8 to 6.

### Claim 6 (depends on 1)

The process defined in claim 1 wherein the polyvalent vaccine further comprises typhus antigens.

### Claim 7 (depends on 1)

The process defined in claim 1 which comprises using 20 to 35 Lf/dose of diphtheria toxoid, 10 to 20 IOU/dose of Bordatella pertussis cell suspension and 5 to 15 BU/dose of tetanus toxoid.

### Claim 8 (depends on 6)

The process defined in claim 6 which comprises using a Salmonella typhi cell suspension containing 10.sup.8 to 10.sup.9 cells/dose.

### Claim 9 (depends on 1)

A long-term storage vaccine made by the process defined in claim 1.

### Claim 10 (depends on 9)

A vaccination method which comprises inoculating a subject with the vaccine defined in claim 9.