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Dry Formulation for Transcutaneous Immunization

a technology of transcutaneous immunization and formulation, which is applied in the direction of antibacterial agents, antibody medical ingredients, immunological disorders, etc., can solve the problems of intestinal fluid secretion, undesirable reaction, similar redness and swelling, etc., to promote skin hydration, enhance immune response, and increase local concentration

Inactive Publication Date: 2009-03-26
UNITED STATES OF AMERICA THE AS REPRESENTED BY THE SEC OF THE ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]The stratum corneum, a layer of dead skin cells and lipids, has traditionally been viewed as a barrier to the hostile world, excluding organisms and noxious substances from the viable cells below the stratum corneum (Bos, 1997a). The secondary protection provided by skin antigen presenting cells such as Langerhans cells has only recently been recognized (Celluzzi and Falo, 1997). Moreover, the ability to immunize through the skin using the crucial concept of a skin-active adjuvant has only been recently described (Glenn et al., 1998a). Scientific recognition of this important advance in vaccination was prompt. “It's a very surprising result, and it's lovely,” said vaccine expert Barry Bloom of the Howard Hughes Medical Institute and the Albert Einstein College of Medicine in New York, the strategy sounds “very easy, very safe, and certainly inexpensive” (CNN News, Feb. 26, 1998).
[0036]In contrast to the expectations of the art, our delivery system provided by transcutaneous immunization is capable of achieving efficient delivery of at least antigen and / or polynucleotide encoding antigen through the skin to the immune system.

Problems solved by technology

These homologous proteins cause intestinal fluid secretion and massive diarrhea (Spangler, 1992), and are viewed as dangerous toxins.
Thus, one could have reasonably expected that CT would be extremely reactogenic when placed on the skin or inserted through the stratum corneum, and would cause similar redness and swelling.
Craig (1965) cautioned, “The absence of skin lesions in clinical cholera certainly does not preclude the possibility that the noxa responsible for gut damage could also have a deleterious effect upon the skin provided it is applied to skin in sufficient concentration.” The extreme reactogenicity of cholera toxin in the skin was used as a test for its toxicity and such prior art evidenced an expectation that cholera toxin would be reactogenic if applied to the skin, producing an undesirable reaction.
This lack of reactogenicity when cholera toxin was placed on the skin for transcutaneous immunization was surprising and contradicted conclusions one would have drawn from the prior art.
A liquid formulation of CT placed on the skin acted as a non-toxic, non-reactogenic adjuvant, in contrast to the expectations of Craig, while injection of CT into the skin results in swelling and redness.
Our findings, however, unexpectedly showed that such formulations are devoid of reactogenicity.
Besides the physical restriction of limiting passage through the skin of low molecular weight, passage of polypeptides was believed to be limited by chemical restrictions.
(U.S. Pat. No. 5,679,647) stated that “it is believed that the bioavailability of peptides following transdermal or mucosal transmission is limited by the relatively high concentration of proteases in these tissues.
Yet unfortunately, reliable means of delivering peptides .

Method used

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  • Dry Formulation for Transcutaneous Immunization
  • Dry Formulation for Transcutaneous Immunization
  • Dry Formulation for Transcutaneous Immunization

Examples

Experimental program
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Effect test

example 1

[0187]BALB / c mice at 6 to 8 weeks of age were immunized transcutaneously as described above in groups of five mice. Mice were immunized using 100 μl of immunization solution, which was comprised of liposomes prepared as described above by mixing with saline. The pre-formed liposomes were then diluted in either saline (“Liposomes” only group) or with CT in saline to yield an immunizing solution containing liposomes at 10 mM to 150 mM phospholipid with 100 μg CT per 100 μl of immunizing solution. CT was mixed in saline to make an immunizing solution containing 100 μg CT per 100 μg of solution for the group receiving CT alone. Solutions were vortexed for 10 seconds prior to immunization.

[0188]The mice were immunized transcutaneously at 0 and 3 weeks. Antibody levels were determined as described above for “ELISA IgG(H+L)” on serum collected three weeks after the boosting immunization, and compared against pre-immune sera. As shown in Table 1, the level of anti-CT antibodies induced by C...

example 2

[0189]BALB / c mice at 6 to 8 weeks of age were immunized transcutaneously as described above in groups of five mice. Mice were immunized at 0 and 3 weeks using 100 μl of immunization solution prepared as follows: BSA was mixed in saline to make an immunizing solution containing 200 μg BSA per 100 μl of saline for the group receiving BSA alone; BSA and CT were mixed in saline to make an immunizing solution containing 200 μg BSA and 100 μg CT per 100 μl of saline for the group receiving BSA and CT. Where liposomes were used, the liposomes were prepared as described above, and were first mixed with saline to form liposomes. They were then diluted in BSA or BSA and CT in saline to yield an immunizing solution containing liposomes at 50 mM phospholipid with 200 μg BSA per 100 μl of immunizing solution, or 200 μg BSA+100 μg CT per 100 μl of immunizing solution. Solutions were vortexed for 10 seconds prior to immunization.

[0190]The antibodies were determined using “ELISA IgG(H+L)” as descri...

example 3

[0191]BALB / c mice at 6 to 8 weeks of age were immunized transcutaneously as described above in groups of five mice. Mice were immunized at 0 and 3 weeks using 100 μl of immunization solution prepared as follows: LT was mixed in saline to make an immunizing solution containing 100 μg of LT per 100 μl of saline for the group receiving LT alone. Where liposomes were used, they were prepared as described above and first mixed with saline to form the liposomes. The pre-formed liposomes were then diluted in LT in saline to yield an immunizing solution containing liposomes at 50 mM phospho-lipid with 100 μg of LT per 100 μl of immunizing solution. Solutions were vortexed for 10 seconds prior to immunization.

[0192]The anti-LT antibodies were determined using ELISA as described above three weeks after the second immunization. The results are shown in Table 3. LT was clearly immunogenic both with and without liposomes, and no significant difference between the groups could be detected. LT and...

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Abstract

A transcutaneous immunization system delivers antigen to immune cells through the skin, and induces an immune response in an animal or human. For example, skin-active adjuvant (e.g., an ADP-ribosylating exotoxin) can be used to induce an antigen-specific immune response (e.g., humoral and / or cellular effectors) after transcutaneous application of a dry formulation containing antigen and adjuvant to skin of the animal or human. The dry formulation may be a powder or a unit-dose patch. Use of adjuvant is not required if the antigen is sufficiently antigenic. Transcutaneous immunization may be induced with or without penetration enhancement

Description

DESCRIPTION OF RELATED APPLICATIONS[0001]This application is a continuation in-part of U.S. application Ser. No. 08 / 896,085 (filed Jul. 17, 1997 and pending); U.S. application Ser. No. 09 / 157,395 (filed Sep. 21, 1998 and pending) which is a divisional of U.S. application Ser. No. 08 / 749,164 (filed Nov. 14, 1996, now U.S. Pat. No. 5,910,306); U.S. application Ser. No. 09 / 257,188 (filed Feb. 25, 1999 and pending); U.S. application Ser. No. 09 / 309,881 (filed May 11, 1999 and pending); and U.S. application Ser. No. 09 / 311,720 (filed May 14, 1999 and pending) which is a continuation in-part of PCT / US97 / 21324 (filed Nov. 14, 1997 designating the U.S., now abandoned).[0002]This application also claims priority benefit from provisional U.S. Appln. No. 60 / 090,169 (filed Jun. 22, 1998) and U.S. Appln. No. 60 / 128,370 (filed Apr. 8, 1999).[0003]All patent applications cited herein, as well as patents issued therefrom, are incorporated by reference in their entirety.BACKGROUND OF THE INVENTION[0...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00
CPCA61K39/0258C12N2760/20134A61K39/099A61K39/102A61K39/104A61K39/107A61K39/116A61K2039/54A61K2039/55555A61K39/008A61K39/015A61K39/05A61K39/12A61K2039/5252A61K2039/53A61K2039/545A61K2039/55505A61K2039/55522A61K2039/55533A61K2039/55544A61K2039/55561A61K2039/70C12N2740/16234C12N2760/16134C12N2760/16234A61K39/08A61P31/04A61P31/10A61P31/16A61P33/00A61P37/04Y02A50/30
Inventor GLENN GREGORY M.ALVING CARL R.SCHARTON-KERSTEN TANYA
Owner UNITED STATES OF AMERICA THE AS REPRESENTED BY THE SEC OF THE ARMY
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