Connect public, paid and private patent data with Google Patents Public Datasets

Vaccines against intracellular pathogens using antigens encapsulated within biodegradable-biocompatible microspheres

Download PDF

Info

Publication number
USRE40786E1
USRE40786E1 US09586747 US58674700A USRE40786E1 US RE40786 E1 USRE40786 E1 US RE40786E1 US 09586747 US09586747 US 09586747 US 58674700 A US58674700 A US 58674700A US RE40786 E1 USRE40786 E1 US RE40786E1
Authority
US
Grant status
Grant
Patent type
Prior art keywords
hiv
microspheres
native
plg
antigen
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 - Fee Related
Application number
US09586747
Inventor
Paul R. Burnett
John E. van Hamont
Robert H. Reid
Jean A. Setterstrom
Thomas C. Van Cott
Deborah L. Birx
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
US Secretary of Army
Original Assignee
US Secretary of Army
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Grant date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1641Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647Polyesters, e.g. poly(lactide-co-glycolide)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/24Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C07K14/245Escherichia (G)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Abstract

This invention relates to parenteral and mucosal vaccines against diseases caused by intercellular pathogens using antigens encapsulated within a biodegradable-biocompatible microspheres(matrix).

Description

II. CROSS REFERENCE

This application is a continuation-in-part of U.S. patent application Ser. No. 08/242,960, filed May 16, 1994, pending; which in turn is a continuation-in-part of U.S. patent application Ser. No. 07/867,301 filed Apr. 10, 1992, now U.S. Pat. No. 5,417,986 which in turn is a continuation-in-part of U.S. patent application Ser. No. 07/805,721 filed Nov. 21, 1991; now abandoned, which in turn is a continuation-in-part of U.S. patent application Ser. No. 07/690,485 filed Apr. 24, 1991, now abandoned; which in turn is a continuation-in-part of U.S. patent application Ser. No. 07/521,945 filed May 11, 1990, now abandoned. Additionally, this application is a continuation-in-part of U.S. patent application Ser. No. 08/446,149 filed May 22, 1995, pending; which in turn is a continuation of U.S. patent application Ser. No. 06,590,308 filed Mar. 16, 1984, now abandoned.

I. GOVERNMENT INTEREST

The invention descried herein may be manufactured, licensed and used by or for governmental purposes without the payment of any royalties to us thereon.

III. FIELD OF THE INVENTION

This invention relates to parenteral and mucosal vaccines against diseases cause by intracellular pathogens using antigens encapsulated within biodegradable-biocompatible microspheres(matrix).

IV. BACKGROUND OF THE INVENTION

Most infections by viruses and other intracellular pathogens are countered in the human host by a combination of humoral (antibody) and cellular (lymphocyte and phagocyte) immune effectors. Although the precise identity of immune effectors capable of protecting the host against some chronic intracellular pathogens (e.g. HIV-1) remains unknown, attempts to develop preventive and therapeutic vaccines still focus on the induction of appropriate humoral and cellular immune responses. Furthermore, since most human viral pathogens (including HIV-1) are transmitted across mucosal surfaces, it is important that vaccines induce such responses locally (at the mucosal surface) as well as systemically and that they are durable for long-term protection.

The issues of durability and mucosal immunogenicity have been previously addressed by encapsulating vaccine antigens in appropriately-sized biodegradable, biocompatible microspheres made of lactide/glycolide copolymer (the same materials used in resorbable sutures). It has been shown that such microspheres can be made to release their load in a controlled manner over a prolonged period of time and can facilitate the interaction of their contents with the local immune system when administrated mucosally.

In the case of HIV-1 infection, there is insufficient information at this time regrading the virus and its interactions with the human immune system to permit the rational design of a preventive vaccine. However, it has been noted that many candidate HIV vaccines tested to date fail to elicit antibodies capable of neutralizing wild-type HIV-1 or binding to native HIV-1 proteins, fail to induce a substantial population of effector cells capable of destroying HIV-1-infected cells, and fail to induce significant responses at mucosal surfaces. A possible approach to overcoming these problems (applicable to both HIV-1 and other chronic intracellular pathogens) is to identify a native protein, accessible to the immune system on the surface of both free virus and infected cells, and present it to the immune system (systemic and mucosal) encapsulated in microspheres to protect and augment its immunogenicity.

V. DESCRIPTION OF DRAWINGS

FIG. 1 indicates controlcytotoxic T lymphocyte induction in mice immunized with rgp 160; and

FIG. 2 indicates “Native”/denatured rgp 120 (IIIB) Binding Ratios.

V. DESCRIPTION OF THE INVENTION

This invention relates to a novel pharmaceutical composition, a microcapsule/sphere formulation, which comprises an antigen encapsulated within a biodegradable polymeric matrix, such as poly(DL-lactide co glycolide) (PLG), wherein the molecular weight of the PLG is about 4,000 to 100,000 daltons and wherein the relative ratio between the lactide and glycolide component of the PLG is within the range of 52:48 to 0:100, and its use, as a vaccine, in the effective induction of antiviral immune responses comprising both virus-specific cytotoxic T lymphocytes and antibodies reactive against native viral antigens. In the practice of this invention, applicants found that when a complex (oligomeric) native envelope protein of HIV-1 was encapsulated in PLG microspheres, it retained its native antigenicity and function upon its release in vitro. Furthermore, when used as a vaccine in animals, this product elicited HIV-specific cytotoxic T lymphocytes and antibodies reactive with native (oligomeric) HIV-1 envelope protein.

The following examples illustrate the invention:

EXAMPLE 1

Materials and Methods

Immunogens, Non-CD4-binding, baculo-expressed, recombinant gp 160IIIB (rgp 160) was obtained from MicroGeneSys (Meriden, Conn.). CD4-binding, oligomeric gp 160 CDC451 (o-gp 160) was obtained from Advanced BioScience Laboratories (Kensington, Md.).

Microencapsulation of immunogens: PLG microspheres ranging from 1 nanometer to 20 um in diameter and containing a 0.5 to 1.0% antigen core load were prepared by a solvent extractive method. 0.5 to 5.0% by weight antigen core load could also be used. The solvent extraction method involves dissolving the viral antigen and sucrose (1:4 ratio w:w) in 1 ml of deionized water. This solution is flash frozen and lyophilized. The resulting antigen-loaded sucrose particles are resuspended in acetonitrile and mixed into PLG copolymer dissolved in acetonitrile. This antigen-polymer mixture is then emulsifyed into heavy mineral oil, transferred into heptane and mixed for 30 min to extract the oil and acetonitrile from the nascent spheres. The spheres are harvested by centrifugation, washed three times in heptane and dried overnight under vacuum. Microsphere size was determined by both light and scanning electron microscopy. The antigen core load was determined by quantitative amino acid analysis of the microspheres following complete hydrolysis in 6N hydrochloric acid.

Analysis of immunogen spontaneously released from microspheres in vitro by binding to soluble CD4 and recognition by HIV-positive patient serum. PLG microspheres loaded with native (oligomeric) gp 160 were suspended in phosphate-buffered saline, pH 7.4 (PBS), incubated at 37 C. for 3 h, and then at 4 C overnight. The microspheres were then sedimented by centrifugation (2 min at 200×g), the supernatants harvested, and the released gp 160 assayed for binding to CD4 and recognition by HIV-positive patient serum by surface plasmon resonance (described below). A sample of the stock protein used for microencapsulation was assayed for comparison.

Immunization of animals. HIV-seronegative, 8-10 week old NZW rabbits were immunized intramuscularly with rgp 160- or o-gp 160-loaded PLG microspheres suspended in PBS or with alum-adjuvanted rgp 160 in PBS. Groups receiving rgp 160-loaded microspheres (n=2) were primed with 50 ug of immunogen on day 0 and boosted with 25 ug on day 42. Groups receiving o-gp 160-loaded microspheres (n=3) were primed with 70 ug of immunogen on day 0 and boosted with 35 ug on day 56. Groups receiving alum-adjuvanted rgp 160 (n=2) got 85 ug of immunogen on days 0, 7, and 28.

BALB/c mice were immunized subcutaneously with rgp 160-loaded PLG microspheres suspend in PBS or with alum-adjuvanted rgp 160 in PBS. The mice in all groups (n=4) received 10 ug of immunogen on days 0 and 21.

Determination of the ratio of antibody binding to “native”/denatured rgp 120IIIB measured by surface plasmon resonance (SPR). Real-time binding interactions between ligand (gp 120 covalently linked to a biosensor matrix) and ligate (Abs in solution) were measured using surface plasmon resonance (BIAcore, Pharmacia Biosensor, Piscataway, N.J.). “Native”rgp 120(IIIB) (Genentech, South San Francisco, Calif.) or reduced, carboxymethylated (denatured) rgp 120(IIIB) (Genentech) was covalently linked to the biosensor dextran matrix. Sera and mAbs were diluted in HBS running buffer (10 mM HEPES, 150 mM NaCl, 3.4 mM EDTA, 0.05% (BIAcore) surfactant P20, pH 7.4) and injected through the dextran matrices at a flow rate of 5 ul/min. The binding value of each serum or mAb was measured in resonance units (RU), and the “native”/denatured gp 120 ratios were determined by dividing the corresponding RU values and correcting for small differences in matrix concentration. Control included an HIV-positive patient serum and mAb 1c1.

Assessment of HIV-specific cell-mediated immunity in immunized mice by secondary CTL assay. The spleens of BALB/c mice immunized on days 0 and 21 were harvested and single cell suspensions prepared aseptically in complete RPMI medium on day 35. The cells were then pooled within experimental groups (n=4), underlay with ficoll, centrifuged 30 min at 450×g (RT), washed, and resuspended in complete RPMI medium. Following a 1 h stimulation with peptide p18 (1 uM) at 37° C., the cell suspensions were diluted with complete RPMI supplemented with 2ME (1:1000) and transferred to flasks for a 6 day incubation at 37° C. After 2 days, recombinant IL-2 (10 u/ml) was added to all flasks. On day 6, P815 target cells were pulsed with peptide p18 (1 uM) or with nothing (control) in PBS supplemented with 0.1% BSA. 3×10A6 target cells were labelled with 300 uCi of 51Cr, washed, and plated out with the effector cells at effector:traget (E:T) ratios of 45:1, 15:1, 5:1, and 1.7:1. After a 6 h incubation at 37° C., the supernatants were harvested and counted, and % specific lysis was calculated.

Results

Comparison of the native (oligomeric) gp 160 prior to microencapsulation and following spontaneous release from PLG microspheres showed the two to be essentially indistinguishable in terms of their binding to CD4 and recognition by HIV-positive patient serum. (Table 1). This retention of conformation-dependent binding shows that structure of the antigen is not appreciably altered by the microencapsulation process.

FIG. 1 shows the data from a cytotoxic T lymphocyte (CTL) assay performed on the speen cells of mice which had had been previously immunized with either HIV-1 envelope protein encapsulated in PLG microspheres (dark squares) or the same protein administered in a conventional way with alum adjuvant (dark diamonds). These data indicate that microencapsulation of HIV-1 envelope protein in PLG microspheres results in a vaccine that induces significantly greater anti-HIV CTL activity than does alum-adjuvanted vaccine. The open symbol groups represent controls run to assure that the activity being measured is virus-specific.

FIG. 2 shows the results of an assay designed to measure the relative binding of antibodies to native vs denatured viral protein. These data show that rabbits immunized with a non-native HIV-1 protein encapsulated in PLG (#5 and 6) develop antibodies which show greater binding to denatured (vs native) protein (indicated by a ratio<1). On the other hand, rabbits immunized with a native HIV-1 protein encapsulated in PLG microspheres (#10-12) develop antibodies which show greater binding to native viral protein (indicated by ratio>1). This retention of each proteins antigenicity constitutes an additional piece of evidence that the structure of antigens loaded in PLG microspheres are preserved.

EXAMPLE 2

Materials and Methods

This experiment was similar to that described in Example 1 except for the method of microencapsulation employed.

Microencapsulation of immunogens: PLG microspheres ranging from 1 to 15 um in diameter and containing a 0.5 to 1.0% antigen core load were prepared by a solvent evaporation method. The solvent evaporation method involves emulsifying the viral antigen dissolved in deionized water into poly(DL-lactide-co-glycolide) polymer dissolved in methylene chloride. This emulsion is mixed into 0.9% polyvinyl alcohol and stirred. After 10 min of stirring, 0.35 l of water is added and gentle mixing is continued for 1.5 h. The resulting spheres are harvested by centrifugation, washed three times in distilled water, and dried overnight under vacuum. Microsphere size was determined by both light and scanning electron microscopy. The antigen core load was determined by quantitative amino acid analysis of the microspheres following complete hydrolysis in 6N hydrochloric acid.

Results

Analysis of spontaneously released antigen showed it to retain its CD4 binding capacity. Its native antigenicity (recognition by the serum of an HIV-positive patient) was only slightly less than that of the antigen prior to encapsulation and following spontaneous release from microspheres produced by a solvent extraction method (Table 1).

The results of immunizing animals with either non-native (denatured) or native oligomeric gp 160 in PLG microspheres produced by a solvent evaporation method were essentially indistinguishable from those obtained using microspheres produced by a solvent extraction method (example 1). Microencapsulated antigen induced significantly greater CTL activity than antigen administered in a conventional alum-adjuvanted formulation. Furthermore, preservation of the structure of PLG-microencapsulated antigens is supported by the findings of preferential binding of antibodies elicited by microspheres loaded with denatured antigen to denatured gp 120 (FIGS. 2, 3, and 4) (FIG. 2, nos. 3 and 4) and the preferred binding of antibodies elicited by microspheres loaded with native (oligomeric) antigen to native gp 120 (FIGS. 2, 7-8) (FIG. 2, nos. 7 and 8).

TABLE 1
BIA (released o-gp160)
Capture o-gp160-451 (stock vs microsphere-released)
on tvc 391 fc3/fc4 sCD4 (4 mg/m)
1 ul/min flow rate foe o-gp160 ini.: 5 ul/min for all others
ligate RU HIV+/sCD4 (RU ratio)
gp120-MN 1:10 3286
HIV+ 1:100 54
NHS 1:100 3
HIV+ pool 1:100 47
o-gp160 (tvc281) 1772
HIV+ 3259 1.84
tvc281 1848
NHS −36
tvc281 1762
HIV+ pool 2597 1.47
tvc281-PLG-EV 3342
HIV+ 4594 1.37
tvc281 3222
NHS 7
tvc281 3210
HIV+ pool 3336 1.04
tvc281-PLG-EX 1855
HIV+ 3760 2.04
tvc281 1839
NHS 2
tvc281 1850
HIV+ pool 2745 1.48
gp120-MN 1:10 2914
HIV+ 1:100 14
NHS 1:100 −2
HIV+ pool 1:100 14
tvc281 1099
HIV+ 1083 0.99
tvc281 1022
HIV+ pool 1395 1.36
tvc281-PLG-EV 1595
HIV+ 1322 0.83
tvc281 1535
HIV+ pool 1781 1.16

In view of the above it will be seen that the objects of the invention are achieved. As various changes could be made in the above materials and methods without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not limiting.

Claims (14)

1. An immunostimulating composition comprising encapsulating encapsulated microspheres comprised of (a) a biodegradable-biocompatible poly(DL-lactide-co-glycolideas poly(DL-lactide-co-glycolide) as the bulk matrix produced by a solvent evaporation process wherein the molecular weight of the copolymer is between 4,000 to 100,000 daltons and (b) an immunogenic substance consisting of a conformationally native subunit of chronic intracellular pathogen which, in the course of natural infection with that pathogen, is exposed to the host immune system on the surface of free pathogen and/or pathogen-infected cells.
2. The immunostimulating composition described in claim 1 wherein the immunogenic substance is an antigen and the antigen is pre-encapsulated into a conformationally stabilizing hydrophilic matrix consisting of an appropriate mono, di- or tri-saccharide or other carbohydrate susbstance substance by lyophilization prior to its final encapsulation into the PLG microsphere by a solvent extraction process employing acetonitrile as the polymer solvent, mineral oil as the emulsion's external phase, and heptane as the extractant.
3. The immunostimulating compositions composition described in claims claim 1 or 2 wherein the immunogenic substance is a native (oligomeric)HIV-1 envelope antigen that is conformationally stabilized by the polymer matrix and serves to elicit in animals the production of HIV specific cytotoxic T lumphocytes lymphocytes and antibodies preferentially reactive against native HIV-1 envelope antigen.
4. The immunostimulating compositions composition described in claim 3 wherein the amount of said immunogenic substance within the microcapsule comprises between 0.5% to 5.0% of the weight of said composition.
5. The immunostimulating compositions describe composition described in claim 4 wherein the relative ratio between the amount of the lactide:glycolide components of said matrix is within the range of 52:48 to 0:100.
6. The immunostimulating compositions composition described in claim 5 wherein the molecular weight of said copolymer is between 4,000 to 50,000 daltons.
7. A vaccine consisting of a blend of the immunostimulating compositions described in claims 5 or 6 composition of claim 5.
8. The immunostimulating compositions composition described in claim 5, employed as a parentally parenterally administered vaccine wherein the diameter size range of said vaccine microspheres lies between 1 nanometer and 20 microns.
9. The immunostimulating compositions composition described in claim 5, employed as a mucosal vaccine wherein the size of more than 50% (by volume) of said vaccine microspheres is between 5 microns to 10 microns in diameter.
10. A composition in accordance with claim 1 wherein the microspheres further contain a pharmaceutically-acceptable adjuvant.
11. A vaccine consisting of a blend of the immunostimulating compositions described in claims 5 or composition of claim 6.
12. The immunostimulating compositions composition described in claim 6 employed as a parentally parenterally administered vaccine wherein the diameter size range of said vaccine microspheres lies between 1 nanometer and 20 microns.
13. The immunostimulating compositions composition described in claim 7 employed as a parentally parenterally administered vaccine wherein the diameter size range of said vaccine microspheres lies between nanogram nanometer and 20 microns.
14. The immunostimulating compositions composition described in claim 6 employed as a mucosal vaccine wherein the size of more than 50% (by volume) of said vaccine microspheres is between 5 microns to 10 microns in diameter.
US09586747 1984-03-16 2000-06-02 Vaccines against intracellular pathogens using antigens encapsulated within biodegradable-biocompatible microspheres Expired - Fee Related USRE40786E1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US59030884 true 1984-03-16 1984-03-16
US52194590 true 1990-05-11 1990-05-11
US69048591 true 1991-04-24 1991-04-24
US80572191 true 1991-11-21 1991-11-21
US07867301 US5417986A (en) 1984-03-16 1992-04-10 Vaccines against diseases caused by enteropathogenic organisms using antigens encapsulated within biodegradable-biocompatible microspheres
US08242960 US5693343A (en) 1984-03-16 1994-05-16 Microparticle carriers of maximal uptake capacity by both M cells and non-M cells
US44614995 true 1995-05-22 1995-05-22
US08598874 US5762965A (en) 1984-03-16 1996-02-09 Vaccines against intracellular pathogens using antigens encapsulated within biodegradble-biocompatible microspheres
US09586747 USRE40786E1 (en) 1984-03-16 2000-06-02 Vaccines against intracellular pathogens using antigens encapsulated within biodegradable-biocompatible microspheres

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US09586747 USRE40786E1 (en) 1984-03-16 2000-06-02 Vaccines against intracellular pathogens using antigens encapsulated within biodegradable-biocompatible microspheres

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08598874 Reissue US5762965A (en) 1984-03-16 1996-02-09 Vaccines against intracellular pathogens using antigens encapsulated within biodegradble-biocompatible microspheres

Publications (1)

Publication Number Publication Date
USRE40786E1 true USRE40786E1 (en) 2009-06-23

Family

ID=40766076

Family Applications (1)

Application Number Title Priority Date Filing Date
US09586747 Expired - Fee Related USRE40786E1 (en) 1984-03-16 2000-06-02 Vaccines against intracellular pathogens using antigens encapsulated within biodegradable-biocompatible microspheres

Country Status (1)

Country Link
US (1) USRE40786E1 (en)

Citations (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3540444A (en) 1968-01-15 1970-11-17 Scherer Corp R P Plastic ampoule for use with hypodermic injector
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
US3788315A (en) 1971-04-20 1974-01-29 S Laurens Disposable cutaneous transjector
US4166800A (en) 1977-08-25 1979-09-04 Sandoz, Inc. Processes for preparation of microspheres
US4384975A (en) 1980-06-13 1983-05-24 Sandoz, Inc. Process for preparation of microspheres
US4389330A (en) * 1980-10-06 1983-06-21 Stolle Research And Development Corporation Microencapsulation process
US4530840A (en) 1982-07-29 1985-07-23 The Stolle Research And Development Corporation Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents
US4542025A (en) 1982-07-29 1985-09-17 The Stolle Research And Development Corporation Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents
US4585482A (en) 1984-05-25 1986-04-29 Southern Research Institute Long-acting biocidal compositions and method therefor
US4622244A (en) 1979-09-04 1986-11-11 The Washington University Process for preparation of microcapsules
US4637905A (en) 1982-03-04 1987-01-20 Batelle Development Corporation Process of preparing microcapsules of lactides or lactide copolymers with glycolides and/or ε-caprolactones
US4675189A (en) 1980-11-18 1987-06-23 Syntex (U.S.A.) Inc. Microencapsulation of water soluble active polypeptides
US4798786A (en) 1982-05-06 1989-01-17 Stolle Research And Development Corporation Living cells encapsulated in crosslinked protein
US4835139A (en) 1983-09-23 1989-05-30 Debiopharm S.A. Process for increasing the antagonistic effect of peptidic compounds on hormone-dependent diseases
US4863735A (en) 1985-02-19 1989-09-05 Massachusetts Institute Of Technology Biodegradable polymeric drug delivery system with adjuvant activity
US4897268A (en) 1987-08-03 1990-01-30 Southern Research Institute Drug delivery system and method of making the same
US4938763A (en) 1988-10-03 1990-07-03 Dunn Richard L Biodegradable in-situ forming implants and methods of producing the same
US4941880A (en) 1987-06-19 1990-07-17 Bioject, Inc. Pre-filled ampule and non-invasive hypodermic injection device assembly
US5000886A (en) 1987-05-26 1991-03-19 American Cyanamid Company Silicone-hardened pharmaceutical microcapsules and process of making the same
US5019096A (en) 1988-02-11 1991-05-28 Trustees Of Columbia University In The City Of New York Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same
US5059187A (en) 1988-11-30 1991-10-22 Dey Laboratories, Inc. Method for the cleansing of wounds using an aerosol container having liquid wound cleansing solution
US5064413A (en) 1989-11-09 1991-11-12 Bioject, Inc. Needleless hypodermic injection device
US5075109A (en) 1986-10-24 1991-12-24 Southern Research Institute Method of potentiating an immune response
US5102872A (en) 1985-09-20 1992-04-07 Cetus Corporation Controlled-release formulations of interleukin-2
US5129825A (en) 1987-12-21 1992-07-14 Discko John Jr Dental syringe and capsule for use therewith
US5133701A (en) 1989-04-06 1992-07-28 Sang In Han Disposable pressure wound irrigation device
WO1992022654A1 (en) * 1991-06-11 1992-12-23 Microgenesys, Inc. Vaccine and treatment method of human immunodeficiency virus infection
US5236355A (en) 1988-12-22 1993-08-17 American Cyanamid Company Apparatus for the treatment of periodontal disease
US5290494A (en) 1990-03-05 1994-03-01 Board Of Regents, The University Of Texas System Process of making a resorbable implantation device
EP0052510B2 (en) 1980-11-18 1994-10-19 Syntex (U.S.A.) Inc. Microencapsulation of water soluble polypeptides
US5360610A (en) 1990-05-16 1994-11-01 Southern Research Institute Method for stimulating nerve fiber growth
US5384133A (en) 1986-08-11 1995-01-24 Innovata Biomed Limited Pharmaceutical formulations comprising microcapsules
US5407609A (en) 1989-05-04 1995-04-18 Southern Research Institute Microencapsulation process and products therefrom
WO1995011010A1 (en) * 1993-10-22 1995-04-27 Genentech, Inc. Methods and compositions for microencapsulation of antigens for use as vaccines
US5417986A (en) 1984-03-16 1995-05-23 The United States Of America As Represented By The Secretary Of The Army Vaccines against diseases caused by enteropathogenic organisms using antigens encapsulated within biodegradable-biocompatible microspheres
US5429822A (en) 1992-03-13 1995-07-04 Cambridge Scientific, Inc. Biodegradable bursting release system
US5500228A (en) 1987-05-26 1996-03-19 American Cyanamid Company Phase separation-microencapsulated pharmaceuticals compositions useful for alleviating dental disease
US5538739A (en) 1989-07-07 1996-07-23 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5639480A (en) 1989-07-07 1997-06-17 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5643605A (en) 1993-10-25 1997-07-01 Genentech, Inc. Methods and compositions for microencapsulation of adjuvants
US5648096A (en) 1992-10-26 1997-07-15 Schwarz Pharma Ag Process for the production of microcapsules
US5650173A (en) 1993-11-19 1997-07-22 Alkermes Controlled Therapeutics Inc. Ii Preparation of biodegradable microparticles containing a biologically active agent
US5693343A (en) 1984-03-16 1997-12-02 The United States Of America As Represented By The Secretary Of The Army Microparticle carriers of maximal uptake capacity by both M cells and non-M cells
US5762965A (en) 1984-03-16 1998-06-09 The United States Of America As Represented By The Secretary Of The Army Vaccines against intracellular pathogens using antigens encapsulated within biodegradble-biocompatible microspheres
US5811128A (en) 1986-10-24 1998-09-22 Southern Research Institute Method for oral or rectal delivery of microencapsulated vaccines and compositions therefor

Patent Citations (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3540444A (en) 1968-01-15 1970-11-17 Scherer Corp R P Plastic ampoule for use with hypodermic injector
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
US3788315A (en) 1971-04-20 1974-01-29 S Laurens Disposable cutaneous transjector
US4166800A (en) 1977-08-25 1979-09-04 Sandoz, Inc. Processes for preparation of microspheres
US4622244A (en) 1979-09-04 1986-11-11 The Washington University Process for preparation of microcapsules
US4384975A (en) 1980-06-13 1983-05-24 Sandoz, Inc. Process for preparation of microspheres
US4389330A (en) * 1980-10-06 1983-06-21 Stolle Research And Development Corporation Microencapsulation process
EP0052510B2 (en) 1980-11-18 1994-10-19 Syntex (U.S.A.) Inc. Microencapsulation of water soluble polypeptides
US4675189A (en) 1980-11-18 1987-06-23 Syntex (U.S.A.) Inc. Microencapsulation of water soluble active polypeptides
US4637905A (en) 1982-03-04 1987-01-20 Batelle Development Corporation Process of preparing microcapsules of lactides or lactide copolymers with glycolides and/or ε-caprolactones
US4798786A (en) 1982-05-06 1989-01-17 Stolle Research And Development Corporation Living cells encapsulated in crosslinked protein
US4542025A (en) 1982-07-29 1985-09-17 The Stolle Research And Development Corporation Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents
US4530840A (en) 1982-07-29 1985-07-23 The Stolle Research And Development Corporation Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents
US4835139A (en) 1983-09-23 1989-05-30 Debiopharm S.A. Process for increasing the antagonistic effect of peptidic compounds on hormone-dependent diseases
US5762965A (en) 1984-03-16 1998-06-09 The United States Of America As Represented By The Secretary Of The Army Vaccines against intracellular pathogens using antigens encapsulated within biodegradble-biocompatible microspheres
US5417986A (en) 1984-03-16 1995-05-23 The United States Of America As Represented By The Secretary Of The Army Vaccines against diseases caused by enteropathogenic organisms using antigens encapsulated within biodegradable-biocompatible microspheres
US5693343A (en) 1984-03-16 1997-12-02 The United States Of America As Represented By The Secretary Of The Army Microparticle carriers of maximal uptake capacity by both M cells and non-M cells
US4585482A (en) 1984-05-25 1986-04-29 Southern Research Institute Long-acting biocidal compositions and method therefor
US4863735A (en) 1985-02-19 1989-09-05 Massachusetts Institute Of Technology Biodegradable polymeric drug delivery system with adjuvant activity
US5102872A (en) 1985-09-20 1992-04-07 Cetus Corporation Controlled-release formulations of interleukin-2
US5384133A (en) 1986-08-11 1995-01-24 Innovata Biomed Limited Pharmaceutical formulations comprising microcapsules
US5820883A (en) 1986-10-24 1998-10-13 Southern Research Institute Method for delivering bioactive agents into and through the mucosally-associated lymphoid tissues and controlling their release
US5853763A (en) 1986-10-24 1998-12-29 Southern Research Institute Method for delivering bioactive agents into and through the mucosally-associated lymphoid tissue and controlling their release
US5075109A (en) 1986-10-24 1991-12-24 Southern Research Institute Method of potentiating an immune response
US5814344A (en) 1986-10-24 1998-09-29 Southern Research Institute Method for delivering bioactive agents into and through the mucosally associated lymphoid tissues and controlling their release
US5811128A (en) 1986-10-24 1998-09-22 Southern Research Institute Method for oral or rectal delivery of microencapsulated vaccines and compositions therefor
US5000886A (en) 1987-05-26 1991-03-19 American Cyanamid Company Silicone-hardened pharmaceutical microcapsules and process of making the same
US5500228A (en) 1987-05-26 1996-03-19 American Cyanamid Company Phase separation-microencapsulated pharmaceuticals compositions useful for alleviating dental disease
US4941880A (en) 1987-06-19 1990-07-17 Bioject, Inc. Pre-filled ampule and non-invasive hypodermic injection device assembly
US4897268A (en) 1987-08-03 1990-01-30 Southern Research Institute Drug delivery system and method of making the same
US5129825A (en) 1987-12-21 1992-07-14 Discko John Jr Dental syringe and capsule for use therewith
US5019096A (en) 1988-02-11 1991-05-28 Trustees Of Columbia University In The City Of New York Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same
US5278202A (en) 1988-10-03 1994-01-11 Atrix Laboratories, Inc. Biodegradable in-situ forming implants and methods of producing the same
US4938763B1 (en) 1988-10-03 1995-07-04 Atrix Lab Inc Biodegradable in-situ forming implants and method of producing the same
US4938763A (en) 1988-10-03 1990-07-03 Dunn Richard L Biodegradable in-situ forming implants and methods of producing the same
US5059187A (en) 1988-11-30 1991-10-22 Dey Laboratories, Inc. Method for the cleansing of wounds using an aerosol container having liquid wound cleansing solution
US5236355A (en) 1988-12-22 1993-08-17 American Cyanamid Company Apparatus for the treatment of periodontal disease
US5133701A (en) 1989-04-06 1992-07-28 Sang In Han Disposable pressure wound irrigation device
US5407609A (en) 1989-05-04 1995-04-18 Southern Research Institute Microencapsulation process and products therefrom
US5688530A (en) 1989-07-07 1997-11-18 Novartis Ag Sustained release formulations of water soluble peptides
US5639480A (en) 1989-07-07 1997-06-17 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5538739A (en) 1989-07-07 1996-07-23 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5064413A (en) 1989-11-09 1991-11-12 Bioject, Inc. Needleless hypodermic injection device
US5290494A (en) 1990-03-05 1994-03-01 Board Of Regents, The University Of Texas System Process of making a resorbable implantation device
US5360610A (en) 1990-05-16 1994-11-01 Southern Research Institute Method for stimulating nerve fiber growth
WO1992022654A1 (en) * 1991-06-11 1992-12-23 Microgenesys, Inc. Vaccine and treatment method of human immunodeficiency virus infection
US5429822A (en) 1992-03-13 1995-07-04 Cambridge Scientific, Inc. Biodegradable bursting release system
US5648096A (en) 1992-10-26 1997-07-15 Schwarz Pharma Ag Process for the production of microcapsules
WO1995011010A1 (en) * 1993-10-22 1995-04-27 Genentech, Inc. Methods and compositions for microencapsulation of antigens for use as vaccines
US5643605A (en) 1993-10-25 1997-07-01 Genentech, Inc. Methods and compositions for microencapsulation of adjuvants
US5650173A (en) 1993-11-19 1997-07-22 Alkermes Controlled Therapeutics Inc. Ii Preparation of biodegradable microparticles containing a biologically active agent

Non-Patent Citations (21)

* Cited by examiner, † Cited by third party
Title
Biotechnology News, Aug. 22, 1997, vol. 17, No. 20, Topical DNA vaccine elicits immune response.
Brown, A hypothetical model of the foreign antigen blinding site of Class II histocompatibility molecules, Nature, vol. 332, Apr. 28, 1988, pp. 845-850.
Brown, Wonder Drugs' Losing Healing Aura, The Washing Post, Jun. 26, 1995, A section.
Cassels, et al., Analysis of Escherichia coli Colonization Factor Antigen I Linear B-Cell Epitopes, as Determined by Primate Responses, following Protein Sequence Verification, Infection and Immunity, Jun. 1992, pp. 2174-2181, vol. 60, No. 6.
Evans, et al. Purification and Characterization of the CFR/1 Antigen of Enterotoxigenic Escherichia coli, Infection and Immunity, Aug. 1979, pp. 738-748, vol. 25.
Gilding, Biodegradable polymers for use in surgery-polyglycolic/poly (ac c acid) homo-and copolymers: 1, Polymer, vol. 20, Dec. 1979, pp. 1459-1464.
Hall, et al., Purification and Analysis of Colonization Factor Antigen 1, Coli Surface Antigen 1, and Coli Surface ANtigen 3 Fimbriae from Enterotoxigenic Escherichis Coli, Journal of Bacteriology, Nov. 1989, pp. 6372-6374, vol. 171, No. 11.
Jeyanthi, et al., Novel, Burst Free Programmable Biodegradable Microspheres For Controlled Release of Polypeptides, Proceedings Int. Symp. control Release Bioact. Mater. (1996) pp. 351-362/.
Jordi, et al., Analysis of the first two genes of the CSI fimbrial operon in human enterotoxigenic Escherichia coli of serotype 0139: H28, FEMS Microbiology Letters 80, (1991) pp. 265-270.
Karjalainen, et al., Molecular Cloning and Nucleotide Sequence of the Colonization Factor Antigen I Gene of Escherichia coli, Infection and Immunity, Apr. 1989, pp. 1126-1130, vol. 57.
Maister, First Oral AIDS Vaccine Trials Near, BioWorld Today, Tuesday, Apr. 19, 1994, p. 4.
McConnel, et al., Antigenic homology within human enterotoxigenic Esherichia coli fimbrial colonization factor antigens: CFA/I, coli-surface-associated antigens (CS)1, CS2, CS4 and CS17, FEMS Microbiology Letters 61 (1989) 105-108.
Perez-Casal, et al., Gene Encoding the Major Subunit of CS1 Pili of Human Enterotoxigenic Escherichia Coli, Infection and Immunity, Nov., 1990, pp. 3594-3600, vol. 58, No. 11.
Rognan, et al., Molecular Modeling of an Antigenic Complex Between a Viral Peptide and a Class I Major Histocompatibility Glycoprotein, Proteins Structure, Function and Genetics 13 70-85 (1992).
Romagnoli, et al. Peptide-MHC Interaction: A Rational Approach to Vaccine Design, Inter, RE. Immunol. 6, 1990, 00 61-73.
Setterstrom, Controlled Release of Antibiotics From biodegradable Microcapsules For Wound Infection Control, Chemical Abstracts, 1983, pp. 215-226.
Tan, et al., Mapping the Antigenic Epitopes of Human Dihydrofolate Reductase by Systematic Synthesis of Peptides on solid Supports, The Journal of Biological Chemistry, vol. 265, No. 14, Issue of May 15, pp. 8022-8026 (1990).
Van der Zee, Efficient mapping and characterization of a T cell epitope by the simultaneous synthesis of multiple peptides, Eur. J. Immunol. 1989, 19: 43-47.
Wang, et al., Influence of formulation methods on the in vitro controlled release of protein from poly (ester) microspheres Journal of Controlled Release, 17 (1991) 23-32.
Yan, Characterization and morphological analysis of protein-loaded poly(lactide-co-glycolide) microparticles prepared by watewr-in-oil-in-water emulsion technique, Journal of Controlled Release, 32 (1994) 231-241.
Yeh, A novel emulsification-solvent extraction technique for production of protein loaded biodegradable microparticles for vaccine and drug delivery, Journal of Controlled Release 33 (1995) 437-445.

Similar Documents

Publication Publication Date Title
Moon et al. Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses
Berman et al. Human immunodeficiency virus type 1 challenge of chimpanzees immunized with recombinant envelope glycoprotein gp120
US5462751A (en) Biological and pharmaceutical agents having a nanomeric biodegradable core
Tam et al. Incorporation of T and B epitopes of the circumsporozoite protein in a chemically defined synthetic vaccine against malaria.
US6902743B1 (en) Therapeutic treatment and prevention of infections with a bioactive material(s) encapuslated within a biodegradable-bio-compatable polymeric matrix
US5573916A (en) Immunogenic constructs comprising b-cell and t-cell epitopes on common carrier
US5603960A (en) Preparation of microparticles and method of immunization
Alonso et al. Biodegradable microspheres as controlled-release tetanus toxoid delivery systems
Allison et al. An adjuvant formulation that selectively elicits the formation of antibodies of protective isotypes and of cell-mediated immunity
Moon et al. Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand Tfh cells and promote germinal center induction
Gutierro et al. Size dependent immune response after subcutaneous, oral and intranasal administration of BSA loaded nanospheres
Makidon et al. Pre-clinical evaluation of a novel nanoemulsion-based hepatitis B mucosal vaccine
US6355271B1 (en) Therapeutic calcium phosphate particles and methods of manufacture and use
Ben-Yedidia et al. Design of peptide and polypeptide vaccines
US5961970A (en) Submicron emulsions as vaccine adjuvants
Sánchez et al. Formulation strategies for the stabilization of tetanus toxoid in poly (lactide-co-glycolide) microspheres
Gupta et al. M-cell targeted biodegradable PLGA nanoparticles for oral immunization against hepatitis B
Toda et al. HIV‐1‐specific cell‐mediated immune responses induced by DNA vaccination were enhanced by mannan‐coated liposomes and inhibited by anti‐interferon‐γ antibody
Eldridge et al. Vaccine-containing biodegradable microspheres specifically enter the gut-associated lymphoid tissue following oral administration and induce a disseminated mucosal immune response
US4816253A (en) Novel mutant strain of Listeria monocytogenes and its use in production of IgM antibodies and as an immunotherapeutic agent
Oliveira et al. Safety and enhanced immunogenicity of a hepatitis B core particle Plasmodium falciparum malaria vaccine formulated in adjuvant Montanide ISA 720 in a phase I trial
Mann et al. Lipid vesicle size of an oral influenza vaccine delivery vehicle influences the Th1/Th2 bias in the immune response and protection against infection
US7285289B2 (en) Nanoparticle vaccines
Arnon et al. Antiviral response elicited by a completely synthetic antigen with built-in adjuvanticity
Eldridge et al. Biodegradable microspheres as a vaccine delivery system

Legal Events

Date Code Title Description
AS Assignment

Owner name: ARMY, UNITED STATES, MARYLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BURNETT, PAUL R.;VAN HAMONT, JOHN E.;REID, ROBERT H.;ANDOTHERS;REEL/FRAME:022293/0134;SIGNING DATES FROM 19960715 TO 19960823

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees