Beating needles into teaspoons is, in a sense, the long-rangegoal of Emisphere Technologies Inc.
The thousands of drug addicts who share needles are at highrisk of contracting AIDS. The hundreds of thousands ofdiabetics who self-inject insulin suffer daily twinges of pain,and inconvenience. The millions of Americans who endureannual flu shots incur only one quick pin prick and possibly asore arm. But the yearly chore of anti-flu vaccination is ofuncer-tain efficacy in warding off the ever-changing strains ofinfluenza virus.
"The protection offered by current vaccines is less thancomplete," states a paper in the August edition ofPharmaceutical Research titled "Oral Immunization of Ratswith Proteinoid Microspheres Encapsulating Influenza VirusAntigens."
The paper's principal author, Sam Milstein, is executive vicepresident and chief scientific officer of Hawthorne, N.Y.-basedEmisphere . Milstein told BioWorld that Emisphere's oral-delivery system "is the way commercial vaccines for flu shouldgo." According to Milstein, the advantages of oral immunization-- by teaspoon, tablet or capsule -- include:
-- a higher level of acceptability among patients;-- less highly-trained personnel are needed;-- no refrigeration is required;-- (oral administration) "induces a vigorous immune responsein mucosal surfaces, which are the commonest sites of entry ofinfectious agents."
Emisphere's oral-delivery system consists of microspheres 0.1to 0.5 microns in diameter that are designed to entrap drugs orantigens now administered parenterally (by injection).
These carriers, Milstein said, bear no physical or chemicalrelation to liposomes, "which are difficult and expensive tomanufacture." He added, "Ours is a trivial undertaking in termsof sphere formation; essentially, you have to mix twosolutions."
Solution one starts with a number of amino acids, whichheating condenses into a material Emisphere calls "proteinoids,"better known as thermal pro-teins, dissolved in water.
"The particular material depends on choice of amino acids, thesequence in which we add them to the reaction mixture,duration and temperature of heating," Milstein said. Thiswitch's brew is in the public domain; covered by patents issuedto Emisphere for a minimum of 2x10 to the 18th formulations."We call that a lot," Milstein observed.
Solution two comprises the drug of interest P in the presentcase, flu virus antigens P dissolved in acid, then mixed withSolution one. The pro-tenoids, when exposed to acid pH, undergophase transition, and in seconds precipitate out of solution asmicrospheres, encapsulating the drug of inter-est.
Shielding their contents from gastric acids and gut digestiveenzymes, the microspheres gradually release their payloadsinto the intestinal mu-cosa, and eventually the bloodstream.
"We're still not sure just what happens in vivo," Milstein said."We be-lieve delivery is occurring somewhere in the vicinity ofthe duodenum." As the empty shells consist of essential aminoacids, he explained, "the body apparently treats them as afoodstuff."
An ingestible influenza vaccine is only one of the orallydeliverable pharmaceuticals in Emisphere's (NASDAQ:EMIS)development pipeline. The others include heparin, thymosinand a poultry vaccine.
To test their oral flu shot, Milstein and his associates purifiedtwo antigenic-envelope proteins P M1 and hemagglutinin-neuraminidase (HA-NA)-from a recombinant strain of thevirus. They fed each antigen, entrapped in proteinoidmicrospheres, to cohorts of five hefty (1.3 lb.) rats. Otherbatches of rodents swallowed empty spheres or the naked viralproteins. A final group of four received the same proteins byinjection into a tail vein to simulate current flu shots.
In the M1-protein experiment group, the four injected animalsdevel-oped vigorous antibody responses. One in particularachieved a titer of 40,000 international units (IU) 14 days afterinjection; 62,000 at 28 days and 330,000 at 42 days.
Three of five rats who got the oral M1 reacted with titers of1,150, 3,000, and 5,200, as early as two weeks post-dosing P-sufficiently proving that oral delivery works, but they didn'tdetermine correct dosage. The groups that got empty spheresor naked protein by mouth turned in negligible antibodyresponses.
Interestingly, there was no immune reaction to the proteinoidspheres per se. The HA-NA experiment produced similarresults.
So far, Emisphere's only publicly identified oral-delivery drugto be tried in humans is heparin, which the company has notyet licensed to a partner. Last year in Wales, 14 healthyhumans in a safety and dose-escalation study swallowed dosesofFragmin, Emisphere's trademarked oral-delivery heparin. AsMilstein reported in November 1992 at the AmericanAssociation of Pharmaceutical Scientists meeting in SanAntonio, Texas, the 14 subjects were "dosed with a microspheresuspension containing Fragmin at doses ranging from 10,000to 800,000 international units. Clinical responses [in bloodsamples] were comparable to those seen in non-humanprimates, and no deleterious effects were noted."
Heparin, Milstein explained, is often prescribed long-term toheart-attack patients to keep arteries open after angioplasty orvalve surgery. At present, it can currently be taken only byinjection or orally as warfarin, a drug with unpleasant sideeffects.
Emisphere is now in late-stage negotiation with a number ofpotential part-ners to license Fragmin. "Once these arecomplete," Milstein said, "within a reasonably short time frame,we will be in the clinic, heading towards ap-proval."
Does Emisphere have any competition for its oral-deliverysystem?
"We're unaware of any specific competition; comparisons areinappropriate," said Milstein. "For example, oftentimes peopletalk about us versus Alza Corp. and Elan Corp. plc. These aretraditional drug-delivery companies, but they specialize intaking a drug given three times a day and making it(necessary) once a day." He added that the others don't have adrug unavailable orally that they're trying to make availableorally. "There are precious few companies that can make thatclaim from the standpoint of having human data," he said. "Ifyou use that as a cut-off criterion, you'll find nobody out therebut us right now."
Its spokeswoman, Bonnie Burdette, told BioWorld: "We'reworking on a number of compounds for oral delivery, amongthem insulin, which to date have not been able to be deliveredvia traditional oral sys-tems." She said she was unable toconfirm or deny any other prod-ucts, such as vaccines, ongrounds of proprietary prudence.0909EMISPHERE
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.