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HEIDELTEC: gummy bears may replace injections

Peptide- and protein-based drugs like those used for treating diabetes, cancer and autoimmune diseases cannot be administered orally. This is because these biomolecules degrade in the gastrointestinal tract, thus preventing them from reaching their target site in the body. Protein- and peptide-base drugs therefore have to be administered by way of injection, which is comparatively complicated and painful. However, a start-up company called Heidelberg Delivery Technologies GmbH has now developed an innovative technology that makes taking medicines as easy as eating gummy bears.

The drugs resemble gummy bears and are easy for patients to take. © HEIDELTEC

Many drugs used for innovative therapies are made from proteins and peptides. These biopharmaceuticals include, for example, insulin and other hormones, growth factors, therapeutic enzymes and monoclonal antibodies. Protein- and peptide-based drugs have the advantage over synthetic drugs in that they have a high specificity for target structures in the body that are inaccessible to classical low molecular weight drugs. However, the disadvantage is that proteins and peptides are highly sensitive. Amongst other things, they have to be kept refrigerated and need to be handled carefully, since flaws arising during transport, storage and even application can render them completely or partially ineffective.

However, the main disadvantage of these drugs is that they cannot be administered orally. They are rapidly broken down in the stomach and are poorly absorbed in the intestines. Injection is therefore the only viable route of application. This makes administration of these drugs comparatively difficult, resulting in poor compliance and even discontinuation of therapy – with fatal consequences for patients, billion-dollar losses for manufacturers and high healthcare system costs due to secondary diseases.

Glossary

  • Antibodies are blood proteins (immunoglobulins) which are produced by the B lymphocytes in response to disease. They recognise foreign substances that have entered the body (e.g. bacteria) and help the body fight against a particular disease and develop an immunity to that disease.
  • Biotechnology is the study of all processes involving life cells or enzymes for the transformation and production of certain substances.
  • A hormone is an active regulatory chemical substance formed in one part of the body and carried by the blood to another part where it exerts a reaction in the cell. E.g., insulin is produced in the pancreas, passes to the muscles where it leads to a reduction of the blood glucose level.
  • Monoclonal antibodies are structurally identical antibodies which hence have an identical antigen-binding site.
  • A protein is a high-molecular complex made up of amino acids. The proteins perform a wide variety of activities in the cells and represent more than 50% of organic mass.
  • Genetic sequences are successions of the bases adenine, thymine, guanine, and cytosine on the DNA (or uracil instead of thymine in the case of RNA).
  • Biopharmaka are Drugs, which are produced with the help of biological systems.
  • A peptide is an organic chemical compound, which consists of two or more amino acids connected to a chain. The amino acids are linked together by peptide bonds. Relative short chains of amino acids (20 - 100) are called peptides, whereas longer chains of amino acids (> 100) are called proteins.
  • A tumour is a swelling of a tissue caused by abnormal cell growth, which can be benign or malignant. Benign tumours are local swellings, whereas malign tumours may seed off and spread into other tissues, causing secondary growths (metastases).
  • Expression means the biosynthesis of a gene product. Usually, DNA is transcribed into mRNA and subsequently translated into proteins.
  • The toxicity is the poisonousness of a substance.
  • Molecular means: at the level of molecules.
  • Polyehylene (abbrevation: PE) is the polymer of ethylene. It belongs to the thermoplastic synthetics.
  • Absorption means in a biological context: the absorption of a drug or of light
  • Autoimmune diseases are diseases that are characterized by an immune system attacking the own body cells. This is caused by a failure of the immune system to discriminate between self and foreign cells or tissues.
  • Biomolecules which can bind active agents are called targets. They can be receptors, enzymes or ion channels. If agent and target interact with each other the term agent-target-specific effect is used. The identification of targets is very important in biomedical and pharmaceutical research because a specific interaction can help to understand basic biomolecular processes. This is essential to identify new points of application.

Liposomes - transport system for protein drugs

Drug formulation involves packaging the active pharmaceutical ingredient into liposomes, which are subsequently turned into a solid dosage form using a matrix-building agent. © HEIDELTEC

Researchers from the Institute of Pharmacy and Molecular Biotechnology at the University of Heidelberg, seeking to improve this situation, started looking as far back as ten years ago for alternatives for administering protein and peptide drugs. Their quest has been successful! In the past few years, two doctoral theses have dealt with the development of a technology that can be used for a drug delivery platform to enable the oral administration of these types of biomolecules. Around a year ago, the scientists involved in the development of this basic drug delivery technology established a company called Heidelberg Delivery Technologies GmbH, HEIDELTEC for short. “Start-up funding is provided under the Exist Transfer of Research programme for a period of two years until September 2018,” says Moritz Stadler, business economist and managing director of the start-up. “What happens after that remains to be seen. This is why we are currently focused on two things simultaneously: experimental laboratory work on the one hand and finding investors to continue funding our developments on the other.”

The technology developed by the HEIDELTEC scientists involves the use of liposomes as vehicles for transporting therapeutic proteins and peptides to specific targets in the human body. The liposomal formulation consisting of liposome and active ingredient is embedded into a matrix-building agent, resulting in a solid dosage form that patients can take without problem. “The dosage form looks kind of like a gummy bear,” says Stadler. “Packaged like this, the biomolecules can be absorbed by the intestines without reducing the efficacy of the drug,” says Stadler. The liposomes used are produced using an innovative method that enables the rapid and efficient production of drug delivery vehicles containing relatively high amounts of active pharmaceutical ingredient (AIP). “This method is excellently scalable, so we can easily produce drugs on a larger scale at a later point in time,” says Stadler.

Drug delivery platform for many active ingredients

Pharmacist Dr. Robin Tremmel (back) and chemist Dr. Frieder Helm (front) are part of HEIDELTEC’s very active team and are involved in the development of the innovative drug delivery platform © HEIDELTEC

At present, the HEIDELTEC researchers are working on formulations for two drug candidates that are already being used for disease treatment. One of these is, amongst other things, used for treating a rare disease characterised by excessive growth. Children affected by this disease need to be given injections three times a day over a period of many years. It is a peptide and is also used in the field of oncology for treating growth hormone-producing tumours. The other drug, a larger peptide, is used for treating diabetes. “One of the reasons we have chosen these two compounds is because of their different size,” says Stadler. “We have already shown that the technology is suitable for differently sized drugs. That said, the technology was specifically designed as a platform technology with the aim of being able to extend it to other drugs at a later stage. The bigger the drug, the greater the challenge when it comes to achieving sufficient bioavailability. However, these peptides and other active pharmaceutical ingredients have shown that the technology works well and that the drugs are suitable for oral application.”

The innovative drug delivery technology developed by the HEIDELTEC researchers not only has the advantage that the drugs can be taken orally, but that they have also good storage stability. This means that they do not need to be handled too carefully or be cooled. However, this always depends on the drug of interest. “In most cases, maintaining a cold chain should not be a problem. Standard blister packaging provides sufficient protection for the dosage form and the active pharmaceutical ingredient.”

Research and the search for industry partners

In addition to Stadler, the HEIDELTEC team also consists of two pharmacists, Dr. Silvia Pantze and Dr. Robin Tremmel, as well as a chemist, Dr. Frieder Helm. In addition, Prof. Dr. Gert Fricker, director of the Institute of Pharmacy and Molecular Biotechnology and pioneer in liposome research, and Dr. Johannes Parmentier, co-developer of the technology, serve as advisors and mentors. The company is still located at the university, where the scientists can use the infrastructure. The pharmaceutical industry has already expressed interest in the technology: “As institute director, Professor Fricker has long-standing contacts with large pharmaceutical manufacturers,” says Stadler. “And some of these companies have expressed a definite interest in our drug delivery platform.” Competing drug delivery systems are already on the market, but these are based on other technologies and have adverse effects that the HEIDELTEC researchers can avoid by embedding the drug into a solid matrix. HEIDELTEC’s PEPTORAL® technology has a high specificity, preventing undesired by-products from entering the body via the intestines.

At present, the scientists at the start-up company are focused on optimising the formulation of the “gummy bears”. “The basic recipe is ready, and we are now working on different matrix liposome compositions with the aim of finding one that can be used to achieve the best possible results,” says the managing director. “When start-up funding comes to an end in September 2018, we will not yet have the final product in hand, but we hope to be able to initiate a long-term survival and toxicity profile evaluation of our system and also adapt the technology to specific AIPs. This will be done in cooperation with industry partners.”

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