GULF COOPERATION COUNCIL: 

Includes the following countries viz. Kuwait, Qatar, Oman, Saudi Arabia, Bahrain, United Arab Emirates.  

One patent application for all member countries. Requirements for patent ability include novelty, innovation and industrial application. The patent should not conflict with Islamic laws or rule of conduct observed in the GCC countries. Paten table subject matter does not include: scientific discoveries and theories , mathematical formulae and computer programs, plant varieties, animal species or biological processes used for production of plants or animals with the exception of microbiological procedures and products of such procedures. Methods of treatment of human or animal body, surgical or medical. 

A patent issued by GCC patent office is valid in all member states. Article (7) of the GCC patent regulations provide for a claim for priority if the GCC application is filed within 12 Gregorian months of the filing date of the first application. The term of patent is 20 years from filing date f the GC application. On cannot have a GCC patent and a patent of a member state. If one has to have a patent from a member state must relinquish that patent before a GCC patent can be issued.

SAUDI ARABIA:

Payment of publication fee. Request for examination. Payment of annuities during pendency of application. Annuities do not have to be paid through the agent of record. In the future it may be possible it may be possible to pay annuities directly to the Saudi patent office. Filing in Saudi Arabia or GCC standards of novelty, inventive step and industrial applicability are the same as those of the GCC. At the present the filing fees and grant fees are higher for a GCC application than for a Saudi application. At present, the annuities for years 1-12 are higher for GCC application than in Saudi Arabia. 

TAIWAN:  

The Taiwan intellectual property office has announced the founding of the intellectual property institute. This institute is made up of people from universities, government, attorneys, patent examiners ad judges. The purpose of the institute is to promote the quality of Taiwan; IP procurement and enforcement.

For clarifications,contact us at 1-514-743-6159 or email  contact@innoworksltd.com 

INDIA: 

To comply with its TRIPS obligation to grant product patents for agrochemicals and pharmaceuticals, India has enacted the Patents Amendment Ordinance 2005 which came into effect on January 1,2005. Apropos, this ordinance, “Invention” is any new process o product, which involves an inventive step and is capable of industrial application. 

Product patents are now available in all categories – pharmaceuticals. Agrochemicals. Food, alloys, chemicals, optical glass, microorganisms etc. Although novelty-new invention is “ any invention or technology which has not been anticipated by publication in any document or used in the country or else here in the world before the date of filing of the patent application with complete specification” Prior publication or prior use any where in the world could destroy novelty of an invention. The inventive step- is a feature of an invention that involves technical advances as compared to the existing knowledge or having economic significance or both and that makes the invention not obvious to a person skilled in the art. 

What are the changes to the patent law-
 

1. The mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance
2. The mere discovery of any new property or new use for a known substance and the mere use of a known process machine or apparatus- unless such process results in a new product or employs at least one new reactant “ is not paten table.
3. New form of a known substance having no therapeutic efficacy is not paten table. This means that salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substances will be considered the same substance unless they differ significantly in properties with regard to efficacy.
4. With the old law, mathematical methods, business method or a computer program per se or algorithm were not paten table. The new ordinance allows, hardware, software in combination with hardware are paten table. However, soft ware per se and business methods are not paten table. There is requirement for Indian resident to obtain foreign filing permit for filing outside of India unless 6 weeks have passed since the filing of a corresponding Indian application. Additional fees are applicable to more than 10 claims. The no. of pages of the specifications should preferably be 30.
5. Examination of complete specification may be done 36 months from the date or filing from the earliest priority date whichever is earlier. Currently, 12 months after date of examination report to place application in condition for grant – must file a first response with in 4 months of the date of the action. The new provision- 6 months to obtain grant after issuance of examination report (3 months extension is available).
6. There is an obligation to advice the controller as to the status of foreign applications and the supply prosecution details (if requested) has been extended from the acceptance date up to the date of grant.
7. It is the duty of the patentee to supply list of prior art cited in corresponding applications.
8. Priority may be claimed from applications file at the EPO, ARIPO or other organizations that are parties to a regional international or bilateral treaty or arrangement to which India is also a party.
9. A working statement must be filed every year. The working requirement can b met by importation. There is a penalty for no filing a working statement reflecting the working of the invention in India has been increased from about 500 USD to 23,000 USD.
10. Permitted importation of patented product form a person who is authorized by the patentee or who is duly authorized under law to produce and sell or distribute the product.
11. There is a possibility that more compulsory license will be granted in the future, especially in the pharmaceutical field.
12. Opposition are possible both pre- and post -grant of the patent.
13. Pre-grant oppositions – challenge grant based on lack of novelty, inventive step, wrongful obtainment, and anticipation by traditional knowledge etc.
14. Post-grant opposition – to be filed within one year from the date of grant also on the same grounds as the pre-grant opposition.
15. Using, making, selling or importation of a patented product is an act of infringement. Importation of a product made by a patented process is also an infringement. Importation, use or sale of a patented product for purposes of obtaining date which is to b submitted to any regulatory authority is exempted and is not an infringement act.

CHINA: 

Enforcement of patent right depends on the province and locality where the action is brought. Better results have been seen in Beijing. The Chinese patent law prevents competition from legitimate competitors an enforcement against legitimate competitors is possible. Also, there is provision for territorial; or global licensing. In line with the WTO, Patent term offered by Chinese patent office is 20 years from filing. 

ISRAEL: 

New data exclusivity legislation is in force. Pro-purports to protect the confidentiality of data submitted to the Israeli Ministry of Health in support of efforts to receive marketing authorization. Party seeking marketing approval of generic drug in Israel will not be able to rely on confidential data submitted in support of the marketing approval of the innovative pharmaceutical until the earlier of five years from the first data on which the innovative drug was first registered in Israel or six months from the date of registration in a recognized country. 

Cons – data exclusivity is only for making use of the confidential data for the purpose of obtaining marketing approval of the generic drug in Israel. Law does not bar use of confidential information for developing and manufacturing a generic drug in Israel during the exclusivity period for export to other countries. Limitations on the ability of innovative drug company to bring an action on the ground of illegal use of its confidentiality data. The patentee is required to submit search results from corresponding applications. 

For clarifications, contact us at 1-514-743-6159 or email  contact@innoworksltd.com  

ARGENTINA: 

Regulation no. 263/2003: allows applicant to waive the part of the examination related to international prior art. This is applicable to any application in which substantive examination has not yet been made. 

Equivalent patent in a country that has similar novelty, inventive step and industrial applicability requirements as Argentina. Although the equivalent patent could have been issued in any jurisdiction- patents granted by the EPO followed by the USPTO are preferred. 

The scope of the claims must be identical or less than those of the equivalent patent. However, the claims may have to be amended to comply with the requirements of Argentinean law-one independent claim and use of a characterizing clause. In many cases, combining the claims to the equivalent patent will expedite prosecution and grant.

AUSTRALIA:

SECTION 40(3) OF THE Australian patent Act provided “ The claim or claims must be fairly based on the matter described in the specification”. The body of the specification has to be read as a whole places no limitation on the invention set out in the “ consistory clause(s)”. Clauses describing the invention generally) then the claims would be fairly based if they reflect the invention set out in the consistory clause. In other words, there must be “a real and reasonably clear disclosure” of the claimed invention in the specification. A specification need not disclose any more than a single embodiment and even with a single embodiment, the patentee would still be able to include claims that were not limited to the embodiment so long as there was “ fair basis” for the other claims. The description of a single embodiment common in the applications for mechanical devices. However for chemical cases, it is still considered necessary to include multiple examples or embodiments in order to support broad claims. The patentee is required to submit search results from corresponding applications.

AIPO grants patents for computerized accounting, electronic commerce systems and the like. 

For clarifications, please contact us at 1-514-743-6159 or email  contact@innoworksltd.com 

QUALITY CONTROL OF PEPTIDE/ PROTEIN  BASED PRODUCTS-  

To ensure efficacy and safety of a drug product, the active compound and its degraded product(s) must be quantified to determine the expiry period of the formulation. Due to the multiplicity of protein degradation pathways, no single test method can be guaranteed to be stability indicating. Only the continued information from various methods can lead to the assurance that the physicochemical integrity and biological activities of a protein are retained throughout manufacturing and shelf life. 

Peptide degradation have been reported as result of the following reasons-  

- Thermal denaturation (heat as well as cold)

- pH denaturation

- Salt denaturation

- Pressure and shear denaturation

- Surface denaturation and

- Freeze drying denaturation 

In addition to monitoring the integrity of the protein primary structure, protein conformation stability at secondary, tertiary and quaternary levels must also be verified to assure maintaining biological function.  

REGULATORY CONSIDERATIONS-  

Internationally, biotechnology products are regulated under the statutory authority of four federal agencies: the Food and Drug Administration, The Environmental Protection Agency, the Occupational Safety and Health Administration and the United Nations department of Agriculture. 

Unlike conventional drugs, peptides and protein drugs have primary, secondary and tertiary structures, all of which must be taken into account in order to gain complete control of the identity, strength, quality and potency of the material. As a result of this, establishing specific standards for the identity, strength, quality, potency and stability of peptide and protein drugs is a complex procedure; the use of the recombinant DNA (rDNA) techniques or hybridoma manufacturing process to produce peptides and proteins introduces additional complexities. 

CONCLUSION-  

Mucosal adhesive dosage forms are now at the starting line. The advantages are tremendous, which make further study in this field extremely important. The formulation of these drug delivery systems depends on the development of suitable polymers bearing excellent mucoadhesive properties, characteristics, size and molecular weight of peptides, their stability individually and in presence of mucoadhesive polymers and the overall biocompatibility of the dosage form. Obviously as the pharmaceutical industry moves into the area of peptide-based therapies, there will be greater stimulus for development of mucosal and like novel technologies of drug delivery.

For clarifications, please contact us at 1-514-743-6159 or email at contact@innoworksltd.com

 

 

Methods used to study mucoadhesion: 

Several test methods have been reported for studying mucoadhesives. These tests are necessary not only to screen a large number of candidate mucoadhesives, but also to study their mechanisms. These tests are also important during the design and development of a bioadhesive modified release system as they ensure compatibility, physical and mechanical stability, surface analysis and bioadhesive bond strength. The test methods can broadly be classified into two major categories: 

1. In vitro/ ex vivo methods; including: 

            - Measurement of tensile strength

            - Measurement of shear strength

            - Adhesion weight method

            - Fluorescent probe method

            - Flow channel method

            - Spectroscopic method

            - Falling liquid film method

            - Colloidal gold staining method

            - Viscometric method

            - Thumb test.

            - Adhesion number evaluation

            - Electrical conductance

 2. In vivo methods:

In vivo techniques for measuring bioadhesive strength are relatively few. Some of the reported methods are based on the measurement of the residence time of bioadhesives at the application site. The gastrointestinal transit time of many bioadhesives have been examined using radioisotopes. 

Bio/ Muco adhesive polymers: 

Polymers that adhere to the mucin- epithelial surface can be conveniently divide into three broad categories: 

1. Polymers that become sticky when placed in water and owe their bioadhesion to stickiness. 

2. Polymers that adhere through non-specific, noncovalent interactions, which are primarily electrostatic in nature. 

3.  Polymers that bind to specific receptor sites on the cell surface. 

All three-polymer types can be used for drug delivery. 

Characteristics of an ideal mucoadhesive polymer: 

The ideal polymer for a mucoadhesive drug delivery system should have the following characteristics: 

1. The polymer and its degradation products should be nontoxic and nonabsorbable from the gi tract. 

2. The polymers should be nonirritant to the mucous membrane. 

3. It should preferably form a strong noncovalent bond with the mucin- epithelial cell surface. 

4. It should adhere quickly to moist tissue and should possess some site specificity.

5. It should allow easy incorporation of the drug and offer no hindrance to its release.

6. The polymer must not decompose on storage or during the shelf life of the dosage form. 

7. The cost of the polymer should not be high, so that the prepared dosage form remains competitive. 

Several polymers viz. carbomers, celluloses e.g. sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose etc., guar gum, sodium alginate, polycarbophils etc. are being studied as potential mucoadhesice agents.

For clarifications, please contact us at 1-514-743-6159 or email at contact@innoworksltd.com

The rational approach for developing innovative polypeptide delivery system must therefore initially address two basic questions: 

1.      What is the rate & time course of systemic drug input (i.e. the input function i(t) that will maximize the therapeutic effect of the compound, minimize side effects and prevent if possible the development of tolerance (tachyphylaxis)?   And 

2.      What routes of administration (and associated pharmaceutical technologies) will provide the best means for achieving this input function in a safe, efficacious, reliable, “patient friendly” and cost-effective manner ? 

The following equation provides a simple theoretical framework for assessing the rate limiting steps responsible for the bioavailability (F) of polypeptides given by the transmucosal route:

 

F  =[            TLM         ]           [               TM   ____]

            TLM + DL + EL          TMB  +  DM

Where in, 

L =       human, M   =   mucosa, B  =  bloodstream, EL  =Elimination from absorption site (pre absorption clearance) 

This mechanistic information is valuable for selecting appropriate routes of administration as well as for developing rational strategies to enhance the bioavailability.

Factors governing mucoadhesion:

The bioadhesive power of a polymer or a series of polymers is affected by the nature of the polymer and also by the nature of the surrounding media:

1. Polymer related factors: 

            - Molecular weight

            - Concentration of the active polymer

            - Flexibility of polymer chains

            - Spatial conformation

            - Polymer swelling index.

2. Environmental related factors:

            - pH

            - Applied strength of adhesives

            - Initial contact time

            - Selection of model substrate surface

            - Concentration of water or water content in substrate

3.Physiologic variables:

            - Mucin turn over

            - Disease state

            - Histology of organ (epithelial tissue)

In the next chapter we shall discuss on techniques used to study muco-adhesion.

For clarifications, please contact us at 1-514-743-6159 or email at contact@innoworksltd.com 

Mucoadhesive drug delivery systems utilize the property of bioadhesion of certain water-soluble polymers, which become adhesive on hydration and hence can be used for targeting a drug to a particular region of the body for extended periods of time.

 

The mucosal layer lines a number of regions of the body including the gastrointestinal tract, the urinogenital tract, the airways, the ear, nose and eye. These represent potential sites for attachment of any bioadhesive system and hence, the mucoadhesive drug delivery system may include the following:

 

1. Buccal and other trans- oral delivery system.

2. Pulmonary delivery system.

3. Vaginal delivery system.

4. Rectal delivery system.

5. Nasal delivery system.

6. Ocular delivery system.

7. Colonic delivery system and

8. Gastrointestinal delivery system. 

 

Rationale for mucosal delivery system of peptides:

 

The idea of mucoadhesives was derived from the need to localize drugs at a certain site in the body. Often the extent of drug absorption is limited by the residence time of the drug at the absorption site.

 

For example, in ocular drug delivery, less than 2 min are available for drug absorption after instillation of a drug into the eye, since it is removed rapidly by solution drainage; hence the ability to extend contact time of an ocular drug delivery system in front of the eye would undoubtedly improve drug bioavailability.

 

In oral drug delivery the drug absorption is limited by the gastrointestinal transit time of the dosage form. Since many drugs are absorbed only from the upper small intestine, localizing oral drug delivery in the stomach or in the duodenum as well as colon targeting for drugs, which degrade in gastric environment, would significantly improve the extent of drug absorption.

 

Since most of the routes of drug administration such as ocular, nasal, buccal, respiratory, gastrointestinal, rectal etc. are coated with the mucus layer, mucoadhesives are logically expected to increase the residence time. In addition, they provide intimate contact between a dosage form and the absorbing tissue, which may result in high drug concentration in a local area and hence high drug flux through absorbing tissue. Furthermore, the intimate contact may increase the total permeability of high molecular weight drugs such as peptides and proteins.

 

Since, peptides are highly susceptible to the strong acid environment and the proteolytic enzymes in the gastro-intestinal tract (gi tract), the systemic bioavailability therefore by the conventional oral administration is extremely low. Peptides are high molecular weight macro molecules (100-150,000 Da) and thus do not easily permeate the intestinal mucosa. Even after successful gastrointestinal absorption, they are further subjected to first pass elimination in the liver. Thus, conventional oral route of delivery produces sub-therapeutic drug levels in the body.  For these reasons, even the smallest peptide may demand new pharmaceutical principles for the development of a satisfactory product.

 

In the next chapter we shall discuss further on the rationale approach in the development of mucosal drug delivery systems. 

For clarifications, please contact us at 1-514-743-6159 or email at contact@innoworksltd.com

 

For additional reading on mucosal DDS, in my next chapter, I shall present a list of references that may be useful to give more insight into this delightful topic. 

Jeng, M. J., Lee, Y. S., & Soong, W. J. (2007). Effects of perfluorochemicals for intrapulmonary vancomycin administration and partial liquid ventilation in an animal model of meconium-injured lungs. Acta Paediatrica Taiwanica, 48, 309-316.

Leary, S., Liu, C., & Apuzzo, M. (2006). Toward the emergence of nanoneurosurgery: Part II--Nanomedicine: Diagnostics and imaging at the nanoscale level. Neurosurgery, 58, 805-823.

Maloney, J., Uhland, S., & Polito, B. (2005). Electrothermally activated microchips for implantable drug delivery and biosensing. Journal of Controlled Release, 109, 244 255.

Medscape Medical News. (2002). 'Pain relief ball' cuts opioid use after gynecologic surgery. Retrieved on March 16, 2008, from http://wwwmedscape.com/viewarticle/433317

Morrow, J., Bawa, R., & Wei, C. (2007). Recent advances in basic and clinical nanomedicine. Medical Clinics of North America, 91,805 843.

Nova Science Now. (n.d.). Cancer nanotech. Retrieved May 10, 2008, from http://www.pbs.org/wgbh/nova/sciencenow/3209/ 03-canc-nf.html

Skryabina, E., & Dunn, T. (2006). Disposable infusion pumps. American Journal of Health System Pharmacists, 63, 1260 1268.

Tasciotti, E., Liu, X., & Bhavane, R. (2008). Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications. Nature Nanotechnology, 3, 151 157.

Triangle Business Journal. (2008, May). BDSI's pain patch does well in human trial. Retrieved May 30, 2008 from http:// triangle.bizjournals.com/triangle/stories/2008/05/05/daily28. html

Wermeling, D. P, Miller, J. L., & Rudy, A. C. (n.d.). Systemic" Intranasal drug delivery: concepts and applications. Drug Delivery Technology. Retrieved March 16, 2008, from http://www. drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=22

Wynne, A. L., Woo, T. M., & Olyaei, A. J. (2007). Pharmacotherapeutics for nurse practitioner prescribers (2nd ed.). Philadelphia: EA. Davis.

Yih, T., & Al-Fandi, M. (2006). Engineered nano particles as precise drug delivery systems. Journal of Cellular Biochemistry, 97, 1184-1190.

Young, E. (2004). Drug-delivering contact lenses revealed. NewScientist.com news service. Retrieved June 1,2008, from http://newsscientist.com/article.ns?id=dn6597

Angelia Colwell Berkowitz, BSN RN CRNI, is a graduate student at The University of Texas Health Science Center at San Antonio, San Antonio, TX.  

The next series shall comprise of the formulation challenges as well as quality considerations and regulatory challenges faced during the development of mucosal DDS.  

For an expert opinion on formulation development of peptide/ protein molecules, please contact us at 1-514-743-6159 or email contact@innoworksltd.com 

For additional reading on mucosal DDS, in my next chapter, I shall present a list of references that may be useful to give more insight into this delightful topic. 

De Campos A.M.;Diebold Y.;Carvalho E.L.S.;Sánchez A.,José Alonso M. Chitosan nanoparticles as new ocular drug delivery systems: in vitro stability, in vivo fate, and cellular toxicity. Pharmaceutical Research, Springer. 2004; 21(5): 803-810(8).  

Alvarez-Lorenzo, C., Hiratani, H., & Concheiro, A. (2006). Contact lenses for drug delivery: Achieving sustained release with novel systems. American Journal of Drug Delivery, 4, 131-151.

American Heart Association. (2005). Management of cardiac arrest recommended by the American Heart Association. Retrieved June 23, 2008, from http://circ.ahajournals.org/cgi/ content/full/112/24_suppl/IV-58

Bajwa, Z., & Warfield, C. (2008). Interventional approaches to the management of cancer pain. Retrieved on May 13, 2008, from www.uptodate.com

Bielinska, A., Janxzak, K., & Landers, J. (2008). Nasal immunization with a recombinant HIV gp120 and nanoemulsion adjuvant produces Thl polarized responses and neutralizing antibodies to primary HIV type isolates. AIDS Research and Human Retroviruses, 24, 271-281.

Bulletin Board. (2008). Nanomedicine, 3, 145-147.

Canadian Press. (2008). Canadian researchers develop automated anesthesia system dubbed McSleepy. Retrieved May 6, 2008, from www.googlenews.com

Chandhari, M., & Mackenzie, P. (2007). Implantable technology for pain management. Anaesthesia & Intensive Care Medicine, 9, 69-74.

Clinical Trials. (2008, February). BioDelivery sciences to present BEMA fentanyl data at the 24th Annual Meeting of the American Academy of Pain Medicine. Retrieved on May 15, 2008, from http://www.drugs.corn/clinical_trials/biodeliverysciences-present- bema-fentanyl-data-24t

Cox, C. (n.d.). Treatment options gel with innovative drug delivery systems. Drug Delivery Technology Retrieved on May 16, 2008, from http://www.drugdeliverytech.com/cgi-bin/articles. cgi?idArticle=55

Gotfried, M. H., Shaw, J. P., Benton, B. M., Krause, K. M., Goldberg, M. R., Kitt, M. M., et al. (2008). Intrapulmonary distribution of intravenous televancin in healthy subjects and effect of pulmonary surfactant on in vitro activities of televancin and other antibiotics. Antimicrobial Agents and Chemotherapy, 52, 92-97.

Hafeli, U. (2004). Magnetically modulated therapeutic systems. International Journal of Pharmaceutics, 277, 19-24.

Hirlekar, R., Patel, P, & Dand, N. (2008). Drug loaded erythrocytes: As novel drug delivery system. Current Pharmaceutical Design, 14, 63 70.

in-Pharma Technologist.com. (January 10, 2005). Contact lenses deliver drugs to eye. Retrieved on May 30, 2008, from http:// www.in-pharmatechnologist.com/news/ng.asp?id=57187-contact-lenses-deliver

Irani, F., Dankert, M., Brensinger, C., Bilker, W., Nair, S., Kohler, C., et al. (2004). Patient attitudes towards surgically implantable, long-term delivery of psychiatric medicine. Neuropsychopharmacology, 29, 960-968.

For an expert opinion on formulation development of peptide/ protein molecules, please contact me at  1-514-743-6159 or email contact@innoworksltd.com