Patent Prospecting on Nanoparticle for Diagnosis and Treatment Of

Review Patent prospecting on nanoparticle for diagnosis and treatment of diseases in central nervous system Hellen Kelen Maria Medeiros Coimbra Viana 1, Ilma Campos Veloso Guerra1 and Hercília Maria Lins Rolim1,*

1. Laboratory of Pharmaceutical Nanosystems (NANOSFAR), Post Graduate Program in Pharmaceutical Sciences, Federal University of Piauí, Brazil. *Correspondence: [email protected]; Tel.: +55-86 3215-1160

Received: 03 Jan 2019; Accepted: 10 May 2020; Published: 28 June 2020.

Abstract: Diseases of central nervous system as anxiety, depression, Alzheimer's, Parkinson's, epilepsy and schizophrenia affect millions globally. The treatment and prevention of these diseases is urgent and necessary. The application of nanotechnology in pharmaceutical industry is a good alternative for production of more effective drugs, with nanoparticles being highlighted by benefits obtained as reduction of side effects, increased bioavailability and greater physicochemical stability. The objective of the present study was to carry out a technological prospection in the databases USPTO, WIPO, EPO and INPI using the term "nanoparticle" and terms associated to CNS diseases, analyzing the quantity and types of patents found. A total of 26,742 patents were obtained with the isolated use of the term "nanoparticle" and 38 patents when associated with CNS diseases, which have the predominant international classification was A61K, related to applications for medical, dental and/or hygiene purposes. The most part of nanoparticles patents were found WIPO database, with the United States holds the highest number of them. Patents not were found in Brazilian database using the association between “nanoparticle” and CNS diseases, demonstrating the need for the development of nanotechnology aimed at the treatment of CNS pathologies in the country.

Keywords: Central nervous system, Nanoparticle, Nanocarrier.

1. Introduction

Depression and anxiety are mental disorders with high prevalence in the general population. Data from the World Health Organization (WHO), depression may become the second leading cause of death or disability in 2020 [1,2]. Nowadays, the pharmacological treatment for anxiety is done with the use of benzodiazepines, buspirone and antidepressants, thatproves to be efficacy. However, these drugs may cause inconvenient side effects to the patient. Thus, in view of the high prevalence and incidence of undesirable effects, the search for new therapeutic agents with anxiolytic properties is necessary [3]. Alzheimer's disease (AD) and Parkinson's disease(PD) are the two most common age-related neurodegenerative diseases [4]. Clinically, patients initially presented short-term memory loss, followed by executive cognitive dysfunction, confusion, agitation, and behavioral disorders [5]. In 2050, In 2050, AD cases are expected to double in comparison with 2020, nearly a million new cases per year, and the estimated total prevalence will be 13.8 million [6]. Recent advances in nanotechnology such as liposomes have been studied for the delivery of drugs and molecules that can pass through the blood brain barrier (BHE) for the treatment of central nervous system (CNS) diseases such as epilepsy, psychiatric disorders as anxiety, depression, schizophrenia and treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's [7,8]. PD is characterized by a slowly and progressive impairment of neural function that affects approximately 1–3% among persons aged 80 and over [9]. Currently, its etiology is not fully understood, but there is a hypothesis that the gradual loss of neurons in the substantia nigra of the midbrain is caused by possible genetic and environmental mental factors and by aging itself [10]. Schizophrenia is a disorder of brain function whose symptoms consist of the inability to separate

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reality and illusion, hallucinations, emotional dysregulation and disorganized behavior. It is one of the main causes of suicide and currently there are no curative treatments for schizophrenia [11-12]. Schizophrenic disorders are serious and chronic mental conditions that affect 20 million people worldwide, is estimated that the global prevalence to be 0.28%, a prevalence considered low[13, 14]. Epilepsy is the most frequent serious neurological disorder and important public health problem. Its incidence in developing countries is twice that of developed countries [15]. Epilepsy is characterized by the occurrence of convulsions in which there are brief periods of uncontrolled agitation. The convulsions may be partial, involving only one side of the body, or generalized, involving the whole body, and may be accompanied by loss of consciousness and control of bowel or bladder function [16]. In some cases the treatment causes undesirable effects, as headache, irritability, dizziness and weight gain, severe casememory problems and depression [17]. Considering that they represent important public health problems, the search for new effective treatments and reducing undesirable effects is necessary. The intervention of nanotechnology through the use of nanoparticles may represent an alternative. The nanoparticles are systems that can be vary from 10 to 100 nm in diameter, can be obtained from different sources and present different structural forms, which entails different physicochemical properties [18]. Nanoparticles began to be studied as carriers of drugs, offering benefits such as increased solubility of drugs in biological fluids and consequently their bioavailability increase the time of permanence of the drug in the body and targeting a specific site [19]. Represent an alternative for improvement of models traditional of the prevention or treatment of diseases of the central nervous system. The main objective of this work was to carry out a technological prospection, conducting a search in patent databases national and international about nanoparticles with application in the treatment or prevention of diseases of the central nervous system, in order to provide a general overview of the state of art in relation to theme.

2. Materials and Methods

The prospection was conducted on the basis of patent applications filed with the European Patent Office (EPO), the World Intellectual Property Organization (WIPO), the United States Patent and Trademark Office Patent and Trademark Office -USPTO) and in the database of the National Institute of Industrial Property (INPI) of Brazil. The research was conducted at December 2018 and were used as keywords the terms “nanoparticle” or “nanopartícula”, “nanoparticle and anxiety” or “nanopartícula e ansiedade”, “nanoparticle and depression” or “nanopartícula e depressão”, “nanoparticle and Alzheimer" or “nanopartícula e Alzheimer” and “nanoparticle and epilepsy” or “nanopartícula e epilepsia”. The terms in English were used for the international bases, whereas the Portuguese terms for the search of documents on a national basis, being considered valid the documents that presented these terms in the title and / or summary. All existing patent applications were reviewed by December 2018 (Figure 2).

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Figure 2 – Methodology for conducting patent search.

3. Results and Discussion

3.1 Patent register per database

According to Teixeira [20] in his work summarized as a general objective of a technological prospecting identify areas of strategic research and emerging generic technologies that have the propensity to generate the greatest economic and social benefits. The forecasting method provides a predictive forecast of the future development of current technologies through quantification and trend extrapolation. In the research, many documents involving the terms “nanoparticle” or “nanopartícula” were found, most prominently in the WIPO database (23,814). However, when envolved the terms “nanoparticle and anxiety” or “nanopartícula e ansiedade”, “nanoparticle and depression” or “nanopartícula e depressão”, “nanoparticle and Alzheimer" or “nanopartícula e Alzheimer” and “nanoparticle and epilepsy” or “nanopartícula e epilepsia”,was observed that the number of application of patent was reduced to 38 patents registered at December 2018 using the combination of terms cited (Table 1). These, only three patents were deposited at the USPTO and one at the EPO, a greater proportion of patent deposits were observed at the WIPO bases, totaling 38 patents, no results were found at the Brazilian base searches (INPI).

Table 1–Number of patents deposit per database using different terms. TERMOS INPI USPTO WIPO EPO “Nanoparticle” or “Nanopartícula” 95 1128 23814 1705 “Nanoparticle + anxiety” or - - 2 - “Nanopartícula + ansiedade” “Nanoparticle + depresion” or - - 4 - “Nanopartícula + depressão” “Nanoparticle + alzheimer” or - 3 14 - “Nanoparícula + alzheimer” “Nanoparticle + epilepsy” or - - 12 1 “Nanopartícula + epilepsia” “Nanoparticle + schizophrenia” or - - - - “Nanopartícula e esquizofrenia” “Nanoparticel + parkinson” or - - 2 - “Nanopartícula + parkinson”

The highest proportion found in WIPO may be justified by the fact that WIPO administers patent deposits through the Patent Cooperation Treaty (PCT), through a patent application on PCT, applicants can

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simultaneously seek the protection of an invention in 152 countries around the world [21]. The other offices deal with patents located in the United States (USPTO), Europe (EPO) and Brazil (INPI).

10 NUMBER OF OF NUMBER PATENTS 5

0 INPI USPTO WIPO EPO DATABASE

Figure 1– Patent registration by database using term "nanoparticle" and terms associated with diseases of the central nervous system.

Another observation can be made by comparing the search results using the term nanoparticle combined with the diseases of the central nervous system in question (Figure 1). The scarcity of patents about the terms of search used in Brazilian database may be attributed to need the generation of technology still existent, despite the development of its drug industry in Brazil. The activities of scientific and technological research have been restricted to the academic environment due to the lack of articulation between the agents of the Innovation Systems, private companies, lack of public policies and financial support.[22].

3.2 Patent deposit along of last twenty years

Figure 2 shows that between 1998 and 2007 there was only one patent registered, however from 2012 until December 2018, 33 patents were identified which corresponds to approximately 87% of the total found between 1998 and 2018. There has been a progressive increase since the year 2012 in the number of nanoparticle-related patent deposits with application in the Central Nervous System, reflecting the expansion in the field of nanotechnology application and as a result of the large number of studies on nanomaterials aimed at human health [23].

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10 9 8 7 6 5 4 3 2

NUMBER OF OF NUMBER PATENTS 1 0

YEARS

Figure 2 –Number of Patent deposit using the terms under study during the years 1998 and 2018.

3.3 Concentration of patents registration by countries

There are a larger number of patents deposited in the WIPO world patent organization followed by the USPTO and EPO, and no patent was found in the Brazilian INPI database. This data demonstrates that there has been research and protection of innovations around the world, mainly in the United States and China (Figure 3).

Number of Patents

Figure 3 –Worldwide concentration of patents in database EPO, WIPO, USPTO and INPI per countries.

3.4 Total number of patents and their stage of analysis (Kind Code)

From these evidences was observed that a greater number of patent register with the combination of the terms under study occurred in the WIPO and EPO bases, the research followed with the analysis regarding the application of the patented nanoparticles for the neurological disorders in question. The Figure 4 is representing the distribution as the International Patent Classification (IPC), which can be seen that

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there was an A61K predominance, in which the "A" corresponds to human needs, and more specifically, A61K subclass is related to applications for medical, dental and / or hygienic purposes. Besides this classification appears the class "B" specifically "B22F" with only one record, which is the production of articles with metallic powder, this patent was found with the association "nanoparticle and depression" with the country of origin Korea. This patent had no relation to CNS diseases, the term "depression" (found in its abstract) referring to the physicochemical characteristics of the particle. Another class found was the "G" facing the field of physics that were found with the associations "nanoparticle and depression" and "nanoparticle and Alzheimer's," having been found subclasses "G01N" related to the analysis of materials and "G21K" related to the manipulation of radioactive particles, both classes had patents for the purpose of improving and increasing the sensitivity of tests that identify CNS diseases.

16 14

12 10 A61K 8 B22F

6 G01N

4 NUMBER OF PATENTS G21K 2

0 Nanoparticle + Nanoparticle + Nanoparticle + Nanoparticle + Nanoparticel + anxiety depresion alzheimer epilepsy parkinson

Figure 4 – Patents deposited in the EPO, WIPO, USPTO and INPI by international classification code.

4. Conclusions

This study reached its main objective, the patents were analyzed and was concluded that although the number of patents has increased in recent years, there are still few patents for nanoparticles to treat diseases related to the central nervous system (anxiety, depression, schizophrenia, Parkinson's, Alzheimer's and epilepsy). Brazilian patents were not found. In addition, it is necessary to continue the research with the use of pharmaceutical nano delivery systems aiming at ways of treatment and prevention of diseases of the central nervous system, since these have affected a greater number of people in recent years.

Funding: Coordination for the Improvement of Higher Education Personnel (CAPES) Acknowledgments: This study was carried out by the Laboratory of Pharmacological Nanosystems (NANOSFAR) with support from the Federal University of Piauí, Brazil. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

1.WHO World Health Organization

2. CNS Central Nervous System

3. BHE Blood brain barrier

4. AD Alzheimer disease

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5. PD Parkinson disease World Intellectual Property Organization 6. WIPO

7. EPO European Patent Office

8. USPTO United States Patent and Trademark Office's Instituto Nacional da Propriedade Industrial 9. INPI

International Patent Classification 10. IPC

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